WorldWideScience

Sample records for identifying potential drug

  1. 3 Drugs Identified to Potentially Fight Zika Virus

    Science.gov (United States)

    ... html 3 Drugs Identified to Potentially Fight Zika Virus But only one is already approved in the ... fetuses protection against the damaging effects of Zika virus, a new multicenter study reports. Researchers identified these ...

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

    Science.gov (United States)

    2015-04-01

    AWARD NUMBER: W81XWH-13-1-0429 TITLE: Using "Click Chemistry" to Identify Potential Drug Targets in Plasmodium PRINCIPAL INVESTIGATOR: Dr. Purnima...SUBTITLE Sa. CONTRACT NUMBER W81XWH-1 3-1-0429 Using "Click Chemistry" to Identify Potential Drug Targets in Plasmodium 5b. GRANT NUMBER 5c. PROGRAM...Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Sporozo ite infection of the liver is the first obl igate step of the Plasmodium

  3. [Identifying potential drug interactions in chronic kidney disease patients].

    Science.gov (United States)

    Marquito, Alessandra Batista; Fernandes, Natália Maria da Silva; Colugnati, Fernando Antonio Basile; de Paula, Rogério Baumgratz

    2014-01-01

    Drug interactions (DIs) are common in clinical practice and are directly related to factors such as polypharmacy, aging, hepatic metabolism and decreased renal function. Individuals with chronic kidney disease (CKD) often require multiple classes of drugs being at important risk for the development of DIs. Identify potential interactions among drugs prescribed to patients with CKD on conservative treatment, and factors associated with their occurrence. Observational cross-sectional study, with analysis of 558 prescriptions. Potential DIs were identified by the database MICROMEDEX®, software that provides an internationally known pharmacopoeia. There was a predominance of males (54.7%), seniors (69.4%), stage 3 CKD (47.5%), overweight and obese patients (66.7%). The most prevalent comorbidities were hypertension (68.5%) and diabetes mellitus (31.9%). Potential DIs were detected in 74.9% of prescriptions. Among the 1364 DIs diagnosed, 5 (0.4%) were contraindicated and 229 (16.8%) of greater severity, which need immediate intervention. Interactions of moderate and low severity were identified in 1049 (76.9%) and 81 (5.9%) prescriptions, respectively. The probability of one DI increased by 2.5 times for each additional drug (CI = 2.18 to 3.03). Obesity, hypertension, diabetes as well as advanced stage of CKD were risk factors strongly associated with DI occurrence. Drug associations in individuals with CKD were related to high prevalence of serious DIs, especially in the later stages of the disease.

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

    Science.gov (United States)

    2016-06-01

    both enzymes are expressed cytoplasmically in sporozoites and liver stages. Using a specific and potent inhibitor of Plasmodium PKG and inhibitor... originally planned. Therefore, we modified our approach so that we could still fulfill the objective of identifying Tsp’s target in sporozoites. To fulfill...essential Ca(2)(+) signals at key decision points in the life cycle of malaria parasites. PLoS Biol 12: e1001806. 2. Falae A, Combe A, Amaladoss A

  5. Virtual target screening to rapidly identify potential protein targets of natural products in drug discovery

    Directory of Open Access Journals (Sweden)

    Yuri Pevzner

    2014-05-01

    Full Text Available Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and in vitro experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery.

  6. In silico repositioning-chemogenomics strategy identifies new drugs with potential activity against multiple life stages of Schistosoma mansoni.

    Science.gov (United States)

    Neves, Bruno J; Braga, Rodolpho C; Bezerra, José C B; Cravo, Pedro V L; Andrade, Carolina H

    2015-01-01

    Morbidity and mortality caused by schistosomiasis are serious public health problems in developing countries. Because praziquantel is the only drug in therapeutic use, the risk of drug resistance is a concern. In the search for new schistosomicidal drugs, we performed a target-based chemogenomics screen of a dataset of 2,114 proteins to identify drugs that are approved for clinical use in humans that may be active against multiple life stages of Schistosoma mansoni. Each of these proteins was treated as a potential drug target, and its amino acid sequence was used to interrogate three databases: Therapeutic Target Database (TTD), DrugBank and STITCH. Predicted drug-target interactions were refined using a combination of approaches, including pairwise alignment, conservation state of functional regions and chemical space analysis. To validate our strategy, several drugs previously shown to be active against Schistosoma species were correctly predicted, such as clonazepam, auranofin, nifedipine, and artesunate. We were also able to identify 115 drugs that have not yet been experimentally tested against schistosomes and that require further assessment. Some examples are aprindine, gentamicin, clotrimazole, tetrabenazine, griseofulvin, and cinnarizine. In conclusion, we have developed a systematic and focused computer-aided approach to propose approved drugs that may warrant testing and/or serve as lead compounds for the design of new drugs against schistosomes.

  7. In silico repositioning-chemogenomics strategy identifies new drugs with potential activity against multiple life stages of Schistosoma mansoni.

    Directory of Open Access Journals (Sweden)

    Bruno J Neves

    2015-01-01

    Full Text Available Morbidity and mortality caused by schistosomiasis are serious public health problems in developing countries. Because praziquantel is the only drug in therapeutic use, the risk of drug resistance is a concern. In the search for new schistosomicidal drugs, we performed a target-based chemogenomics screen of a dataset of 2,114 proteins to identify drugs that are approved for clinical use in humans that may be active against multiple life stages of Schistosoma mansoni. Each of these proteins was treated as a potential drug target, and its amino acid sequence was used to interrogate three databases: Therapeutic Target Database (TTD, DrugBank and STITCH. Predicted drug-target interactions were refined using a combination of approaches, including pairwise alignment, conservation state of functional regions and chemical space analysis. To validate our strategy, several drugs previously shown to be active against Schistosoma species were correctly predicted, such as clonazepam, auranofin, nifedipine, and artesunate. We were also able to identify 115 drugs that have not yet been experimentally tested against schistosomes and that require further assessment. Some examples are aprindine, gentamicin, clotrimazole, tetrabenazine, griseofulvin, and cinnarizine. In conclusion, we have developed a systematic and focused computer-aided approach to propose approved drugs that may warrant testing and/or serve as lead compounds for the design of new drugs against schistosomes.

  8. Spontaneously hypertensive rats: a potential model to identify drugs for treatment of learning disorders.

    Science.gov (United States)

    Meneses, A; Hong, E

    1998-04-01

    Spontaneously hypertensive rats (SHR) of 3 to 12 months of age learned and retrieved less information than normotensive Wistar-Kyoto rats (WKY), although no difference was found with animals from 18 and 24 months of age. The combined influence of hypertension and aging had an additive detrimental effect on cognitive functions. Notwithstanding these deficiencies in learning and memory, SHR have seldom been used as a model in the screening of drugs with therapeutic potential for treatment of disorders of cognitive processes. Moreover, the calcium channel blocker nimodipine has beneficial effects on learning in both aged and hypertensive animals and humans. However, no attempt has been made to investigate whether nimodipine can reverse the additive deleterious effects of aging and hypertension in the same subject. We recently reported that deteriorated animals (middle-aged and/or hypertensive) chronically treated with nimodipine (via osmotic minipumps) exhibit higher learning scores. This information indicates that nimodipine can reverse the impairing effects of either aging or hypertension on learning; the presence of the two conditions, however, produces a severe impairment that can be partially reversed by this drug. Therefore, we propose that mature and middle-aged SHR represent a model for the screening of potentially useful drugs in the treatment of learning disorders, probably associated with hypertension and/or aging. Nevertheless, it must be remembered that the SHR is a genetic model and the appearance of neural disturbances could be a parallel genetic phenomenon and not necessarily or exclusively related to hypertension per se.

  9. In Sillico Analysis of Newly Identified Potential Drug Lead Compound against VP40 for the Treatment of Ebola Virus Infection

    Directory of Open Access Journals (Sweden)

    *Biswadip Bandyopadhyay

    2016-11-01

    Full Text Available Ebola Virus (EBOV, also referred as Zaire Ebola Virus, member of filoviridae family, is a single stranded, filamentous, enveloped, mononegavirales virus. It causes acute hemorrhagic fever which is naturally resistant to various antibiotics. After the outbreak of Ebola virus, the CADD (Computer Aided Drug Discovery became necessary as classical model of drug discovery takes lots of time to find target protein and potential lead compound. Computational techniques made it much easier. The matrix protein of Ebola VP40 whose virulent activity and functions in pathogenesis affirmed it as a potential drug target. To inhibit Ebola infection, CADD and molecular docking approaches are one of the effective tools to discover new drug leads against these sporadic targets. In this study lead compounds identified that matches the drug likeliness criteria using “Lipinski’s rule of five” for different crystalline structures of target receptor protein. The discovery of such drug lead molecules which inhibits those protein molecules may constitute successful multidrug resistant Ebola virus infection.

  10. Genomic profiling of murine mammary tumors identifies potential personalized drug targets for p53-deficient mammary cancers

    Directory of Open Access Journals (Sweden)

    Adam D. Pfefferle

    2016-07-01

    Full Text Available Targeted therapies against basal-like breast tumors, which are typically ‘triple-negative breast cancers (TNBCs’, remain an important unmet clinical need. Somatic TP53 mutations are the most common genetic event in basal-like breast tumors and TNBC. To identify additional drivers and possible drug targets of this subtype, a comparative study between human and murine tumors was performed by utilizing a murine Trp53-null mammary transplant tumor model. We show that two subsets of murine Trp53-null mammary transplant tumors resemble aspects of the human basal-like subtype. DNA-microarray, whole-genome and exome-based sequencing approaches were used to interrogate the secondary genetic aberrations of these tumors, which were then compared to human basal-like tumors to identify conserved somatic genetic features. DNA copy-number variation produced the largest number of conserved candidate personalized drug targets. These candidates were filtered using a DNA-RNA Pearson correlation cut-off and a requirement that the gene was deemed essential in at least 5% of human breast cancer cell lines from an RNA-mediated interference screen database. Five potential personalized drug target genes, which were spontaneously amplified loci in both murine and human basal-like tumors, were identified: Cul4a, Lamp1, Met, Pnpla6 and Tubgcp3. As a proof of concept, inhibition of Met using crizotinib caused Met-amplified murine tumors to initially undergo complete regression. This study identifies Met as a promising drug target in a subset of murine Trp53-null tumors, thus identifying a potential shared driver with a subset of human basal-like breast cancers. Our results also highlight the importance of comparative genomic studies for discovering personalized drug targets and for providing a preclinical model for further investigations of key tumor signaling pathways.

  11. Database identifies FDA-approved drugs with potential to be repurposed for treatment of orphan diseases.

    Science.gov (United States)

    Xu, Kui; Coté, Timothy R

    2011-07-01

    Facing substantial obstacles to developing new therapies for rare diseases, some sponsors are looking to 'repurpose' drugs already approved for other conditions and use those therapies to treat rare diseases. In an effort to facilitate such repurposing and speed the delivery of new therapies to people who need them, we have established a new resource, the Rare Disease Repurposing Database (RDRD). The advantages of repurposed compounds include their demonstrated efficacy (in some clinical contexts), their observed toxicity profiles and their clearly described manufacturing controls. To create the RDRD, we matched the US Food and Drug Administration (FDA) orphan designation database to FDA drug and biological product approval lists. The RDRD lists 236 products that have received orphan status designation--that is, were found to be 'promising' for the treatment of a rare disease--and though not yet approved for marketing for that rare disease, they are already approved for marketing to treat some other disease or condition. The RDRD contains three tables: Orphan-designated products with at least one marketing approval for a common disease indication (N = 109); orphan-designated products with at least one marketing approval for a rare disease indication (N = 76); and orphan-designated products with marketing approvals for both common and rare disease indications (N = 51). While the data included in the database is a re-configuration/cross-indexing of information already released by the FDA, it offers sponsors a new tool for finding special opportunities to develop niche therapies for rare disease patients.

  12. Identifying novel drug indications through automated reasoning.

    Directory of Open Access Journals (Sweden)

    Luis Tari

    Full Text Available BACKGROUND: With the large amount of pharmacological and biological knowledge available in literature, finding novel drug indications for existing drugs using in silico approaches has become increasingly feasible. Typical literature-based approaches generate new hypotheses in the form of protein-protein interactions networks by means of linking concepts based on their cooccurrences within abstracts. However, this kind of approaches tends to generate too many hypotheses, and identifying new drug indications from large networks can be a time-consuming process. METHODOLOGY: In this work, we developed a method that acquires the necessary facts from literature and knowledge bases, and identifies new drug indications through automated reasoning. This is achieved by encoding the molecular effects caused by drug-target interactions and links to various diseases and drug mechanism as domain knowledge in AnsProlog, a declarative language that is useful for automated reasoning, including reasoning with incomplete information. Unlike other literature-based approaches, our approach is more fine-grained, especially in identifying indirect relationships for drug indications. CONCLUSION/SIGNIFICANCE: To evaluate the capability of our approach in inferring novel drug indications, we applied our method to 943 drugs from DrugBank and asked if any of these drugs have potential anti-cancer activities based on information on their targets and molecular interaction types alone. A total of 507 drugs were found to have the potential to be used for cancer treatments. Among the potential anti-cancer drugs, 67 out of 81 drugs (a recall of 82.7% are indeed known cancer drugs. In addition, 144 out of 289 drugs (a recall of 49.8% are non-cancer drugs that are currently tested in clinical trials for cancer treatments. These results suggest that our method is able to infer drug indications (original or alternative based on their molecular targets and interactions alone and has

  13. Incidence of potential drug-drug interactions with antidiabetic drugs.

    Science.gov (United States)

    Samardzic, I; Bacic-Vrca, V

    2015-06-01

    In an effort to achieve normoglycemia more than one antidiabetic agent is usually needed. Diabetes is associated with several comorbidities and patients with diabetes are often treated with multiple medications. Therefore, patients with diabetes are especially exposed to drug-drug interactions (DDIs). The aim of this study was to analyse the incidence and type of potential DDIs of antidiabetic drugs in patients with diabetes. This retrospective study analyzed pharmacy record data of 225 patients with diabetes mellitus. Both type 1 and type 2 diabetic patients who were taking at least one antidiabetic agent during the period of six months were included. We investigated associated therapy in that period in order to identify potential DDIs with antidiabetic therapy. Potential interactions were identified by Lexicomp Lexi-Interat Online (Lexi-Comp, Inc., Hudson, USA) software which categorizes potential DDIs according to clinical significance in five types (A, B, C, D and X). Categories C, D and X are of clinical concern and always require medical attention (therapy monitoring, therapy modification or avoiding combination). We found that 80.9% of patients had at least one potential category C interaction while there were no D and X interactions. Most frequently encountered potential DDI (n = 176) included antidiabetic drugs and thiazide or thiazide like diuretics. Patients with diabetes are exposed to a large number of potential clinically significant DDIs that may require appropriate monitoring. Using databases of DDIs could be helpful in reducing the risk of potential clinically significant DDIs.

  14. Identifying mechanistic similarities in drug responses

    KAUST Repository

    Zhao, C.

    2012-05-15

    Motivation: In early drug development, it would be beneficial to be able to identify those dynamic patterns of gene response that indicate that drugs targeting a particular gene will be likely or not to elicit the desired response. One approach would be to quantitate the degree of similarity between the responses that cells show when exposed to drugs, so that consistencies in the regulation of cellular response processes that produce success or failure can be more readily identified.Results: We track drug response using fluorescent proteins as transcription activity reporters. Our basic assumption is that drugs inducing very similar alteration in transcriptional regulation will produce similar temporal trajectories on many of the reporter proteins and hence be identified as having similarities in their mechanisms of action (MOA). The main body of this work is devoted to characterizing similarity in temporal trajectories/signals. To do so, we must first identify the key points that determine mechanistic similarity between two drug responses. Directly comparing points on the two signals is unrealistic, as it cannot handle delays and speed variations on the time axis. Hence, to capture the similarities between reporter responses, we develop an alignment algorithm that is robust to noise, time delays and is able to find all the contiguous parts of signals centered about a core alignment (reflecting a core mechanism in drug response). Applying the proposed algorithm to a range of real drug experiments shows that the result agrees well with the prior drug MOA knowledge. © The Author 2012. Published by Oxford University Press. All rights reserved.

  15. Aquaporins as potential drug targets

    Institute of Scientific and Technical Information of China (English)

    Fang WANG; Xue-chao FENG; Yong-ming LI; Hong YANG; Tong-hui MA

    2006-01-01

    The aquaporins (AQP) are a family of integral membrane proteins that selectively transport water and,in some cases,small neutral solutes such as glycerol and urea.Thirteen mammalian AQP have been molecularly identified and localized to various epithelial,endothelial and other tissues.Phenotype studies of transgenic mouse models of AQP knockout,mutation,and in some cases humans with AQP mutations have demonstrated essential roles for AQP in mammalian physiology and pathophysiology,including urinary concentrating function,exocrine glandular fluid secretion,brain edema formation,regulation of intracranial and intraocular pressure,skin hydration,fat metabolism,tumor angiogenesis and cell migration.These studies suggest that AQP may be potential drug targets for not only new diuretic reagents for various forms of pathological water retention,but also targets for novel therapy of brain edema,inflammatory disease,glaucoma,obesity,and cancer.However,potent AQP modulators for in vivo application remain to be discovered.

  16. Potential intravenous drug interactions in intensive care

    Directory of Open Access Journals (Sweden)

    Maiara Benevides Moreira

    Full Text Available Abstract OBJECTIVE To analyze potential intravenous drug interactions, and their level of severity associated with the administration of these drugs based on the prescriptions of an intensive care unit. METHOD Quantitative study, with aretrospective exploratory design, and descriptive statistical analysis of the ICU prescriptions of a teaching hospital from March to June 2014. RESULTS The sample consisted of 319 prescriptions and subsamples of 50 prescriptions. The mean number of drugs per patient was 9.3 records, and a higher probability of drug interaction inherent to polypharmacy was evidenced. The study identified severe drug interactions, such as concomitant administration of Tramadol with selective serotonin reuptake inhibitor drugs (e.g., Metoclopramide and Fluconazole, increasing the risk of seizures due to their epileptogenic actions, as well as the simultaneous use of Ranitidine-Fentanyl®, which can lead to respiratory depression. CONCLUSION A previous mapping of prescriptions enables the characterization of the drug therapy, contributing to prevent potential drug interactions and their clinical consequences.

  17. Opioid Peptides: Potential for Drug Development

    OpenAIRE

    Aldrich, Jane V.; McLaughlin, Jay P.

    2012-01-01

    Opioid receptors are important targets for the treatment of pain and potentially for other disease states (e.g. mood disorders and drug abuse) as well. Significant recent advances have been made in identifying opioid peptide analogs that exhibit promising in vivo activity for treatment of these maladies. This review focuses on the development and evaluation of opioid peptide analogs demonstrating activity after systemic administration, and recent clinical evaluations of opioid peptides for po...

  18. Genomes2Drugs: identifies target proteins and lead drugs from proteome data.

    LENUS (Irish Health Repository)

    Toomey, David

    2009-01-01

    BACKGROUND: Genome sequencing and bioinformatics have provided the full hypothetical proteome of many pathogenic organisms. Advances in microarray and mass spectrometry have also yielded large output datasets of possible target proteins\\/genes. However, the challenge remains to identify new targets for drug discovery from this wealth of information. Further analysis includes bioinformatics and\\/or molecular biology tools to validate the findings. This is time consuming and expensive, and could fail to yield novel drugs if protein purification and crystallography is impossible. To pre-empt this, a researcher may want to rapidly filter the output datasets for proteins that show good homology to proteins that have already been structurally characterised or proteins that are already targets for known drugs. Critically, those researchers developing novel antibiotics need to select out the proteins that show close homology to any human proteins, as future inhibitors are likely to cross-react with the host protein, causing off-target toxicity effects later in clinical trials. METHODOLOGY\\/PRINCIPAL FINDINGS: To solve many of these issues, we have developed a free online resource called Genomes2Drugs which ranks sequences to identify proteins that are (i) homologous to previously crystallized proteins or (ii) targets of known drugs, but are (iii) not homologous to human proteins. When tested using the Plasmodium falciparum malarial genome the program correctly enriched the ranked list of proteins with known drug target proteins. CONCLUSIONS\\/SIGNIFICANCE: Genomes2Drugs rapidly identifies proteins that are likely to succeed in drug discovery pipelines. This free online resource helps in the identification of potential drug targets. Importantly, the program further highlights proteins that are likely to be inhibited by FDA-approved drugs. These drugs can then be rapidly moved into Phase IV clinical studies under \\'change-of-application\\' patents.

  19. Genomes2Drugs: identifies target proteins and lead drugs from proteome data.

    Directory of Open Access Journals (Sweden)

    David Toomey

    Full Text Available BACKGROUND: Genome sequencing and bioinformatics have provided the full hypothetical proteome of many pathogenic organisms. Advances in microarray and mass spectrometry have also yielded large output datasets of possible target proteins/genes. However, the challenge remains to identify new targets for drug discovery from this wealth of information. Further analysis includes bioinformatics and/or molecular biology tools to validate the findings. This is time consuming and expensive, and could fail to yield novel drugs if protein purification and crystallography is impossible. To pre-empt this, a researcher may want to rapidly filter the output datasets for proteins that show good homology to proteins that have already been structurally characterised or proteins that are already targets for known drugs. Critically, those researchers developing novel antibiotics need to select out the proteins that show close homology to any human proteins, as future inhibitors are likely to cross-react with the host protein, causing off-target toxicity effects later in clinical trials. METHODOLOGY/PRINCIPAL FINDINGS: To solve many of these issues, we have developed a free online resource called Genomes2Drugs which ranks sequences to identify proteins that are (i homologous to previously crystallized proteins or (ii targets of known drugs, but are (iii not homologous to human proteins. When tested using the Plasmodium falciparum malarial genome the program correctly enriched the ranked list of proteins with known drug target proteins. CONCLUSIONS/SIGNIFICANCE: Genomes2Drugs rapidly identifies proteins that are likely to succeed in drug discovery pipelines. This free online resource helps in the identification of potential drug targets. Importantly, the program further highlights proteins that are likely to be inhibited by FDA-approved drugs. These drugs can then be rapidly moved into Phase IV clinical studies under 'change-of-application' patents.

  20. IN IDENTIFYING FAKE AND SUBSTANDARD DRUGS IN NIGERIA ...

    African Journals Online (AJOL)

    user

    2017-07-01

    Jul 1, 2017 ... National Agency for Food and Drug Administration and Control ... NAFDAC's choice of MAS as a new strategy in identifying fake and substandard drugs in. Nigeria. .... As a result, cloning of fast moving drugs is so perfect that even .... Some of the factors encouraging counterfeiting of drugs in Nigeria include:.

  1. Severe potential drug-drug interactions in older adults with dementia and associated factors

    Directory of Open Access Journals (Sweden)

    Michele Bogetti-Salazar

    2016-01-01

    Full Text Available OBJECTIVE: To identify the main severe potential drug-drug interactions in older adults with dementia and to examine the factors associated with these interactions. METHOD: This was a cross-sectional study. The enrolled patients were selected from six geriatrics clinics of tertiary care hospitals across Mexico City. The patients had received a clinical diagnosis of dementia based on the current standards and were further divided into the following two groups: those with severe drug-drug interactions (contraindicated/severe (n=64 and those with non-severe drug-drug interactions (moderate/minor/absent (n=117. Additional socio-demographic, clinical and caregiver data were included. Potential drug-drug interactions were identified using Micromedex Drug Reax 2.0® database. RESULTS: A total of 181 patients were enrolled, including 57 men (31.5% and 124 women (68.5% with a mean age of 80.11±8.28 years. One hundred and seven (59.1% patients in our population had potential drug-drug interactions, of which 64 (59.81% were severe/contraindicated. The main severe potential drug-drug interactions were caused by the combinations citalopram/anti-platelet (11.6%, clopidogrel/omeprazole (6.1%, and clopidogrel/aspirin (5.5%. Depression, the use of a higher number of medications, dementia severity and caregiver burden were the most significant factors associated with severe potential drug-drug interactions. CONCLUSIONS: Older people with dementia experience many severe potential drug-drug interactions. Anti-depressants, antiplatelets, anti-psychotics and omeprazole were the drugs most commonly involved in these interactions. Despite their frequent use, anti-dementia drugs were not involved in severe potential drug-drug interactions. The number and type of medications taken, dementia severity and depression in patients in addition to caregiver burden should be considered to avoid possible drug interactions in this population.

  2. Potential drug interactions in patients given antiretroviral therapy

    Directory of Open Access Journals (Sweden)

    Wendel Mombaque dos Santos

    Full Text Available ABSTRACT Objective: to investigate potential drug-drug interactions (PDDI in patients with HIV infection on antiretroviral therapy. Methods: a cross-sectional study was conducted on 161 adults with HIV infection. Clinical, socio demographic, and antiretroviral treatment data were collected. To analyze the potential drug interactions, we used the software Micromedex(r. Statistical analysis was performed by binary logistic regression, with a p-value of ≤0.05 considered statistically significant. Results: of the participants, 52.2% were exposed to potential drug-drug interactions. In total, there were 218 potential drug-drug interactions, of which 79.8% occurred between drugs used for antiretroviral therapy. There was an association between the use of five or more medications and potential drug-drug interactions (p = 0.000 and between the time period of antiretroviral therapy being over six years and potential drug-drug interactions (p < 0.00. The clinical impact was prevalent sedation and cardiotoxicity. Conclusions: the PDDI identified in this study of moderate and higher severity are events that not only affect the therapeutic response leading to toxicity in the central nervous and cardiovascular systems, but also can interfere in tests used for detection of HIV resistance to antiretroviral drugs.

  3. Pharmacosomes: A Potential Vesicular Drug Delivery System

    Directory of Open Access Journals (Sweden)

    D. Nagasamy Venkatesh

    2014-04-01

    Full Text Available Lipid based drug delivery systems have been examined in various studies and exhibited their potential in controlled and targeted drug delivery. Pharmacosomes, a novel vesicular drug delivery system, offering a unique advantage over liposomes and niosomes, and serve as potential alternative to these conventional vesicles. They constitute an amphiphilic phospholipid complex with drug bearing an active hydrogen atom covalently that bind to phospholipids. They provide an efficient delivery of drug required at the site of action, which ultimately reduces the drug toxicity with reduced adverse effects and also reduces the cost of therapy by imparting better biopharmaceutical properties to the drug, resulting in increases bioavailability, especially in case of poorly soluble drugs. As the system is formed by binding the drug (pharmakon to carrier (soma, they are termed as pharmacosomes. Depending upon the chemical structure of the drug lipid complex they may exist as ultrafine vesicular, micellar and hexagonal aggregate. Drug having active hydrogen group such as carboxyl, hydroxyl group can be esterified to lipids, resulting in amphiphilic compound. Pharmacosomes are widely used as carriers for various non-steroidal anti-inflammatory drugs, proteins, cardiovascular and antineoplastic drugs. The release of drug from pharmacosomes is generally governed by the process of enzymatic reaction and acid hydrolysis. Here, in the present review paper we have discussed the potential of pharmacosomes as a controlled and targeted drug delivery system and highlighted the method of preparation and characterization.

  4. Prediction of potential drug targets based on simple sequence properties

    Directory of Open Access Journals (Sweden)

    Lai Luhua

    2007-09-01

    Full Text Available Abstract Background During the past decades, research and development in drug discovery have attracted much attention and efforts. However, only 324 drug targets are known for clinical drugs up to now. Identifying potential drug targets is the first step in the process of modern drug discovery for developing novel therapeutic agents. Therefore, the identification and validation of new and effective drug targets are of great value for drug discovery in both academia and pharmaceutical industry. If a protein can be predicted in advance for its potential application as a drug target, the drug discovery process targeting this protein will be greatly speeded up. In the current study, based on the properties of known drug targets, we have developed a sequence-based drug target prediction method for fast identification of novel drug targets. Results Based on simple physicochemical properties extracted from protein sequences of known drug targets, several support vector machine models have been constructed in this study. The best model can distinguish currently known drug targets from non drug targets at an accuracy of 84%. Using this model, potential protein drug targets of human origin from Swiss-Prot were predicted, some of which have already attracted much attention as potential drug targets in pharmaceutical research. Conclusion We have developed a drug target prediction method based solely on protein sequence information without the knowledge of family/domain annotation, or the protein 3D structure. This method can be applied in novel drug target identification and validation, as well as genome scale drug target predictions.

  5. Risk factors for potential drug interactions in general practice

    DEFF Research Database (Denmark)

    Bjerrum, Lars; Gonzalez Lopez-Valcarcel, Beatriz; Petersen, Gert

    2008-01-01

    Pharmacoepidemiologic Database, OPED) covering prescriptions to all inhabitants in the county of Funen, Denmark. All individuals exposed to concurrent use of two or more drugs (polypharmacy) were identified. Combinations of drugs with potential interactions were registered and classified as major, moderate, or minor......, depending on the severity of outcome and the quality of documentation. A two-level random coefficient logistic regression model was used to investigate factors related to potential drug interactions. Results: One-third of the population was exposed to polypharmacy, and 6% were exposed to potential drug...

  6. A cellular genetics approach identifies gene-drug interactions and pinpoints drug toxicity pathway nodes

    Directory of Open Access Journals (Sweden)

    Oscar Takeo Suzuki

    2014-08-01

    Full Text Available New approaches to toxicity testing have incorporated high-throughput screening across a broad-range of in vitro assays to identify potential key events in response to chemical or drug treatment. To date, these approaches have primarily utilized repurposed drug discovery assays. In this study, we describe an approach that combines in vitro screening with genetic approaches for the experimental identification of genes and pathways involved in chemical or drug toxicity. Primary embryonic fibroblasts isolated from 32 genetically-characterized inbred mouse strains were treated in concentration-response format with 65 compounds, including pharmaceutical drugs, environmental chemicals, and compounds with known modes-of-action. Integrated cellular responses were measured at 24 and 72 hours using high-content imaging and included cell loss, membrane permeability, mitochondrial function, and apoptosis. Genetic association analysis of cross-strain differences in the cellular responses resulted in a collection of candidate loci potentially underlying the variable strain response to each chemical. As a demonstration of the approach, one candidate gene involved in rotenone sensitivity, Cybb, was experimentally validated in vitro and in vivo. Pathway analysis on the combined list of candidate loci across all chemicals identified a number of over-connected nodes that may serve as core regulatory points in toxicity pathways.

  7. Severe potential drug-drug interactions in older adults with dementia and associated factors

    OpenAIRE

    Michele Bogetti-Salazar; Cesar González-González; Teresa Juárez-Cedillo; Sergio Sánchez-García; Oscar Rosas-Carrasco

    2016-01-01

    OBJECTIVE: To identify the main severe potential drug-drug interactions in older adults with dementia and to examine the factors associated with these interactions. METHOD: This was a cross-sectional study. The enrolled patients were selected from six geriatrics clinics of tertiary care hospitals across Mexico City. The patients had received a clinical diagnosis of dementia based on the current standards and were further divided into the following two groups: those with severe drug-drug inte...

  8. Epidemiology of Polypharmacy and Potential Drug-Drug Interactions Among Pediatric Patients in ICUs of U.S. Children's Hospitals.

    Science.gov (United States)

    Dai, Dingwei; Feinstein, James A; Morrison, Wynne; Zuppa, Athena F; Feudtner, Chris

    2016-05-01

    Polypharmacy is common in hospitalized children in the United States and has been identified as a major risk factor for exposure to potential drug-drug interactions. Little is known about the characteristics and prevalence of exposure of pediatric patients to polypharmacy and potential drug-drug interactions in PICUs. Retrospective cohort study using the Pediatric Health Information System database. Forty-two freestanding children's hospitals throughout the United States. A total of 54,549 patients less than 18 years old cared for in PICUs in 2011. Patients in neonatal ICUs were not included. PICU patients were on average exposed to 10 distinct drugs each hospital day and to 20 drugs cumulatively during their hospitalization. Seventy-five percent of patients were exposed to greater than or equal to one potential drug-drug interaction regardless of severity level, 6% to greater than or equal to one contraindicated potential drug-drug interaction, 69% to greater than or equal to one major potential drug-drug interaction, 57% to greater than or equal to one moderate potential drug-drug interaction, 19% to greater than or equal to one minor potential drug-drug interaction. Potential drug-drug interaction exposures were significantly associated with specific diagnoses (p risk of adverse drug events following specific potential drug-drug interaction exposures, especially the risk of adverse drug events due to multiple potential drug-drug interaction exposures, and determine the probability and magnitude of the actual harm (if any) for each specific potential drug-drug interaction, especially for multiple potential drug-drug interaction exposures.

  9. Potential Drug-drug Interactions in Post-CCU of a Teaching Hospital.

    Science.gov (United States)

    Haji Aghajani, Mohammad; Sistanizad, Mohammad; Abbasinazari, Mohammad; Abiar Ghamsari, Mahdieh; Ayazkhoo, Ladan; Safi, Olia; Kazemi, Katayoon; Kouchek, Mehran

    2013-01-01

    Drug-drug interactions (DDIs) can lead to increased toxicity or reduction in therapeutic efficacy. This study was designed to assess the incidence of potential drug interactions (PDI) and rank their clinical value in post coronary care unit (Post-CCU) of a teaching hospital in Tehran, Iran. In this prospective study, three pharmacists with supervision of a clinical pharmacist actively gathered necessary information for detection of DDIs. Data were tabulated according to the combinations of drugs in treatment chart. Verification of potential drug interactions was carried out using the online Lexi-Interact™ 2011. A total of 203 patients (113 males and 90 females) were enrolled in the study. The mean age of patients was 61 ± 12.55 years (range = 26-93). A total of 90 drugs were prescribed to 203 patients and most prescribed drugs were atorvastatin, clopidogrel and metoprolol. Mean of drugs was 11.22 per patient. A total of 3166 potential drug interactions have been identified by Lexi- Interact™, 149 (4.71%) and 55 (1.73%) of which were categorized as D and X, respectively. The most serious interactions were clopidogrel+omeprazole and metoprolol+salbutamol. Drug interactions leading to serious adverse effects are to be cautiously watched for when multiple drugs are used simultaneously. In settings with multiple drug use attendance of a pharmacist or clinical pharmacist, taking the responsibility for monitoring drug interactions and notifying the physician about potential problems could decrease the harm in patient and increase the patient safety.

  10. Identifying Potential Child Abuse through Oral Examination

    Directory of Open Access Journals (Sweden)

    Jillian N. Printz

    2017-01-01

    Full Text Available Limited reports of oropharyngeal trauma exist in the literature even though this type of injury is extremely common in pediatric populations. There are no widely agreed upon diagnostic and management tools for such injuries in abuse cases, emphasizing the importance of reporting rare cases of orofacial trauma. This case report of a soft palate laceration demonstrates an instance of initially unrecognized potential child abuse. We aim to clarify understanding of such injuries. Furthermore, the report highlights the need for recognition of oral signs of child abuse in order to promote early detection, reporting, and appropriate management.

  11. Identifying the Potential Biosphere of Mars

    CERN Document Server

    Jones, Eriita G

    2008-01-01

    Our current knowledge of life on Earth indicates a basic requirement for liquid water. The locations of present liquid water are therefore the logical sites to search for current life on Mars. We develop a picture of where on Mars the regions with the highest potential near-surface liquid water abundance can be found through a study of gullies. We also use rampart craters to sound the depth of water ice on Mars and where the highest concentrations of water ice occur. We estimate that low latitude gullies and rampart craters with depths greater than 100 m at 30 degrees (absolute) latitude, greater than 1.3 km at 35 degrees and greater than 2.6 km at 40 degrees latitude will give access to current liquid water environments capable of supporting microbial life. Our data is most consistent with the formation of these gullies through shallow aquifer discharge. These features should therefore be high priority targets for further study and high-resolution imaging with HiRISE.

  12. Identifying Drug–Drug Interactions by Data Mining

    DEFF Research Database (Denmark)

    Hansen, Peter Wæde; Clemmensen, Line Katrine Harder; Sehested, Thomas S.G.

    2016-01-01

    Background—Knowledge about drug–drug interactions commonly arises from preclinical trials, from adverse drug reports, or based on knowledge of mechanisms of action. Our aim was to investigate whether drug–drug interactions were discoverable without prior hypotheses using data mining. We focused...... registries. Additionally, we discovered a few potentially novel interactions. This opens up for the use of data mining to discover unknown drug–drug interactions in cardiovascular medicine....... on warfarin–drug interactions as the prototype. Methods and Results—We analyzed altered prothrombin time (measured as international normalized ratio [INR]) after initiation of a novel prescription in previously INR-stable warfarin-treated patients with nonvalvular atrial fibrillation. Data sets were retrieved...

  13. Combinatorial Drug Screening Identifies Ewing Sarcoma-specific Sensitivities

    DEFF Research Database (Denmark)

    Radic-Sarikas, Branka; Tsafou, Kalliopi P; Emdal, Kristina B.;

    2017-01-01

    including approved drugs. We were able to retrieve highly synergistic drug combinations specific for Ewing sarcoma and identified signaling processes important for Ewing sarcoma cell proliferation determined by EWS-FLI1 We generated a molecular target profile of PKC412, a multikinase inhibitor with strong...... and IGF1R inhibitors. The mechanism of the drug synergy between these inhibitors is different from the sum of the mechanisms of the single agents. The combination effectively inhibited pathway crosstalk and averted feedback loop repression, in EWS-FLI1-dependent manner. Mol Cancer Ther; 16(1); 88...

  14. Potential drug-drug interactions in intensive care units of a hospital in Southern Brazil

    Directory of Open Access Journals (Sweden)

    Gustavo Henrique Oliveira-Paula

    2014-12-01

    Full Text Available Drug-drug interactions are important causes of adverse reactions in health units. The high consumption of medicines in intensive care units predisposes patients to potential drug-drug interactions. This study aimed at examining the frequency and the characteristics of drug-drug interactions in intensive care units of Hospital Universitario of Universidade Estadual de Londrina. We analyzed the prescriptions of patients over 18 years, admitted from January to May 2010, who remained hospitalized for at least four days. The analysis of drug-drug interactions was carried out using the Micromedex Drug-Reax® system. The interactions were classified by severity, time required for the onset of adverse effects, mechanism of action and quality of scientific evidence. Moreover, the possible adverse events were analyzed, as well as the recommended strategies of management and monitoring. Altogether, 198 different potential drug-drug interactions were identified with the occurrence of 1242 episodes. Of these, 43% were characterized by moderate interactions, 35% major, 16% minor and 6% contraindicated. The therapeutic inefficacy was the most frequent possible adverse event (18% and the main recommended strategy of management was the dose adjustment (35.6%. The most frequent interactions were: fentanyl + midazolam (8.6%, phenytoin + ranitidine (5.5% and midazolam + ranitidine (4.8%. These results demonstrate the importance of drug-drug interactions as a significant adverse event in intensive care units and thus, preventive measures are required to minimize this problem.

  15. Urinary peptidomics identifies potential biomarkers for major depressive disorder.

    Science.gov (United States)

    Wang, Ying; Chen, Jianjun; Chen, Liang; Zheng, Peng; Xu, Hong-Bo; Lu, Jia; Zhong, Jiaju; Lei, Yang; Zhou, Chanjuan; Ma, Qingwei; Li, Yan; Xie, Peng

    2014-06-30

    Major depressive disorder (MDD) is a debilitating psychiatric illness with no available objective laboratory-based diagnostic test. In this study, matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS)-based peptidomics was applied to identify potential urinary diagnostic biomarkers for MDD. A training set of 42 first-episode drug-naive MDD patients and 28 age- and gender-matched healthy controls (HC) was used to develop a peptide diagnostic pattern. Then, the diagnostic efficacy of this pattern was assessed in an independent blinded test set consisting of 24 MDD patients and 13 age- and gender-matched HC. A combination of five potential biomarkers was identified, yielding a sensitivity of 91.7% and specificity of 84.6% in the test set. Moreover, the protein precursors of four of the five peptides were identified by tandem mass spectrometric analysis: serum albumin, apolipoprotein A-I, protein AMBP, and basement membrane-specific heparan sulfate proteoglycan core protein. Taken together, the peptide pattern may be valuable for establishing an objective laboratory-based diagnostic test for MDD.

  16. Quantitative bioassay to identify antimicrobial drugs through drug interaction fingerprint analysis.

    Science.gov (United States)

    Weinstein, Zohar B; Zaman, Muhammad H

    2017-02-16

    Drug interaction analysis, which reports the extent to which the presence of one drug affects the efficacy of another, is a powerful tool to select potent combinatorial therapies and predict connectivity between cellular components. Combinatorial effects of drug pairs often vary even for drugs with similar mechanism of actions. Therefore, drug interaction fingerprinting may be harnessed to differentiate drug identities. We developed a method to analyze drug interactions for the application of identifying active pharmaceutical ingredients, an essential step to assess drug quality. We developed a novel approach towards the identification of active pharmaceutical ingredients by comparing drug interaction fingerprint similarity metrics such as correlation and Euclidean distance. To expedite this method, we used bioluminescent E. coli in a simplified checkerboard assay to generate unique drug interaction fingerprints of antimicrobial drugs. Of 30 antibiotics studied, 29 could be identified based on their drug interaction fingerprints. We present drug interaction fingerprint analysis as a cheap, sensitive and quantitative method towards substandard and counterfeit drug detection.

  17. Identifying problematic drugs based on the characteristics of their targets

    Directory of Open Access Journals (Sweden)

    Tiago Jose eDa Silva Lopes

    2015-09-01

    Full Text Available Identifying promising compounds during the early stages of drug development is a major challenge for both academia and the pharmaceutical industry. The difficulties are even more pronounced when we consider multi-target pharmacology, where the compounds often target more than one protein, or multiple compounds are used together. Here, we address this problem by using machine learning and network analysis to process sequence and interaction data from human proteins to identify promising compounds. We used this strategy to identify properties that make certain proteins more likely to cause harmful effects when targeted; such proteins usually have domains commonly found throughout the human proteome. Additionally, since currently marketed drugs hit multiple targets simultaneously, we combined the information from individual proteins to devise a score that quantifies the likelihood of a compound being harmful to humans. This approach enabled us to distinguish between approved and problematic drugs with an accuracy of 60%¬–70%. Moreover, our approach can be applied as soon as candidate drugs are available, as demonstrated with predictions for more than 5000 experimental drugs. These resources are available at http://sourceforge.net/projects/psin/.

  18. Newer Approaches to Identify Potential Untoward Effects in Functional Foods.

    Science.gov (United States)

    Marone, Palma Ann; Birkenbach, Victoria L; Hayes, A Wallace

    2016-01-01

    Globalization has greatly accelerated the numbers and variety of food and beverage products available worldwide. The exchange among greater numbers of countries, manufacturers, and products in the United States and worldwide has necessitated enhanced quality measures for nutritional products for larger populations increasingly reliant on functionality. These functional foods, those that provide benefit beyond basic nutrition, are increasingly being used for their potential to alleviate food insufficiency while enhancing quality and longevity of life. In the United States alone, a steady import increase of greater than 15% per year or 24 million shipments, over 70% products of which are food related, is regulated under the Food and Drug Administration (FDA). This unparalleled growth has resulted in the need for faster, cheaper, and better safety and efficacy screening methods in the form of harmonized guidelines and recommendations for product standardization. In an effort to meet this need, the in vitro toxicology testing market has similarly grown with an anticipatory 15% increase between 2010 and 2015 of US$1.3 to US$2.7 billion. Although traditionally occupying a small fraction of the market behind pharmaceuticals and cosmetic/household products, the scope of functional food testing, including additives/supplements, ingredients, residues, contact/processing, and contaminants, is potentially expansive. Similarly, as functional food testing has progressed, so has the need to identify potential adverse factors that threaten the safety and quality of these products.

  19. Assessing the proarrhythmic potential of drugs

    DEFF Research Database (Denmark)

    Thomsen, Morten Bækgaard; Matz, Jørgen; Volders, Paul G A

    2006-01-01

    Torsades de pointes (TdP) is a potentially lethal cardiac arrhythmia that can occur as an unwanted adverse effect of various pharmacological therapies. Before a drug is approved for marketing, its effects on cardiac repolarisation are examined clinically and experimentally. This paper expresses...... models is emphasised in the present paper. It is feasible for the pharmaceutical industry to establish one or more of these proarrhythmic animal models and large benefits are potentially available if pharmaceutical industries and patient-care authorities embraced these models. Furthermore, suggested...... surrogate parameters possessing predictive power of TdP arrhythmia are reviewed. As these parameters are not developed to finalisation, any meaningful study of the proarrhythmic potential of a new drug will include evaluation in an integrated model of TdP arrhythmia....

  20. [Potential drug-drug interactions among elderly using antihypertensives from the Brazilian List of Essential Medicines].

    Science.gov (United States)

    Mibielli, Pablo; Rozenfeld, Suely; Matos, Guacira Corrêa de; Acurcio, Francisco de Assis

    2014-09-01

    The aim of this study was to estimate the prevalence of potential interactions between antihypertensives and other drugs. A household survey was conducted with individuals 60 years or older residing in Rio de Janeiro, Brazil. Potential moderately or very severe drug-drug interactions with antihypertensives, documented as suspected, probable or established, were identified. A total of 577 elderly were interviewed (mean age = 72 years), 45.2% of whom were using antihypertensives, of which 31.0% were subject to potential drug-drug interactions. Most of the interactions were moderately severe. Compared to the other elderly, those with potential drug-drug interactions showed more than fourfold odds of using five or more medicines and more than twofold odds of having been hospitalized in the previous year. Among the most frequent pairs of interactions, 75% cause a reduction in the hypotensive effect (65/87), which can result in low effectiveness of blood pressure control, prescribing of more drugs, and risk of other adverse events and interactions.

  1. Structure-based drug design identifies novel LPA3 antagonists.

    Science.gov (United States)

    Fells, James I; Tsukahara, Ryoko; Liu, Jianxiong; Tigyi, Gabor; Parrill, Abby L

    2009-11-01

    Compound 5 ([5-(3-nitrophenoxy)-1,3-dioxo-1,3-dihydro-2-isoindol-2-yl]acetic acid) was identified as a weak selective LPA(3) antagonist (IC(50)=4504 nM) in a virtual screening effort to optimize a dual LPA(2 and 3) antagonist. Structure-based drug design techniques were used to prioritize similarity search matches of compound 5. This strategy rapidly identified 10 novel antagonists. The two most efficacious compounds identified inhibit activation of the LPA(3) receptor by 200 nM LPA with IC(50) values of 752 nM and 2992 nM. These compounds additionally define changes to our previously reported pharmacophore that will improve its ability to identify more potent and selective LPA(3) receptor antagonists. The results of the combined computational and experimental screening are reported.

  2. Prevalence of potential drug-drug interactions in cancer patients treated with oral anticancer drugs

    NARCIS (Netherlands)

    R.W.F. van Leeuwen (Roelof); D.H.S. Brundel (D. H S); C. Neef (Cees); T. van Gelder (Teun); A.H.J. Mathijssen (Ron); D.M. Burger (David); F.G.A. Jansman (Frank)

    2013-01-01

    textabstractBackground: Potential drug-drug interactions (PDDIs) in patients with cancer are common, but have not previously been quantified for oral anticancer treatment. We assessed the prevalence and seriousness of potential PDDIs among ambulatory cancer patients on oral anticancer treatment.

  3. Prevalence of potential drug-drug interactions in cancer patients treated with oral anticancer drugs

    NARCIS (Netherlands)

    van Leeuwen, R. W. F.; Brundel, D. H. S.; Neef, C.; van Gelder, T.; Mathijssen, R. H. J.; Burger, D. M.; Jansman, F. G. A.

    2013-01-01

    Background: Potential drug-drug interactions (PDDIs) in patients with cancer are common, but have not previously been quantified for oral anticancer treatment. We assessed the prevalence and seriousness of potential PDDIs among ambulatory cancer patients on oral anticancer treatment. Methods: A

  4. Identifying injection drug users at risk of nonfatal overdose.

    Science.gov (United States)

    Coffin, Phillip O; Tracy, Melissa; Bucciarelli, Angela; Ompad, Danielle; Vlahov, David; Galea, Sandro

    2007-07-01

    Drug overdose is the second leading cause of accidental deaths among U.S. adults aged 15-64 years. Emergency physicians have a unique opportunity to provide overdose prevention interventions, because habitual drug users are in frequent need of medical care. The authors evaluated associations between individual-level risk factors and experiencing an overdose in the past six months to determine which characteristics and behaviors may be most predictive of overdose. The authors used data from a sample of street-recruited habitual drug users who participated in face-to-face interviews about overdose from November 2001 to February 2004. This analysis was restricted to 772 respondents who had been injecting for at least one year and who had injected heroin within the past two months. A total of 16.6% of participants had overdosed in the past six months. Characteristics and behaviors that were independently associated with an increased risk of a recent overdose were having had a prior overdose (odds ratio [OR], 28.58; 95% confidence interval [CI] = 14.10 to 57.96), using cocaine/crack in the past six months (OR, 2.07; 95% CI = 1.25 to 3.45), using alcohol in the past six months (OR, 1.90; 95% CI = 1.01 to 3.57), experiencing serious withdrawal symptoms in the past two months (OR, 2.70; 95% CI = 1.58 to 4.61), and younger age. Drug users who have previously experienced a nonfatal overdose are at very high risk of experiencing future overdoses. Further longitudinal studies are needed to identify robust predictors of overdose risk over time in habitual drug users, but these data suggest that drug users who have overdosed warrant aggressive prevention efforts such as agonist maintenance treatment or provision of take-home naloxone.

  5. Therapeutic potential of cannabis-related drugs.

    Science.gov (United States)

    Alexander, Stephen P H

    2016-01-04

    In this review, I will consider the dual nature of Cannabis and cannabinoids. The duality arises from the potential and actuality of cannabinoids in the laboratory and clinic and the 'abuse' of Cannabis outside the clinic. The therapeutic areas currently best associated with exploitation of Cannabis-related medicines include pain, epilepsy, feeding disorders, multiple sclerosis and glaucoma. As with every other medicinal drug of course, the 'trick' will be to maximise the benefit and minimise the cost. After millennia of proximity and exploitation of the Cannabis plant, we are still playing catch up with an understanding of its potential influence for medicinal benefit.

  6. Drug regimens identified and optimized by output-driven platform markedly reduce tuberculosis treatment time

    Science.gov (United States)

    Lee, Bai-Yu; Clemens, Daniel L.; Silva, Aleidy; Dillon, Barbara Jane; Masleša-Galić, Saša; Nava, Susana; Ding, Xianting; Ho, Chih-Ming; Horwitz, Marcus A.

    2017-01-01

    The current drug regimens for treating tuberculosis are lengthy and onerous, and hence complicated by poor adherence leading to drug resistance and disease relapse. Previously, using an output-driven optimization platform and an in vitro macrophage model of Mycobacterium tuberculosis infection, we identified several experimental drug regimens among billions of possible drug-dose combinations that outperform the current standard regimen. Here we use this platform to optimize the in vivo drug doses of two of these regimens in a mouse model of pulmonary tuberculosis. The experimental regimens kill M. tuberculosis much more rapidly than the standard regimen and reduce treatment time to relapse-free cure by 75%. Thus, these regimens have the potential to provide a markedly shorter course of treatment for tuberculosis in humans. As these regimens omit isoniazid, rifampicin, fluoroquinolones and injectable aminoglycosides, they would be suitable for treating many cases of multidrug and extensively drug-resistant tuberculosis. PMID:28117835

  7. A series of case studies: practical methodology for identifying antinociceptive multi-target drugs.

    Science.gov (United States)

    Pang, Min-Hee; Kim, Yuntae; Jung, Kyung Woon; Cho, Sunyoung; Lee, Doo H

    2012-05-01

    Since the introduction of drug discovery based on single targets, the number of newly developed drugs has steadily declined, and the reliablility of the current drug-discovery paradigm has been unceasingly questioned. As an alternative, an emerging approach pursuing multi-targeting drugs has arisen to reflect multifactorial diseases caused by the complex networks of various mechanisms. The purpose of this paper is to review multi-target drugs and introduce our progress in establishing a practical methodology for identifying antinociceptive multi-target drugs. We have adopted a system of ex vivo efficacy screening using long-term potentiation in rat spinal cord as a surrogate biomarker for neuropathic pain. A bait-target approach is also adopted to lure an unknown target combination that induces synergistic mechanisms.

  8. Herbal drug patenting in India: IP potential.

    Science.gov (United States)

    Sahoo, Niharika; Manchikanti, Padmavati; Dey, Satya Hari

    2011-09-01

    Herbal drugs are gaining worldwide prominence due to their distinct advantages. Developing countries have started exploring the ethnopharmacological approach of drug discovery and have begun to file patents on herbal drugs. The expansion of R&D in Indian herbal research organizations and presence of manufacturing units at non-Indian sites is an indication of the capability to develop new products and processes. The present study attempts to identify innovations in the Indian herbal drug sector by analyzing the patenting trends in India, US and EU. Based on key word and IPC based search at the IPO, USPTO, Esp@cenet and WIPO databases, patent applications and grant in herbal drugs by Indian applicants/assignees was collected for the last ten years (from 1st January 2001 to 31st October 2010). From this collection patents related to human therapeutic use only were selected. Analysis was performed to identify filing trends, major applicants/assignees, disease area and major plant species used for various treatments. There is a gradual increase in patent filing through the years. In India, individual inventors have maximum applications and grants. CSIR, among research organizations and Hindustan Unilever, Avesthagen, Piramal Life Science, Sahajanand Biotech and Indus Biotech among the companies have the maximum granted patents in India, US and EU respectively. Diabetes, cancer and inflammatory disorders are the major areas for patenting in India and abroad. Recent patents are on new herbal formulations for treatment of AIDS, hepatitis, skin disorders and gastrointestinal disorders. A majority of the herbal patents applications and grants in India are with individual inventors. Claim analysis indicates that these patents include novel multi-herb compositions with synergistic action. Indian research organizations are more active than companies in filing for patents. CSIR has maximum numbers of applications not only in India but also in the US and EU. Patents by research

  9. Identifying co-targets to fight drug resistance based on a random walk model

    Directory of Open Access Journals (Sweden)

    Chen Liang-Chun

    2012-01-01

    Full Text Available Abstract Background Drug resistance has now posed more severe and emergent threats to human health and infectious disease treatment. However, wet-lab approaches alone to counter drug resistance have so far still achieved limited success due to less knowledge about the underlying mechanisms of drug resistance. Our approach apply a heuristic search algorithm in order to extract active network under drug treatment and use a random walk model to identify potential co-targets for effective antibacterial drugs. Results We use interactome network of Mycobacterium tuberculosis and gene expression data which are treated with two kinds of antibiotic, Isoniazid and Ethionamide as our test data. Our analysis shows that the active drug-treated networks are associated with the trigger of fatty acid metabolism and synthesis and nicotinamide adenine dinucleotide (NADH-related processes and those results are consistent with the recent experimental findings. Efflux pumps processes appear to be the major mechanisms of resistance but SOS response is significantly up-regulation under Isoniazid treatment. We also successfully identify the potential co-targets with literature confirmed evidences which are related to the glycine-rich membrane, adenosine triphosphate energy and cell wall processes. Conclusions With gene expression and interactome data supported, our study points out possible pathways leading to the emergence of drug resistance under drug treatment. We develop a computational workflow for giving new insights to bacterial drug resistance which can be gained by a systematic and global analysis of the bacterial regulation network. Our study also discovers the potential co-targets with good properties in biological and graph theory aspects to overcome the problem of drug resistance.

  10. History as a tool in identifying "new" old drugs.

    Science.gov (United States)

    Riddle, John M

    2002-01-01

    To trace the history of a natural product and its use, it is necessary to identify to correct plant among around a half-million species. One must also know how and when harvest the plant and the morphology of location and extraction. Within the same species plant chemistry varies, depending upon climatic and soil conditions, stage of maturity and even diurnal factors. To all of these variations must be added the diagnostic ability of physicians and native healers (to distinguish between Hippocratically-trained Western physicians and whose knowledge is less formally taught). Seldom was a disease identified as we Know it today, but the constellations of symptoms described, when studied carefully within the framework historical setting of the culture, can be related to modern medicine. It is essential to study the historical contemporary usage data in the language in which those accounts were writTen. Translators are often philologists who are not sensitive to medical nuances. Modern readers of translated historical documents often are unaware of the precision the authors delivered in describing medical afflictions and their treatments. Natural product drugs are truly products of human knowledge. Because so many modern pharmaceuticals are manufactured synthetically we forget that once either the compound or its affinity had a home in a natural product. Over 2,500 years ago man first used a drug obtained from white willow bark, which was aspirin or acetylsalicylic acid. Today's scientists continue to be bewildered by just what aspirin's mechanisms of action are, discovering new modes of action, and how they relate to medical diagnostics. Whatever the science of aspirin, an intelligent person today takes it just as our ancestors did fo millennia. Throughout time, explanations continue to vary just as purpose of administration do as well. Nevertheless, aspirin is perceived as being beneficial. Historical in-use data can also be a factor in judging a drug's safety, since

  11. Study of Potential Drug-Drug Interactions in Prescriptions of University- Based Pharmacies

    Directory of Open Access Journals (Sweden)

    Sarah Mousavi

    2015-10-01

    Full Text Available Background: Drug-Drug Interactions (DDIs are adverse reactions caused by a combination of drugs; they are often predictable and therefore avoidable or manageable. The objective of this study was to evaluate the nature, type and prevalence of potential DDIs in prescriptions dispensed in university-based community pharmacies in Tehran, Iran.Methods: From July 2012 to February 2014, sample of 1260 prescriptions were collected from community and outpatient hospital pharmacies affiliated to Tehran University of Medical Sciences (TUMS, Iran. The prescriptions were assessed using the reference text “drug interaction facts”. The identified DDIs were categorized according to their level of significance into three classes (minor, moderate, major.Results: At least one drug-drug interaction was present in 339 (26.9% of prescriptions and a total of 751 cases of interactions were found in prescriptions. Major DDIs represented 7.3% of all DDIs detected, whereas moderate DDIs were 75% of all DDIs. The mean number of drugs per prescriptions was 3.2, with a median of 4 (range, 2-10.There was a positive association between number of prescribed drugs and occurrence of DDIs (OR: 2.14, 95% CI: 1.9-2.4. The prescriptions of medical specialist had greater risk of occurrence of moderate severity DDIs than general practitioners (OR: 1.52, 95%CI: 1.08-2.15.Conclusion: Despite the prescriptions were collected from university-based pharmacies, but the overall prevalence of potential DDIs were high among patients. Physicians should be aware of potentially harmful DDIs. Meanwhile Pharmacists can contribute to the detection and prevention of drug-related injuries. Appropriate education, collaborating drug selection and pharmaceutical care are strongly recommended for physicians and pharmacists.

  12. Potential drug-drug interactions in cardiothoracic intensive care unit of a pulmonary teaching hospital.

    Science.gov (United States)

    Farzanegan, Behrooz; Alehashem, Maryam; Bastani, Marjan; Baniasadi, Shadi

    2015-02-01

    Little is known about clinically significant drug-drug interactions (DDIs) in respiratory settings. DDIs are more likely to occur in critically ill patients due to complex pharmacotherapy regimens and organ dysfunctions. The aim of this study was to identify the pattern of potential DDIs (pDDIs) occurring in cardiothoracic intensive care unit (ICU) of a pulmonary hospital. A prospective observational study was conducted for 6 months. All pDDIs for admitted patients in cardiothoracic ICU were identified with Lexi-Interact program and assessed by a clinical pharmacologist. The interacting drugs, reliability, mechanisms, potential outcomes, and clinical management were evaluated for severe and contraindicated interactions. The study included 195 patients. Lung cancer (14.9%) was the most common diagnosis followed by tracheal stenosis (14.3%). The rate of pDDIs was 720.5/100 patients. Interactions were more commonly observed in transplant patients. 17.7% of pDDIs were considered as severe and contraindicated interactions. Metabolism (54.8%) and additive (24.2%) interactions were the most frequent mechanisms leading to pDDIs, and azole antifungals and fluoroquinolones were the main drug classes involved. The pattern of pDDIs in cardiothoracic ICU differs from other ICU settings. Specialized epidemiological knowledge of drug interactions may help clinical practitioners to reduce the risk of adverse drug events.

  13. Incidence of Potential Drug-Drug Interaction and Related Factors in Hospitalized Neurological Patients in two Iranian Teaching Hospitals

    Directory of Open Access Journals (Sweden)

    Soha Namazi

    2014-11-01

    Full Text Available Background: Reciprocal drug interactions are among the most common causes of adverse drug reactions. We investigated the incidence and related risk factors associated with mutual drug interactions in relation to prescriptions written in the neurology wards of two major teaching hospitals in Shiraz, southern Iran. Methods: Data was collected from hand-written prescriptions on a daily basis. Mutual drug interactions were identified using Lexi-Comp 2012 version 1.9.1. Type D and X drug interactions were considered as potential drug-drug interactions. The potential risk factors associated with drug-drug interactions included the patient’s age and gender, number of medications and orders, length of hospitalization and the type of neurological disorder. To determine potential drug-drug interactions, relevant interventions were suggested to the physicians or nurses and the outcome of the interventions were documented. Results: The study comprised 589 patients, of which 53% were males and 47% females, with a mean age of 56.65±18.19 SD years. A total of 4942 drug orders and 3784 medications were prescribed among which 4539 drug-drug interactions were detected, including 4118 type C, 403 type D, and 18 type X. Using a logistic regression model, the number of medications, length of hospitalization and non-vascular type of the neurological disorder were found to be significantly associated with potential drug-drug interactions. From the total interventions, 74.24% were accepted by physicians and nurses. Conclusion: Potentially hazardous reciprocal drug interactions are common among patients in neurology wards. Clinical pharmacists can play a critical role in the prevention of drug-drug interactions in hospitalized patients.

  14. Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi.

    Directory of Open Access Journals (Sweden)

    Joseph D Planer

    2014-07-01

    Full Text Available An estimated 8 million persons, mainly in Latin America, are infected with Trypanosoma cruzi, the etiologic agent of Chagas disease. Existing antiparasitic drugs for Chagas disease have significant toxicities and suboptimal effectiveness, hence new therapeutic strategies need to be devised to address this neglected tropical disease. Due to the high research and development costs of bringing new chemical entities to the clinic, we and others have investigated the strategy of repurposing existing drugs for Chagas disease. Screens of FDA-approved drugs (described in this paper have revealed a variety of chemical classes that have growth inhibitory activity against mammalian stage Trypanosoma cruzi parasites. Aside from azole antifungal drugs that have low or sub-nanomolar activity, most of the active compounds revealed in these screens have effective concentrations causing 50% inhibition (EC50's in the low micromolar or high nanomolar range. For example, we have identified an antihistamine (clemastine, EC50 of 0.4 µM, a selective serotonin reuptake inhibitor (fluoxetine, EC50 of 4.4 µM, and an antifolate drug (pyrimethamine, EC50 of 3.8 µM and others. When tested alone in the murine model of Trypanosoma cruzi infection, most compounds had insufficient efficacy to lower parasitemia thus we investigated using combinations of compounds for additive or synergistic activity. Twenty-four active compounds were screened in vitro in all possible combinations. Follow up isobologram studies showed at least 8 drug pairs to have synergistic activity on T. cruzi growth. The combination of the calcium channel blocker, amlodipine, plus the antifungal drug, posaconazole, was found to be more effective at lowering parasitemia in mice than either drug alone, as was the combination of clemastine and posaconazole. Using combinations of FDA-approved drugs is a promising strategy for developing new treatments for Chagas disease.

  15. Anticancer drugs in Portuguese surface waters - Estimation of concentrations and identification of potentially priority drugs.

    Science.gov (United States)

    Santos, Mónica S F; Franquet-Griell, Helena; Lacorte, Silvia; Madeira, Luis M; Alves, Arminda

    2017-10-01

    Anticancer drugs, used in chemotherapy, have emerged as new water contaminants due to their increasing consumption trends and poor elimination efficiency in conventional water treatment processes. As a result, anticancer drugs have been reported in surface and even drinking waters, posing the environment and human health at risk. However, the occurrence and distribution of anticancer drugs depend on the area studied and the hydrological dynamics, which determine the risk towards the environment. The main objective of the present study was to evaluate the risk of anticancer drugs in Portugal. This work includes an extensive analysis of the consumption trends of 171 anticancer drugs, sold or dispensed in Portugal between 2007 and 2015. The consumption data was processed aiming at the estimation of predicted environmental loads of anticancer drugs and 11 compounds were identified as potentially priority drugs based on an exposure-based approach (PECb> 10 ng L(-1) and/or PECc> 1 ng L(-1)). In a national perspective, mycophenolic acid and mycophenolate mofetil are suspected to pose high risk to aquatic biota. Moderate and low risk was also associated to cyclophosphamide and bicalutamide exposition, respectively. Although no evidences of risk exist yet for the other anticancer drugs, concerns may be associated with long term effects. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Assessment of potential drug-drug interactions and its associated factors in the hospitalized cardiac patients.

    Science.gov (United States)

    Murtaza, Ghulam; Khan, Muhammad Yasir Ghani; Azhar, Saira; Khan, Shujaat Ali; Khan, Tahir M

    2016-03-01

    Drug-drug interactions (DDIs) may result in the alteration of therapeutic response. Sometimes they may increase the untoward effects of many drugs. Hospitalized cardiac patients need more attention regarding drug-drug interactions due to complexity of their disease and therapeutic regimen. This research was performed to find out types, prevalence and association between various predictors of potential drug-drug interactions (pDDIs) in the Department of Cardiology and to report common interactions. This study was performed in the hospitalized cardiac patients at Ayub Teaching Hospital, Abbottabad, Pakistan. Patient charts of 2342 patients were assessed for pDDIs using Micromedex® Drug Information. Logistic regression was applied to find predictors of pDDIs. The main outcome measure in the study was the association of the potential drug-drug interactions with various factors such as age, gender, polypharmacy, and hospital stay of the patients. We identified 53 interacting-combinations that were present in total 5109 pDDIs with median number of 02 pDDIs per patient. Overall, 91.6% patients had at least one pDDI; 86.3% were having at least one major pDDI, and 84.5% patients had at least one moderate pDDI. Among 5109 identified pDDIs, most were of moderate (55%) or major severity (45%); established (24.2%), theoretical (18.8%) or probable (57%) type of scientific evidence. Top 10 common pDDIs included 3 major and 7 moderate interactions. Results obtained by multivariate logistic regression revealed a significant association of the occurrence of pDDIs in patient with age of 60 years or more (p < 0.001), hospital stay of 7 days or longer (p < 0.001) and taking 7 or more drugs (p < 0.001). We found a high prevalence for pDDIs in the Department of Cardiology, most of which were of moderate severity. Older patients, patients with longer hospital stay and with elevated number of prescribed drugs were at higher risk of pDDIs.

  17. Identifying drug-target proteins based on network features

    Institute of Scientific and Technical Information of China (English)

    ZHU MingZhu; GAO Lei; LI Xia; LIU ZhiCheng

    2009-01-01

    Proteins rarely function in isolation Inside and outside cells, but operate as part of a highly Intercon-nected cellular network called the interaction network. Therefore, the analysis of the properties of drug-target proteins in the biological network is especially helpful for understanding the mechanism of drug action In terms of informatice. At present, no detailed characterization and description of the topological features of drug-target proteins have been available in the human protein-protein interac-tion network. In this work, by mapping the drug-targets in DrugBank onto the interaction network of human proteins, five topological indices of drug-targets were analyzed and compared with those of the whole protein interactome set and the non-drug-target set. The experimental results showed that drug-target proteins have higher connectivity and quicker communication with each other in the PPI network. Based on these features, all proteins In the interaction network were ranked. The results showed that, of the top 100 proteins, 48 are covered by DrugBank; of the remaining 52 proteins, 9 are drug-target proteins covered by the TTD, Matador and other databases, while others have been dem-onstrated to be drug-target proteins in the literature.

  18. Identifying drug-target proteins based on network features

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Proteins rarely function in isolation inside and outside cells, but operate as part of a highly intercon- nected cellular network called the interaction network. Therefore, the analysis of the properties of drug-target proteins in the biological network is especially helpful for understanding the mechanism of drug action in terms of informatics. At present, no detailed characterization and description of the topological features of drug-target proteins have been available in the human protein-protein interac- tion network. In this work, by mapping the drug-targets in DrugBank onto the interaction network of human proteins, five topological indices of drug-targets were analyzed and compared with those of the whole protein interactome set and the non-drug-target set. The experimental results showed that drug-target proteins have higher connectivity and quicker communication with each other in the PPI network. Based on these features, all proteins in the interaction network were ranked. The results showed that, of the top 100 proteins, 48 are covered by DrugBank; of the remaining 52 proteins, 9 are drug-target proteins covered by the TTD, Matador and other databases, while others have been dem- onstrated to be drug-target proteins in the literature.

  19. Assessment of potential drug-drug interactions among outpatients receiving cardiovascular medications at Jimma University specialized hospital, South West Ethiopia

    Directory of Open Access Journals (Sweden)

    Legese Chelkeba

    2013-04-01

    Full Text Available Background: The quality of pharmacotherapy is highly dependent on the process of choosing a drug in relation to nature of the disease. Several factors should be considered in choosing optimal pharmacotherapeutics strategy including efficacy, safety, availability and cost of the drugs. The objective of this study was to assess potential drug-drug interactions and risk factors in outpatients taking cardiovascular drugs at Jimma University specialized hospital. Methods: A cross-sectional study was conducted from Feb. to April, 2011on patients visiting the cardiac clinic of Jimma University Specialized hospital. A sample of 332 outpatients who were taking cardiovascular medications at study clinic was studied. MicroMedex software was used to screen drug-drug interactions and SPSS for windows software versions-16.0 was used for data analysis. Results: A total of 1249 drugs with average of 3.76 drugs per prescription were prescribed for the 332 patients. The frequency of potential DDIs was found to be 241 (72.6%. Among these 200 (67.3% were of "moderate" severity and 164 (55.2% were delayed in onset. The most common potential DDI observed was between Enalapril and Furosemide (20%. Patients who prescribed many drugs (AOR=4.09; P=0.00 by medical intern had a higher risk of developing potential DDIs (AOR=4.6; P=0.00. Conclusions: Patients with cardiovascular disorders are subjected to high risk of potential drug-drug interactions and the number of drugs prescribed and educational level of the prescribers has a high significantly associated with the occurrence of potential drug-drug interactions. Therefore, it is imperative that further studies need to be conducted to identify reasons for and tackle the problem and provide appropriate mechanisms for management. [Int J Basic Clin Pharmacol 2013; 2(2.000: 144-152

  20. Modelling intelligence-led policing to identify its potential

    NARCIS (Netherlands)

    Hengst-Bruggeling, M. den; Graaf, H.A.L.M. de; Scheepstal, P.G.M. van

    2014-01-01

    lntelligence-led policing is a concept of policing that has been applied throughout the world. Despite some encouraging reports, the effect of intelligence-led policing is largely unknown. This paper presents a method with which it is possible to identify intelligence-led policing's potential to

  1. Modelling intelligence-led policing to identify its potential

    NARCIS (Netherlands)

    Hengst-Bruggeling, M. den; Graaf, H.A.L.M. de; Scheepstal, P.G.M. van

    2014-01-01

    lntelligence-led policing is a concept of policing that has been applied throughout the world. Despite some encouraging reports, the effect of intelligence-led policing is largely unknown. This paper presents a method with which it is possible to identify intelligence-led policing's potential to inc

  2. pH-dependent drug-drug interactions for weak base drugs: potential implications for new drug development.

    Science.gov (United States)

    Zhang, L; Wu, F; Lee, S C; Zhao, H; Zhang, L

    2014-08-01

    Absorption of an orally administered drug with pH-dependent solubility may be altered when it is coadministered with a gastric acid-reducing agent (ARA). Assessing a drug's potential for pH-dependent drug-drug interactions (DDIs), considering study design elements for such DDI studies, and interpreting and communicating study results in the drug labeling to guide drug dosing are important for drug development. We collected pertinent information related to new molecular entities approved from January 2003 to May 2013 by the US Food and Drug Administration for which clinical DDI studies with ARAs were performed. On the basis of assessments of data on pH solubility and in vivo DDIs with ARAs, we proposed a conceptual framework for assessing the need for clinical pH-dependent DDI studies for weak base drugs (WBDs). Important study design considerations include selection of ARAs and timing of dosing of an ARA relative to the WBD in a DDI study. Labeling implications for drugs having DDIs with ARAs are also illustrated.

  3. Potential drug-drug interactions in infant, child, and adolescent patients in children's hospitals.

    Science.gov (United States)

    Feinstein, James; Dai, Dingwei; Zhong, Wenjun; Freedman, Jason; Feudtner, Chris

    2015-01-01

    Hospitalized infants, children, and adolescents are typically exposed to numerous distinct medications during inpatient admissions, increasing their risk of potential drug-drug interactions (PDDIs). We assessed the prevalence and characteristics of PDDI exposure of pediatric patients treated in children's hospitals. This retrospective cohort study included patients hospitalized in children's hospitals throughout the United States. PDDIs were identified by using the MicroMedex DRUG-REAX system. We calculated the patients exposed to PDDIs, stratified according to the seriousness of the interaction; daily and cumulative counts of PDDI exposures; and characterization of the cited potential adverse effects. Of 498 956 hospitalizations in 2011, 49% were associated with ≥1 PDDI, with a "contraindicated" PDDI occurring in 5% of all hospitalizations, a "major" PDDI present in 41%, a "moderate" PDDI in 28%, and a "minor" PDDI in 11%. Opioids were involved in 25% of all PDDIs, followed by antiinfective agents (17%), neurologic agents (15%), gastrointestinal agents (13%), and cardiovascular agents (13%). One-half of all PDDI exposures were due to specific drug pairs occurring in ≤3% of patients per hospital day. The most common potential adverse drug events included additive respiratory depression (in 21% of PDDIs), bleeding risk (5%), QT interval prolongation (4%), reduced iron absorption/availability (4%), central nervous system depression (4%), hyperkalemia (3%), and altered diuretic effectiveness (3%). Exposure to PDDIs is common among hospitalized children. Empirical data are needed to determine the probability and magnitude of the actual harm for each specific PDDI, particularly for less common drug pairs. Copyright © 2015 by the American Academy of Pediatrics.

  4. Microspheres a potential carrier for drugs

    Directory of Open Access Journals (Sweden)

    Abdul Majeed

    2015-01-01

    Full Text Available Microparticles are one of the recent controlled release dosage form, compressed in the form of tablets or filled in capsules. In this review different methods of preparations and their effects on physical properties i.e. Size, shape and porosity which can be controlled by ingredients used or process variables and characterization will be discussed. Future dimensions of these dosage forms are numerous when it comes to its application in drug delivery and to overcome issues associated with new drug molecule in drug discovery process.

  5. Antibody Arrays Identify Potential Diagnostic Markers of Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Brian J. Peter

    2008-01-01

    Full Text Available Hepatocellular carcinoma (HCC is the third leading cause of cancer deaths worldwide. Effective treatment of HCC patients is hampered by the lack of sensitive and specific diagnostic markers of HCC. Alpha-fetoprotein (AFP, the currently used HCC marker, misses 30%–50% of HCC patients, who therefore remain undiagnosed and untreated. In order to identify novel diagnostic markers that can be used individually or in combination with AFP, we used an antibody array platform to detect the levels of candidate proteins in the plasma of HCC patients (n = 48 and patients with chronic hepatitis B or C viral infections (n = 19 (both of which are the major risk factors of HCC. We identified 7 proteins that significantly differentiate HCC patients from hepatitis patients (p < 0.05 (AFP, CTNNB, CSF1, SELL, IGFBP6, IL6R, and VCAM1.Importantly, we also identified 8 proteins that significantly differentiate HCC patients with ‘normal’ levels of AFP (<20 ng/ml from hepatitis patients (p < 0.05 (IL1RN, IFNG, CDKN1A, RETN, CXCL14, CTNNB, FGF2, and SELL. These markers are potentially important complementary markers to AFP. Using an independent immunoassay method in an independent group of 23 HCC patients and 22 hepatitis patients, we validated that plasma levels of CTNNB were significantly higher in the HCC group (p = 0.020. In conclusion, we used an antibody array platform to identify potential circulating diagnostic markers of HCC, some of which may be valuable when used in combination with AFP. The clinical utility of these newly identified HCC diagnostic markers needs to be systematically evaluated.

  6. A study of potential drug-drug interactions among hospitalized cardiac patients in a teaching hospital in Western Nepal

    Directory of Open Access Journals (Sweden)

    Sushmita Sharma

    2014-01-01

    Full Text Available Aim: Drug-drug interaction (DDI is of major concern in patients with complex therapeutic regimens. The involvement of cardiovascular medicines in drug interaction is even higher. However, reports of DDI between these groups of drugs are few. The study aims to identify the potential DDI among hospitalized cardiac patients. Furthermore, we assessed the possible risk factors associated with these interactions. Subjects and Methods: The prospective observational study was conducted from May 2012 to August 2012 among hospitalized cardiac patients. Cardiac patients who were taking at least two drugs and who had a hospital stay of at least 24 h were enrolled. The medications of the patients were analyzed for possible interactions using the standard drug interaction database - Micromedex -2 (Thomson Reuters × 2.0. Results: From a total of 150 enrolled patients, at least one interacting drug combination was identified among 32 patients. The incidence of potential DDI was 21.3%. A total of 48 potentially hazardous drug interactions were identified. Atorvastatin/azithromycin (10.4%, enalapril/metformin (10.4%, enalapril/potassium chloride (10.4%, atorvastatin/clarithromycin (8.3% and furosemide/gentamicin (6.3% were the most common interacting pairs. Drugs most commonly involved were atorvastatin, enalapril, digoxin, furosemide, clopidogrel and warfarin. Majority of interactions were of moderate severity (62.5% and pharmacokinetic (58.3% in nature. Increased number of medicines, prolonged hospital stays and comorbid conditions were the risk factors found associated with the potential DDI. Conclusions: This study highlighted the need of intense monitoring of patients who have identified risk factors to help detect and prevent them from serious health hazards associated with drug interactions.

  7. Therapeutic potential of cannabinoid-based drugs.

    Science.gov (United States)

    Klein, Thomas W; Newton, Catherine A

    2007-01-01

    Cannabinoid-based drugs modeled on cannabinoids originally isolated from marijuana are now known to significantly impact the functioning of the endocannabinoid system of mammals. This system operates not only in the brain but also in organs and tissues in the periphery including the immune system. Natural and synthetic cannabinoids are tricyclic terpenes, whereas the endogenous physiological ligands are eicosanoids. Several receptors for these compounds have been extensively described, CB1 and CB2, and are G protein-coupled receptors; however, cannabinoid-based drugs are also demonstrated to function independently of these receptors. Cannabinoids regulate many physiological functions and their impact on immunity is generally antiinflammatory as powerful modulators of the cytokine cascade. This anti-inflammatory potency has led to the testing of these drugs in chronic inflammatory laboratory paradigms and even in some human diseases. Psychoactive and nonpsychoactive cannabinoid-based drugs such as Delta9-tetrahydrocannabinol, cannabidiol, HU-211, and ajulemic acid have been tested and found moderately effective in clinical trials of multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain. Furthermore, although clinical trials are not yet reported, preclinical data with cannabinoid-based drugs suggest efficacy in other inflammatory diseases such as inflammatory bowel disease, Alzheimer's disease, atherosclerosis, and osteoporosis.

  8. COUNTERFEIT (FAKE DRUGS & NEW TECHNOLOGIES TO IDENTIFY IT IN INDIA

    Directory of Open Access Journals (Sweden)

    P. Gupta*, K. Singhal and A. Pandey

    2012-11-01

    Full Text Available A counterfeit medicine is one which is deliberately and fraudulently mislabeled with respect to identity or source. Counterfeiting apply to both branded and generic product which include products with the wrong ingredients, without active ingredients, with insufficient active ingredients. According to WHO, 25% of medicines consumed in poor countries could be counterfeit or below standard.An estimate suggests that these drugs are a $200 billion industry worldwide. India could be an easy target for counterfeits, as the manufacturing costs is 40% cheaper here as compared to other countries. Deputy drug controller general of India says, counterfeit medicines often resemble the originals in chemical composition, but he thinks the biggest problem is in the packaging. A committee set up by the Indian Ministry of Health has approved a proposal to put 2D bar codes and scratch-off labels on medicines. The user scratches off the cover and tests what is underneath to a free phone number, to find out if a pill is real. Quick Response (QR codes are also being tested. These printed squares are an advanced version of the 2D bar codes. Anyone with a camera-enabled phone and web access can scan the code and be taken instantly to the pharmacy company website to authenticate the drug. The uses of holograms, tracers, traggants and inks, plastic tags, radio frequency identification, mass encryption technology are some other techniques to limit the counterfeiting of drugs.

  9. TCGA researchers identify potential drug targets, markers for leukemia risk

    Science.gov (United States)

    Investigators for The Cancer Genome Atlas (TCGA) Research Network have detailed and broadly classified the genomic alterations that frequently underlie the development of acute myeloid leukemia (AML), a deadly cancer of the blood and bone marrow. Their wo

  10. Network-Assisted Prediction of Potential Drugs for Addiction

    OpenAIRE

    Jingchun Sun; Liang-Chin Huang; Hua Xu; Zhongming Zhao

    2014-01-01

    Drug addiction is a chronic and complex brain disease, adding much burden on the community. Though numerous efforts have been made to identify the effective treatment, it is necessary to find more novel therapeutics for this complex disease. As network pharmacology has become a promising approach for drug repurposing, we proposed to apply the approach to drug addiction, which might provide new clues for the development of effective addiction treatment drugs. We first extracted 44 addictive dr...

  11. Carbon nanotubes buckypapers for potential transdermal drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Schwengber, Alex [PINMATE-Departamento de Industrias, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, C1428EGA Buenos Aires (Argentina); Prado, Héctor J. [PINMATE-Departamento de Industrias, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, C1428EGA Buenos Aires (Argentina); Cátedra de Tecnología Farmacéutica II, Departamento de Tecnología Farmacéutica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, C1113AAD Buenos Aires (Argentina); Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Av. Rivadavia 1917, C1033AAJ Buenos Aires (Argentina); Zilli, Darío A. [PINMATE-Departamento de Industrias, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, C1428EGA Buenos Aires (Argentina); Bonelli, Pablo R. [PINMATE-Departamento de Industrias, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, C1428EGA Buenos Aires (Argentina); Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Av. Rivadavia 1917, C1033AAJ Buenos Aires (Argentina); and others

    2015-12-01

    Drug loaded buckypapers based on different types of carbon nanotubes (CNTs) were prepared and characterized in order to evaluate their potentialities for the design of novel transdermal drug delivery systems. Lab-synthesized CNTs as well as commercial samples were employed. Clonidine hydrochloride was used as model drug, and the influence of composition of the drug loaded buckypapers and processing variables on in vitro release profiles was investigated. To examine the influence of the drug nature the evaluation was further extended to buckypapers prepared with flurbiprofen and one type of CNTs, their selection being based on the results obtained with the former drug. Scanning electronic microscopy images indicated that the model drugs were finely dispersed on the CNTs. Differential scanning calorimetry, and X-ray diffraction pointed to an amorphous state of both drugs in the buckypapers. A higher degree of CNT–drug superficial interactions resulted in a slower release of the drug. These interactions were in turn affected by the type of CNTs employed (single wall or multiwall CNTs), their functionalization with hydroxyl or carboxyl groups, the chemical structure of the drug, and the CNT:drug mass ratio. Furthermore, the application of a second layer of drug free CNTs on the loaded buckypaper, led to decelerate the drug release and to reduce the burst effect. - Highlights: • Drug loaded buckypapers from carbon nanotubes were prepared and characterized. • Their potentialities for transdermal drug delivery applications were evaluated. • Characteristics of carbon nanotubes and the structure of the drug affected release • A higher carbon nanotube:drug mass ratio decelerated release • Up to one week controlled release profiles were obtained for the drug flurbiprofen.

  12. Potent Inhibitor of Drug-Resistant HIV-1 Strains Identified from the Medicinal Plant Justicia gendarussa.

    Science.gov (United States)

    Zhang, Hong-Jie; Rumschlag-Booms, Emily; Guan, Yi-Fu; Wang, Dong-Ying; Liu, Kang-Lun; Li, Wan-Fei; Nguyen, Van H; Cuong, Nguyen M; Soejarto, Djaja D; Fong, Harry H S; Rong, Lijun

    2017-06-23

    Justicia gendarussa, a medicinal plant collected in Vietnam, was identified as a potent anti-HIV-1 active lead from the evaluation of over 4500 plant extracts. Bioassay-guided separation of the extracts of the stems and roots of this plant led to the isolation of an anti-HIV arylnaphthalene lignan (ANL) glycoside, patentiflorin A (1). Evaluation of the compound against both the M- and T-tropic HIV-1 isolates showed it to possess a significantly higher inhibition effect than the clinically used anti-HIV drug AZT. Patentiflorin A and two congeners were synthesized, de novo, as an efficient strategy for resupply as well as for further structural modification of the anti-HIV ANL glycosides in the search for drug leads. Subsequently, it was determined that the presence of a quinovopyranosyloxy group in the structure is likely essential to retain the high degree of anti-HIV activity of this type of compounds. Patentiflorin A was further investigated against the HIV-1 gene expression of the R/U5 and U5/gag transcripts, and the data showed that the compound acts as a potential inhibitor of HIV-1 reverse transcription. Importantly, the compound displayed potent inhibitory activity against drug-resistant HIV-1 isolates of both the nucleotide analogue (AZT) and non-nucleotide analogue (nevaripine). Thus, the ANL glycosides have the potential to be developed as novel anti-HIV drugs.

  13. Identifying Potential Norovirus Epidemics in China via Internet Surveillance

    Science.gov (United States)

    Chen, Bin; Jiang, Tao; Cai, Gaofeng; Jiang, Zhenggang; Chen, Yongdi; Wang, Zhengting; Gu, Hua; Chai, Chengliang

    2017-01-01

    Background Norovirus is a common virus that causes acute gastroenteritis worldwide, but a monitoring system for norovirus is unavailable in China. Objective We aimed to identify norovirus epidemics through Internet surveillance and construct an appropriate model to predict potential norovirus infections. Methods The norovirus-related data of a selected outbreak in Jiaxing Municipality, Zhejiang Province of China, in 2014 were collected from immediate epidemiological investigation, and the Internet search volume, as indicated by the Baidu Index, was acquired from the Baidu search engine. All correlated search keywords in relation to norovirus were captured, screened, and composited to establish the composite Baidu Index at different time lags by Spearman rank correlation. The optimal model was chosen and possibly predicted maps in Zhejiang Province were presented by ArcGIS software. Results The combination of two vital keywords at a time lag of 1 day was ultimately identified as optimal (ρ=.924, Ptimes during the outbreak. In addition to Jiaxing Municipality, Hangzhou Municipality might have had some potential epidemics in the study time from the predicted model. Conclusions Although there are limitations with early warning and unavoidable biases, Internet surveillance may be still useful for the monitoring of norovirus epidemics when a monitoring system is unavailable. PMID:28790023

  14. Drug discrimination: A versatile tool for characterization of CNS safety pharmacology and potential for drug abuse.

    Science.gov (United States)

    Swedberg, Michael D B

    2016-01-01

    Drug discrimination studies for assessment of psychoactive properties of drugs in safety pharmacology and drug abuse and drug dependence potential evaluation have traditionally been focused on testing novel compounds against standard drugs for which drug abuse has been documented, e.g. opioids, CNS stimulants, cannabinoids etc. (e.g. Swedberg & Giarola, 2015), and results are interpreted such that the extent to which the test drug causes discriminative effects similar to those of the standard training drug, the test drug would be further characterized as a potential drug of abuse. Regulatory guidance for preclinical assessment of abuse liability by the European Medicines Agency (EMA, 2006), the U.S. Food and Drug Administration (FDA, 2010), the International Conference of Harmonization (ICH, 2009), and the Japanese Ministry of Health Education and Welfare (MHLW, 1994) detail that compounds with central nervous system (CNS) activity, whether by design or not, need abuse and dependence liability assessment. Therefore, drugs with peripheral targets and a potential to enter the CNS, as parent or metabolite, are also within scope (see Swedberg, 2013, for a recent review and strategy). Compounds with novel mechanisms of action present a special challenge due to unknown abuse potential, and should be carefully assessed against defined risk criteria. Apart from compounds sharing mechanisms of action with known drugs of abuse, compounds intended for indications currently treated with drugs with potential for abuse and or dependence are also within scope, regardless of mechanism of action. Examples of such compounds are analgesics, anxiolytics, cognition enhancers, appetite control drugs, sleep control drugs and drugs for psychiatric indications. Recent results (Swedberg et al., 2014; Swedberg & Raboisson, 2014; Swedberg, 2015) on the metabotropic glutamate receptor type 5 (mGluR5) antagonists demonstrate that compounds causing hallucinatory effects in humans did not exhibit

  15. Identifying the Right Disease Targets to Develop Better Drugs, Faster | NIH MedlinePlus the Magazine

    Science.gov (United States)

    ... JavaScript on. Identifying the Right Disease Targets to Develop Better Drugs, Faster Past Issues / Spring 2014 Table ... a-dozen pharmaceutical companies are now racing to develop drugs that lower cholesterol by blocking PCSK9. Are ...

  16. Developmental Potential for Endomorphin Opioidmimetic Drugs

    Directory of Open Access Journals (Sweden)

    Yoshio Okada

    2012-01-01

    Full Text Available Morphine, which is agonist for μ-opioid receptors, has been used as an anti-pain drug for millennia. The opiate antagonists, naloxone and naltrexone, derived from morphine, were employed for drug addiction and alcohol abuse. However, these exogenous agonists and antagonists exhibit numerous and unacceptable side effects. Of the endogenous opioid peptides, endomorphin(EM-1 and endomorphin(EM-2 with their high μ-receptor affinity and exceptionally high selectivity relative to δ- and κ-receptors in vitro and in vivo provided a sufficiently sequence-flexible entity in order to prepare opioid-based drugs. We took advantage of this unique feature of the endomorphins by exchanging the N-terminal residue Tyr1 with 2′,6′-dimethyl-L-tyrosine (Dmt to increase their stability and the spectrum of bioactivity. We systematically altered specific residues of [Dmt1]EM-1 and [Dmt1]EM-2 to produce various analogues. Of these analogues, [N-allyl-Dmt1]EM-1 (47 and [N-allyl-Dmt1]EM-2 (48 exhibited potent and selective antagonism to μ-receptors: they completely inhibited naloxone- and naltrexone-induced withdrawal from following acute morphine dependency in mice and reversed the alcohol-induced changes observed in sIPSC in hippocampal slices. Overall, we developed novel and efficacious opioid drugs without deleterious side effects that were able to resist enzymatic degradation and were readily transported intact through epithelial membranes in the gastrointestinal tract and the blood-brain-barrier.

  17. Carbon nanotubes buckypapers for potential transdermal drug delivery.

    Science.gov (United States)

    Schwengber, Alex; Prado, Héctor J; Zilli, Darío A; Bonelli, Pablo R; Cukierman, Ana L

    2015-12-01

    Drug loaded buckypapers based on different types of carbon nanotubes (CNTs) were prepared and characterized in order to evaluate their potentialities for the design of novel transdermal drug delivery systems. Lab-synthesized CNTs as well as commercial samples were employed. Clonidine hydrochloride was used as model drug, and the influence of composition of the drug loaded buckypapers and processing variables on in vitro release profiles was investigated. To examine the influence of the drug nature the evaluation was further extended to buckypapers prepared with flurbiprofen and one type of CNTs, their selection being based on the results obtained with the former drug. Scanning electronic microscopy images indicated that the model drugs were finely dispersed on the CNTs. Differential scanning calorimetry, and X-ray diffraction pointed to an amorphous state of both drugs in the buckypapers. A higher degree of CNT-drug superficial interactions resulted in a slower release of the drug. These interactions were in turn affected by the type of CNTs employed (single wall or multiwall CNTs), their functionalization with hydroxyl or carboxyl groups, the chemical structure of the drug, and the CNT:drug mass ratio. Furthermore, the application of a second layer of drug free CNTs on the loaded buckypaper, led to decelerate the drug release and to reduce the burst effect.

  18. The potential biomarkers of drug addiction: proteomic and metabolomics challenges.

    Science.gov (United States)

    Wang, Lv; Wu, Ning; Zhao, Tai-Yun; Li, Jin

    2016-07-28

    Drug addiction places a significant burden on society and individuals. Proteomics and metabolomics approaches pave the road for searching potential biomarkers to assist the diagnosis and treatment. This review summarized putative drug addiction-related biomarkers in proteomics and metabolomics studies and discussed challenges and prospects in future studies. Alterations of several hundred proteins and metabolites were reported when exposure to abused drug, which enriched in energy metabolism, oxidative stress response, protein modification and degradation, synaptic function and neurotrasmission, etc. Hsp70, peroxiredoxin-6 and α- and β-synuclein, as well as n-methylserotonin and purine metabolites, were promising as potential biomarker for drug addiction.

  19. Using SCOPE to identify potential regulatory motifs in coregulated genes.

    Science.gov (United States)

    Martyanov, Viktor; Gross, Robert H

    2011-05-31

    SCOPE is an ensemble motif finder that uses three component algorithms in parallel to identify potential regulatory motifs by over-representation and motif position preference. Each component algorithm is optimized to find a different kind of motif. By taking the best of these three approaches, SCOPE performs better than any single algorithm, even in the presence of noisy data. In this article, we utilize a web version of SCOPE to examine genes that are involved in telomere maintenance. SCOPE has been incorporated into at least two other motif finding programs and has been used in other studies. The three algorithms that comprise SCOPE are BEAM, which finds non-degenerate motifs (ACCGGT), PRISM, which finds degenerate motifs (ASCGWT), and SPACER, which finds longer bipartite motifs (ACCnnnnnnnnGGT). These three algorithms have been optimized to find their corresponding type of motif. Together, they allow SCOPE to perform extremely well. Once a gene set has been analyzed and candidate motifs identified, SCOPE can look for other genes that contain the motif which, when added to the original set, will improve the motif score. This can occur through over-representation or motif position preference. Working with partial gene sets that have biologically verified transcription factor binding sites, SCOPE was able to identify most of the rest of the genes also regulated by the given transcription factor. Output from SCOPE shows candidate motifs, their significance, and other information both as a table and as a graphical motif map. FAQs and video tutorials are available at the SCOPE web site which also includes a "Sample Search" button that allows the user to perform a trial run. Scope has a very friendly user interface that enables novice users to access the algorithm's full power without having to become an expert in the bioinformatics of motif finding. As input, SCOPE can take a list of genes, or FASTA sequences. These can be entered in browser text fields, or read from

  20. Identifying Potential Regions of Copy Number Variation for Bipolar Disorder

    Directory of Open Access Journals (Sweden)

    Yi-Hsuan Chen

    2014-02-01

    Full Text Available Bipolar disorder is a complex psychiatric disorder with high heritability, but its genetic determinants are still largely unknown. Copy number variation (CNV is one of the sources to explain part of the heritability. However, it is a challenge to estimate discrete values of the copy numbers using continuous signals calling from a set of markers, and to simultaneously perform association testing between CNVs and phenotypic outcomes. The goal of the present study is to perform a series of data filtering and analysis procedures using a DNA pooling strategy to identify potential CNV regions that are related to bipolar disorder. A total of 200 normal controls and 200 clinically diagnosed bipolar patients were recruited in this study, and were randomly divided into eight control and eight case pools. Genome-wide genotyping was employed using Illumina Human Omni1-Quad array with approximately one million markers for CNV calling. We aimed at setting a series of criteria to filter out the signal noise of marker data and to reduce the chance of false-positive findings for CNV regions. We first defined CNV regions for each pool. Potential CNV regions were reported based on the different patterns of CNV status between cases and controls. Genes that were mapped into the potential CNV regions were examined with association testing, Gene Ontology enrichment analysis, and checked with existing literature for their associations with bipolar disorder. We reported several CNV regions that are related to bipolar disorder. Two CNV regions on chromosome 11 and 22 showed significant signal differences between cases and controls (p < 0.05. Another five CNV regions on chromosome 6, 9, and 19 were overlapped with results in previous CNV studies. Experimental validation of two CNV regions lent some support to our reported findings. Further experimental and replication studies could be designed for these selected regions.

  1. A physarum-inspired prize-collecting steiner tree approach to identify subnetworks for drug repositioning.

    Science.gov (United States)

    Sun, Yahui; Hameed, Pathima Nusrath; Verspoor, Karin; Halgamuge, Saman

    2016-12-05

    Drug repositioning can reduce the time, costs and risks of drug development by identifying new therapeutic effects for known drugs. It is challenging to reposition drugs as pharmacological data is large and complex. Subnetwork identification has already been used to simplify the visualization and interpretation of biological data, but it has not been applied to drug repositioning so far. In this paper, we fill this gap by proposing a new Physarum-inspired Prize-Collecting Steiner Tree algorithm to identify subnetworks for drug repositioning. Drug Similarity Networks (DSN) are generated using the chemical, therapeutic, protein, and phenotype features of drugs. In DSNs, vertex prizes and edge costs represent the similarities and dissimilarities between drugs respectively, and terminals represent drugs in the cardiovascular class, as defined in the Anatomical Therapeutic Chemical classification system. A new Physarum-inspired Prize-Collecting Steiner Tree algorithm is proposed in this paper to identify subnetworks. We apply both the proposed algorithm and the widely-used GW algorithm to identify subnetworks in our 18 generated DSNs. In these DSNs, our proposed algorithm identifies subnetworks with an average Rand Index of 81.1%, while the GW algorithm can only identify subnetworks with an average Rand Index of 64.1%. We select 9 subnetworks with high Rand Index to find drug repositioning opportunities. 10 frequently occurring drugs in these subnetworks are identified as candidates to be repositioned for cardiovascular diseases. We find evidence to support previous discoveries that nitroglycerin, theophylline and acarbose may be able to be repositioned for cardiovascular diseases. Moreover, we identify seven previously unknown drug candidates that also may interact with the biological cardiovascular system. These discoveries show our proposed Prize-Collecting Steiner Tree approach as a promising strategy for drug repositioning.

  2. Potential of metabolomics in preclinical and clinical drug development.

    Science.gov (United States)

    Kumar, Baldeep; Prakash, Ajay; Ruhela, Rakesh Kumar; Medhi, Bikash

    2014-12-01

    Metabolomics is an upcoming technology system which involves detailed experimental analysis of metabolic profiles. Due to its diverse applications in preclinical and clinical research, it became an useful tool for the drug discovery and drug development process. This review covers the brief outline about the instrumentation and interpretation of metabolic profiles. The applications of metabolomics have a considerable scope in the pharmaceutical industry, almost at each step from drug discovery to clinical development. These include finding drug target, potential safety and efficacy biomarkers and mechanisms of drug action, the validation of preclinical experimental models against human disease profiles, and the discovery of clinical safety and efficacy biomarkers. As we all know, nowadays the drug discovery and development process is a very expensive, and risky business. Failures at any stage of drug discovery and development process cost millions of dollars to the companies. Some of these failures or the associated risks could be prevented or minimized if there were better ways of drug screening, drug toxicity profiling and monitoring adverse drug reactions. Metabolomics potentially offers an effective route to address all the issues associated with the drug discovery and development. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  3. Acid-Sensitive Magnetic Nanoparticles as Potential Drug Depots.

    Science.gov (United States)

    Wuang, Shy Chyi; Neoh, Koon Gee; Kang, En-Tang; Leckband, Deborah E; Pack, Daniel W

    2011-06-01

    Superparamagnetic magnetic nanoparticles were successfully functionalized with poly(methacrylic acid) via atom transfer radical polymerization, followed by conjugation to doxorubicin (Dox). Because of pH-sensitive hydrazone linkages, the rate and extent of Dox release from the particles was higher at a lower pH and/or a higher temperature than at physiological conditions. Appropriate changes to the pH and temperature can increase the drug release from the particles. Because of the released drug, the particles were found to be cytotoxic to human breast cancer cells in vitro. Such magnetic nanoparticles, with the potential to retain drug under physiological conditions and release the drug in conditions where the pH is lower or temperature is higher, may be useful in magnetic drug targeting by reducing the side effects of the drug caused to healthy tissues. In addition, they may serve as hyperthermia agents where the high temperatures used in hyperthermia can trigger further drug release.

  4. Are isothiocyanates potential anti-cancer drugs?

    Institute of Scientific and Technical Information of China (English)

    Xiang WU; Qing-hua ZHOU; Ke XU

    2009-01-01

    Isothiocyanates are naturally occurring small molecules that are formed from glucosinolate precursors of cruciferous vegetables. Many isothiocyanates, both natural and synthetic, display anticarcinogenic activity because they reduce activation of carcinogens and increase their detoxification. Recent studies show that they exhibit anti-tumor activity by affecting multiple pathways including apoptosis, MAPK signaling, oxidative stress, and cell cycle progression. This review summarizes the current knowledge on isothiocyanates and focuses on their role as potential anti-cancer agents.

  5. Potential drug-drug and drug-disease interactions in prescriptions for ambulatory patients over 50 years of age in family medicine clinics in Mexico City

    Directory of Open Access Journals (Sweden)

    Torres-Arreola Laura del Pilar

    2007-09-01

    Full Text Available Abstract Background In Mexico, inappropriate prescription of drugs with potential interactions causing serious risks to patient health has been little studied. Work in this area has focused mainly on hospitalized patients, with only specific drug combinations analyzed; moreover, the studies have not produced conclusive results. In the present study, we determined the frequency of potential drug-drug and drug-disease interactions in prescriptions for ambulatory patients over 50 years of age, who used Mexican Institute of Social Security (IMSS family medicine clinics. In addition, we aimed to identify the associated factors for these interactions. Methods We collected information on general patient characteristics, medical histories, and medication (complete data. The study included 624 ambulatory patients over 50 years of age, with non-malignant pain syndrome, who made ambulatory visits to two IMSS family medicine clinics in Mexico City. The patients received 7-day prescriptions for non-opioid analgesics. The potential interactions were identified by using the Thompson Micromedex program. Data were analyzed using descriptive, bivariate and multiple logistic regression analyses. Results The average number of prescribed drugs was 5.9 ± 2.5. About 80.0% of patients had prescriptions implying one or more potential drug-drug interactions and 3.8% of patients were prescribed drug combinations with interactions that should be avoided. Also, 64.0% of patients had prescriptions implying one or more potential drug disease interactions. The factors significantly associated with having one or more potential interactions included: taking 5 or more medicines (adjusted Odds Ratio (OR: 4.34, 95%CI: 2.76–6.83, patient age 60 years or older (adjusted OR: 1.66, 95% CI: 1.01–2.74 and suffering from cardiovascular diseases (adjusted OR: 7.26, 95% CI: 4.61–11.44. Conclusion The high frequency of prescription of drugs with potential drug interactions showed in

  6. Chemical biology drug sensitivity screen identifies sunitinib as synergistic agent with disulfiram in prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Kirsi Ketola

    Full Text Available BACKGROUND: Current treatment options for castration- and treatment-resistant prostate cancer are limited and novel approaches are desperately needed. Our recent results from a systematic chemical biology sensitivity screen covering most known drugs and drug-like molecules indicated that aldehyde dehydrogenase inhibitor disulfiram is one of the most potent cancer-specific inhibitors of prostate cancer cell growth, including TMPRSS2-ERG fusion positive cancers. However, the results revealed that disulfiram alone does not block tumor growth in vivo nor induce apoptosis in vitro, indicating that combinatorial approaches may be required to enhance the anti-neoplastic effects. METHODS AND FINDINGS: In this study, we utilized a chemical biology drug sensitivity screen to explore disulfiram mechanistic details and to identify compounds potentiating the effect of disulfiram in TMPRSS2-ERG fusion positive prostate cancer cells. In total, 3357 compounds including current chemotherapeutic agents as well as drug-like small molecular compounds were screened alone and in combination with disulfiram. Interestingly, the results indicated that androgenic and antioxidative compounds antagonized disulfiram effect whereas inhibitors of receptor tyrosine kinase, proteasome, topoisomerase II, glucosylceramide synthase or cell cycle were among compounds sensitizing prostate cancer cells to disulfiram. The combination of disulfiram and an antiangiogenic agent sunitinib was studied in more detail, since both are already in clinical use in humans. Disulfiram-sunitinib combination induced apoptosis and reduced androgen receptor protein expression more than either of the compounds alone. Moreover, combinatorial exposure reduced metastatic characteristics such as cell migration and 3D cell invasion as well as induced epithelial differentiation shown as elevated E-cadherin expression. CONCLUSIONS: Taken together, our results propose novel combinatorial approaches to inhibit

  7. Chemical Biology Drug Sensitivity Screen Identifies Sunitinib as Synergistic Agent with Disulfiram in Prostate Cancer Cells

    Science.gov (United States)

    Ketola, Kirsi; Kallioniemi, Olli; Iljin, Kristiina

    2012-01-01

    Background Current treatment options for castration- and treatment-resistant prostate cancer are limited and novel approaches are desperately needed. Our recent results from a systematic chemical biology sensitivity screen covering most known drugs and drug-like molecules indicated that aldehyde dehydrogenase inhibitor disulfiram is one of the most potent cancer-specific inhibitors of prostate cancer cell growth, including TMPRSS2-ERG fusion positive cancers. However, the results revealed that disulfiram alone does not block tumor growth in vivo nor induce apoptosis in vitro, indicating that combinatorial approaches may be required to enhance the anti-neoplastic effects. Methods and Findings In this study, we utilized a chemical biology drug sensitivity screen to explore disulfiram mechanistic details and to identify compounds potentiating the effect of disulfiram in TMPRSS2-ERG fusion positive prostate cancer cells. In total, 3357 compounds including current chemotherapeutic agents as well as drug-like small molecular compounds were screened alone and in combination with disulfiram. Interestingly, the results indicated that androgenic and antioxidative compounds antagonized disulfiram effect whereas inhibitors of receptor tyrosine kinase, proteasome, topoisomerase II, glucosylceramide synthase or cell cycle were among compounds sensitizing prostate cancer cells to disulfiram. The combination of disulfiram and an antiangiogenic agent sunitinib was studied in more detail, since both are already in clinical use in humans. Disulfiram-sunitinib combination induced apoptosis and reduced androgen receptor protein expression more than either of the compounds alone. Moreover, combinatorial exposure reduced metastatic characteristics such as cell migration and 3D cell invasion as well as induced epithelial differentiation shown as elevated E-cadherin expression. Conclusions Taken together, our results propose novel combinatorial approaches to inhibit prostate cancer cell

  8. Clinical Drug-Drug Pharmacokinetic Interaction Potential of Sucralfate with Other Drugs

    DEFF Research Database (Denmark)

    Sulochana, Suresh P; Syed, Muzeeb; Chandrasekar, Devaraj V

    2016-01-01

    of drugs. This review covers several category of drugs such as non-steroidal anti-inflammatory drugs, fluoroquinolones, histamine H2-receptor blockers, macrolides, anti-fungals, anti-diabetics, salicylic acid derivatives, steroidal anti-inflammatory drugs and provides pharmacokinetic data summary along...

  9. Rapid, computer vision-enabled murine screening system identifies neuropharmacological potential of two new mechanisms

    Directory of Open Access Journals (Sweden)

    Steven L Roberds

    2011-09-01

    Full Text Available The lack of predictive in vitro models for behavioral phenotypes impedes rapid advancement in neuropharmacology and psychopharmacology. In vivo behavioral assays are more predictive of activity in human disorders, but such assays are often highly resource-intensive. Here we describe the successful application of a computer vision-enabled system to identify potential neuropharmacological activity of two new mechanisms. The analytical system was trained using multiple drugs that are used clinically to treat depression, schizophrenia, anxiety, and other psychiatric or behavioral disorders. During blinded testing the PDE10 inhibitor TP-10 produced a signature of activity suggesting potential antipsychotic activity. This finding is consistent with TP-10’s activity in multiple rodent models that is similar to that of clinically used antipsychotic drugs. The CK1ε inhibitor PF-670462 produced a signature consistent with anxiolytic activity and, at the highest dose tested, behavioral effects similar to that of opiate analgesics. Neither TP-10 nor PF-670462 was included in the training set. Thus, computer vision-based behavioral analysis can facilitate drug discovery by identifying neuropharmacological effects of compounds acting through new mechanisms.

  10. NMR characterisation and transdermal drug delivery potential of microemulsion systems

    DEFF Research Database (Denmark)

    Kreilgaard, Mads; Pedersen, E J; Jaroszewski, J W

    2000-01-01

    The purpose of this study was to investigate the influence of structure and composition of microemulsions (Labrasol/Plurol Isostearique/isostearylic isostearate/water) on their transdermal delivery potential of a lipophilic (lidocaine) and a hydrophilic model drug (prilocaine hydrochloride......), and to compare the drug delivery potential of microemulsions to conventional vehicles. Self-diffusion coefficients determined by pulsed-gradient spin-echo NMR spectroscopy and T(1) relaxation times were used to characterise the microemulsions. Transdermal flux of lidocaine and prilocaine hydrochloride through...... and transdermal flux was indicated. The increased transdermal drug delivery from microemulsion formulations was found to be due mainly to the increased solubility of drugs and appeared to be dependent on the drug mobility in the individual vehicle. The microemulsions did not perturb the skin barrier, indicating...

  11. An update on the use of C. elegans for preclinical drug discovery: screening and identifying anti-infective drugs.

    Science.gov (United States)

    Kim, Wooseong; Hendricks, Gabriel Lambert; Lee, Kiho; Mylonakis, Eleftherios

    2017-06-01

    The emergence of antibiotic-resistant and -tolerant bacteria is a major threat to human health. Although efforts for drug discovery are ongoing, conventional bacteria-centered screening strategies have thus far failed to yield new classes of effective antibiotics. Therefore, new paradigms for discovering novel antibiotics are of critical importance. Caenorhabditis elegans, a model organism used for in vivo, offers a promising solution for identification of anti-infective compounds. Areas covered: This review examines the advantages of C. elegans-based high-throughput screening over conventional, bacteria-centered in vitro screens. It discusses major anti-infective compounds identified from large-scale C. elegans-based screens and presents the first clinically-approved drugs, then known bioactive compounds, and finally novel small molecules. Expert opinion: There are clear advantages of using a C. elegans-infection based screening method. A C. elegans-based screen produces an enriched pool of non-toxic, efficacious, potential anti-infectives, covering: conventional antimicrobial agents, immunomodulators, and anti-virulence agents. Although C. elegans-based screens do not denote the mode of action of hit compounds, this can be elucidated in secondary studies by comparing the results to target-based screens, or conducting subsequent target-based screens, including the genetic knock-down of host or bacterial genes.

  12. Potential drug-drug interactions in Alzheimer patients with behavioral symptoms.

    Science.gov (United States)

    Pasqualetti, Giuseppe; Tognini, Sara; Calsolaro, Valeria; Polini, Antonio; Monzani, Fabio

    2015-01-01

    The use of multi drug regimens among the elderly population has increased tremendously over the last decade although the benefits of medications are always accompanied by potential harm, even when prescribed at recommended doses. The elderly populations are particularly at an increased risk of adverse drug reactions considering comorbidity, poly-therapy, physiological changes affecting the pharmacokinetics and pharmacodynamics of many drugs and, in some cases, poor compliance due to cognitive impairment and/or depression. In this setting, drug-drug interaction may represent a serious and even life-threatening clinical condition. Moreover, the inability to distinguish drug-induced symptoms from a definitive medical diagnosis often results in addition of yet another drug to treat the symptoms, which in turn increases drug-drug interactions. Cognitive enhancers, including acetylcholinesterase inhibitors and memantine, are the most widely prescribed agents for Alzheimer's disease (AD) patients. Behavioral and psychological symptoms of dementia, including psychotic symptoms and behavioral disorders, represent noncognitive disturbances frequently observed in AD patients. Antipsychotic drugs are at high risk of adverse events, even at modest doses, and may interfere with the progression of cognitive impairment and interact with several drugs including anti-arrhythmics and acetylcholinesterase inhibitors. Other medications often used in AD patients are represented by anxiolytic, like benzodiazepine, or antidepressant agents. These agents also might interfere with other concomitant drugs through both pharmacokinetic and pharmacodynamic mechanisms. In this review we focus on the most frequent drug-drug interactions, potentially harmful, in AD patients with behavioral symptoms considering both physiological and pathological changes in AD patients, and potential pharmacodynamic/pharmacokinetic drug interaction mechanisms.

  13. 78 FR 54899 - Draft Guidance for Industry on Specification of the Unique Facility Identifier System for Drug...

    Science.gov (United States)

    2013-09-06

    ... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Specification of the Unique Facility Identifier System for Drug Establishment Registration; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) is announcing...

  14. A novel in vitro image-based assay identifies new drug leads for giardiasis.

    Science.gov (United States)

    Hart, Christopher J S; Munro, Taylah; Andrews, Katherine T; Ryan, John H; Riches, Andrew G; Skinner-Adams, Tina S

    2017-01-27

    Giardia duodenalis is an intestinal parasite that causes giardiasis, a widespread human gastrointestinal disease. Treatment of giardiasis relies on a small arsenal of compounds that can suffer from limitations including side-effects, variable treatment efficacy and parasite drug resistance. Thus new anti-Giardia drug leads are required. The search for new compounds with anti-Giardia activity currently depends on assays that can be labour-intensive, expensive and restricted to measuring activity at a single time-point. Here we describe a new in vitro assay to assess anti-Giardia activity. This image-based assay utilizes the Perkin-Elmer Operetta(®) and permits automated assessment of parasite growth at multiple time points without cell-staining. Using this new approach, we assessed the "Malaria Box" compound set for anti-Giardia activity. Three compounds with sub-μM activity (IC50 0.6-0.9 μM) were identified as potential starting points for giardiasis drug discovery.

  15. Identification and Characterization of Genes Involved in Leishmania Pathogenesis: The Potential for Drug Target Selection

    Directory of Open Access Journals (Sweden)

    Robert Duncan

    2011-01-01

    Full Text Available Identifying and characterizing Leishmania donovani genes and the proteins they encode for their role in pathogenesis can reveal the value of this approach for finding new drug targets. Effective drug targets are likely to be proteins differentially expressed or required in the amastigote life cycle stage found in the patient. Several examples and their potential for chemotherapeutic disruption are presented. A pathway nearly ubiquitous in living cells targeted by anticancer drugs, the ubiquitin system, is examined. New findings in ubiquitin and ubiquitin-like modifiers in Leishmania show how disruption of those pathways could point to additional drug targets. The programmed cell death pathway, now recognized among protozoan parasites, is reviewed for some of its components and evidence that suggests they could be targeted for antiparasitic drug therapy. Finally, the endoplasmic reticulum quality control system is involved in secretion of many virulence factors. How disruptions in this pathway reduce virulence as evidence for potential drug targets is presented.

  16. Predicted essential proteins ofPlasmodium falciparum for potential drug targets

    Institute of Scientific and Technical Information of China (English)

    Qing-Feng He; Li Deng; Qin-Ying Xu; Zheng Shao

    2012-01-01

    ABSTRACT Objective:To identify novel drug targets for treatment ofPlasmodium falciparum.Methods:LocalBLASTP were used to find the proteins non-homologous to human essential proteins as novel drug targets. Functional domains of novel drug targets were identified by InterPro and Pfam,3D structures of potential drug targets were predicated by theSWISS-MODELworkspace. Ligands and ligand-binding sites of the proteins were searched byEf-seek.Results:Three essential proteins were identified that might be considered as potential drug targets.AAN37254.1 belonged to1-deoxy-D-xylulose5-phosphate reductoisomerase,CAD50499.1 belonged to chorismate synthase,CAD51220.1 belonged toFAD binging3 family, but the function of CAD51220.1 was unknown. The3D structures, ligands and ligand-binding sites ofAAN37254.1 andCAD50499.1 were successfully predicated.Conclusions:Two of these potential drug targets are key enzymes in2-C-methyl-d-erythritol4-phosphate pathway and shikimate pathway, which are absent in humans, so these two essential proteins are good potential drug targets. The function and3D structures ofCAD50499.1 is still unknown, it still need further study.

  17. Multiscale modeling of drug-polymer nanoparticle assembly identifies parameters influencing drug encapsulation efficiency.

    Science.gov (United States)

    Mackenzie, R; Booth, J; Alexander, C; Garnett, M C; Laughton, C A

    2015-06-09

    Using a multiscale (dual resolution) approach combining an atomistic (GROMOS96) and coarse-grain (MARTINI) force field, we have been able to simulate the process of drug-polymer nanoparticle assembly by nanoprecipitation from mixed solvents. Here, we present the development and application of this method to the interaction of three poly(glycerol adipate) polymer variants with the anticancer drug dexamethasone phosphate. Differences in encapsulation efficiency and drug loading between the polymers are in agreement with the experimental trend. Reference atomistic simulations at key points along the predicted aggregation pathway support the accuracy of the much more computationally efficient multiscale methodology.

  18. Complementary Approaches to Existing Target Based Drug Discovery for Identifying Novel Drug Targets

    Directory of Open Access Journals (Sweden)

    Suhas Vasaikar

    2016-11-01

    Full Text Available In the past decade, it was observed that the relationship between the emerging New Molecular Entities and the quantum of R&D investment has not been favorable. There might be numerous reasons but few studies stress the introduction of target based drug discovery approach as one of the factors. Although a number of drugs have been developed with an emphasis on a single protein target, yet identification of valid target is complex. The approach focuses on an in vitro single target, which overlooks the complexity of cell and makes process of validation drug targets uncertain. Thus, it is imperative to search for alternatives rather than looking at success stories of target-based drug discovery. It would be beneficial if the drugs were developed to target multiple components. New approaches like reverse engineering and translational research need to take into account both system and target-based approach. This review evaluates the strengths and limitations of known drug discovery approaches and proposes alternative approaches for increasing efficiency against treatment.

  19. A genetic strategy to identify targets for the development of drugs that prevent bacterial persistence.

    Science.gov (United States)

    Kim, Jee-Hyun; O'Brien, Kathryn M; Sharma, Ritu; Boshoff, Helena I M; Rehren, German; Chakraborty, Sumit; Wallach, Joshua B; Monteleone, Mercedes; Wilson, Daniel J; Aldrich, Courtney C; Barry, Clifton E; Rhee, Kyu Y; Ehrt, Sabine; Schnappinger, Dirk

    2013-11-19

    Antibacterial drug development suffers from a paucity of targets whose inhibition kills replicating and nonreplicating bacteria. The latter include phenotypically dormant cells, known as persisters, which are tolerant to many antibiotics and often contribute to failure in the treatment of chronic infections. This is nowhere more apparent than in tuberculosis caused by Mycobacterium tuberculosis, a pathogen that tolerates many antibiotics once it ceases to replicate. We developed a strategy to identify proteins that Mycobacterium tuberculosis requires to both grow and persist and whose inhibition has the potential to prevent drug tolerance and persister formation. This strategy is based on a tunable dual-control genetic switch that provides a regulatory range spanning three orders of magnitude, quickly depletes proteins in both replicating and nonreplicating mycobacteria, and exhibits increased robustness to phenotypic reversion. Using this switch, we demonstrated that depletion of the nicotinamide adenine dinucleotide synthetase (NadE) rapidly killed Mycobacterium tuberculosis under conditions of standard growth and nonreplicative persistence induced by oxygen and nutrient limitation as well as during the acute and chronic phases of infection in mice. These findings establish the dual-control switch as a robust tool with which to probe the essentiality of Mycobacterium tuberculosis proteins under different conditions, including those that induce antibiotic tolerance, and NadE as a target with the potential to shorten current tuberculosis chemotherapies.

  20. Shared mechanism of teratogenicity of anti-angiogenic drugs identified in the chicken embryo model

    Science.gov (United States)

    Beedie, Shaunna L.; Mahony, Chris; Walker, Heather M.; Chau, Cindy H.; Figg, William D.; Vargesson, Neil

    2016-01-01

    Angiogenesis, the formation of new blood vessels, is essential for tumor growth, stabilization and progression. Angiogenesis inhibitors are now widely used in the clinic; however, there are relatively few published studies on the mechanism of their presumed teratogenic effects. To address this issue, we screened a variety of angiogenesis inhibitors in developing zebrafish and chicken embryo models to assess for developmental defects and potential teratogenic effects. We confirmed previous reports that sunitinib, sorafenib and TNP-470 are teratogenic and demonstrate that axitinib, pazopanib, vandetanib, and everolimus are also teratogens in these models. A dose response study identified the drugs inhibit HUVEC cell proliferation in vitro, and also target the developing blood vessels of embryos in vivo. This provides further evidence for the potential risk of fetal toxicity when using these drugs in a clinical setting, and emphasizes the importance of the development and maintenance of the vasculature in the embryo. We conclude that angiogenesis inhibitors, regardless of the molecular target, are teratogenic when exposed to chicken embryos. PMID:27443489

  1. New agents with potential leishmanicidal activity identified by virtual screening of chemical databases: New agents with potential leishmanicidal activity

    Directory of Open Access Journals (Sweden)

    Juan Rebollo

    2013-04-01

    Full Text Available Introduction and Objectives: Leishmaniosis, a disease caused by a protozoan parasite, remains a serious public health problem threatening about 350 million people around the world, of which 12 million are believed to be currently infected (WHO 2010. To date, there are no vaccines against the species of parasites and the treatment is based only on chemotherapy with toxic-, expensive- and inefficient- drugs. There is an urgent need for better drugs against Leishmania, the etiological agent of the disease. The main anti-leishmanial drug used in Colombia is meglumineantimoniate [chemical name according to the International Union of Pure and Applied Chemistry (IUPAC: Hydroxy-dioxostiborane; (2R,3R,4R,5S- 6-methylaminohexane-1,2,3,4,5-pentol, (C7H17NO5], which is not efficient in the treatment of infections caused by Leishmania braziliensis, the most prevalent specie in the Caribbean coast of Colombia. Methods: We performed an in silico virtual screening of several datasets including ChemBridge and Pubchem. We virtually screened a total of 28.755 compounds against a 3D model of 6-phosphoglucono -lactonase (6-PGL from Leishmania braziliensis to identify novel inhibitors.Molecular docking of databases was performed using the software Sybyl 8.0 and AutoDockVina. Results: The initial virtual screening using a structure-based method identified 10 compounds, which were later tested with AutodockVina and classified according to their docking scores. Conclusions: These novel and potential inhibitors constitute new drug candidates that must be biologically tested to define their value as an alternative chemotherapeutic agent in the treatment of these protozoan infections. Salud UIS 2013; 45 (1: 33-40

  2. Effect of functionalization on drug delivery potential of carbon nanotubes.

    Science.gov (United States)

    Sharma, Sonam; Mehra, Neelesh Kumar; Jain, Keerti; Jain, Narendra Kumar

    2016-12-01

    The main aim of the present investigation was to explore the effect of functionalization on drug delivery potential of carbon nanotubes (CNTs) and to compare the in vitro and in vivo cancer targeting potential of doxorubicin HCL (DOX)-loaded ox-/multi-walled CNTs (MWCNTs), DOX-loaded PEG-MWCNTs and DOX-loaded FA-PEG-MWCNTs. The DOX/PEG-FA-MWCNTs showed enhanced cytotoxicity and were most preferentially taken up by the cancerous cells. The obtained results also support the extended resistance time and sustained release profile of drug-loaded surface-engineered MWCNTs. Overall, we concluded that the developed MWCNTs nanoformulations have higher cancer targeting potential.

  3. Identifying Drugs

    Science.gov (United States)

    ... Oxycodone PCP (Phencyclidine) Peyote and Mescaline Psilocybin Rohypnol Salvia Divinorum Spice/ K2, Synthetic Marijuana Steroids U-47700 Flakka ( ... Oxycodone PCP (Phencyclidine) Peyote and Mescaline Psilocybin Rohypnol Salvia Divinorum Spice/ K2, Synthetic Marijuana Steroids U-47700 Aerosol ...

  4. Venlafaxine pharmacokinetics focused on drug metabolism and potential biomarkers.

    Science.gov (United States)

    Magalhães, Paulo; Alves, Gilberto; Llerena, Adrián; Falcão, Amílcar

    2014-01-01

    Venlafaxine (VEN) is one of the safest and most effective drugs used in the treatment of selective serotonin reuptake inhibitors-resistant depression, and thereby it is nowadays one of the most commonly prescribed antidepressants. Nevertheless, patients treated with antidepressant drugs including VEN have exhibited large inter-individual variability in drug outcomes, possibly due to the influence of genetic and nongenetic factors on the drug pharmacokinetics and/or pharmacodynamics. Among them, an increased interest has emerged over the last few years on the genetic and/or phenotypic profile for drug-metabolizing cytochrome P450 isoenzymes and drug transporters such as potential predictive pharmacokinetic-based biomarkers of the variability found in drug biodisposition and antidepressant response. The integration of some of these key therapeutic biomarkers with classic therapeutic drug monitoring constitutes a promising way to individualization of VEN's pharmacotherapy, offering to clinicians the ability to better predict and manage pharmacological treatments to maximize the drug effectiveness. Thus, this review provides an extensive discussion of the pharmacokinetics of VEN focusing in particular on metabolism issues, without forgetting the clinically relevant sources of pharmacokinetics variability (mainly the genetic sources) and aiming on the identification of phenotypic and/or genetic biomarkers for therapy optimization.

  5. Identifying prognostic features by bottom-up approach and correlating to drug repositioning.

    Directory of Open Access Journals (Sweden)

    Wei Li

    Full Text Available Traditionally top-down method was used to identify prognostic features in cancer research. That is to say, differentially expressed genes usually in cancer versus normal were identified to see if they possess survival prediction power. The problem is that prognostic features identified from one set of patient samples can rarely be transferred to other datasets. We apply bottom-up approach in this study: survival correlated or clinical stage correlated genes were selected first and prioritized by their network topology additionally, then a small set of features can be used as a prognostic signature.Gene expression profiles of a cohort of 221 hepatocellular carcinoma (HCC patients were used as a training set, 'bottom-up' approach was applied to discover gene-expression signatures associated with survival in both tumor and adjacent non-tumor tissues, and compared with 'top-down' approach. The results were validated in a second cohort of 82 patients which was used as a testing set.Two sets of gene signatures separately identified in tumor and adjacent non-tumor tissues by bottom-up approach were developed in the training cohort. These two signatures were associated with overall survival times of HCC patients and the robustness of each was validated in the testing set, and each predictive performance was better than gene expression signatures reported previously. Moreover, genes in these two prognosis signature gave some indications for drug-repositioning on HCC. Some approved drugs targeting these markers have the alternative indications on hepatocellular carcinoma.Using the bottom-up approach, we have developed two prognostic gene signatures with a limited number of genes that associated with overall survival times of patients with HCC. Furthermore, prognostic markers in these two signatures have the potential to be therapeutic targets.

  6. Field potential soil variability index to identify precision agriculture opportunity

    Science.gov (United States)

    Precision agriculture (PA) technologies used for identifying and managing within-field variability are not widely used despite decades of advancement. Technological innovations in agronomic tools, such as canopy reflectance or electrical conductivity sensors, have created opportunities to achieve a ...

  7. Teratogenic Potential of Antiepileptic Drugs in the Zebrafish Model

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    Sung Hak Lee

    2013-01-01

    Full Text Available The zebrafish model is an attractive candidate for screening of developmental toxicity during early drug development. Antiepileptic drugs (AEDs arouse concern for the risk of teratogenicity, but the data are limited. In this study, we evaluated the teratogenic potential of seven AEDs (carbamazepine (CBZ, ethosuximide (ETX, valproic acid (VPN, lamotrigine (LMT, lacosamide (LCM, levetiracetam (LVT, and topiramate (TPM in the zebrafish model. Zebrafish embryos were exposed to AEDs from initiation of gastrula (5.25 hours post-fertilization (hpf to termination of hatching (72 hpf which mimic the mammalian teratogenic experimental design. The lethality and teratogenic index (TI of AEDs were determined and the TI values of each drug were compared with the US FDA human pregnancy categories. Zebrafish model was useful screening model for teratogenic potential of antiepilepsy drugs and was in concordance with in vivo mammalian data and human clinical data.

  8. Role of text mining in early identification of potential drug safety issues.

    Science.gov (United States)

    Liu, Mei; Hu, Yong; Tang, Buzhou

    2014-01-01

    Drugs are an important part of today's medicine, designed to treat, control, and prevent diseases; however, besides their therapeutic effects, drugs may also cause adverse effects that range from cosmetic to severe morbidity and mortality. To identify these potential drug safety issues early, surveillance must be conducted for each drug throughout its life cycle, from drug development to different phases of clinical trials, and continued after market approval. A major aim of pharmacovigilance is to identify the potential drug-event associations that may be novel in nature, severity, and/or frequency. Currently, the state-of-the-art approach for signal detection is through automated procedures by analyzing vast quantities of data for clinical knowledge. There exists a variety of resources for the task, and many of them are textual data that require text analytics and natural language processing to derive high-quality information. This chapter focuses on the utilization of text mining techniques in identifying potential safety issues of drugs from textual sources such as biomedical literature, consumer posts in social media, and narrative electronic medical records.

  9. Drug-related problems identified in medication reviews by Australian pharmacists

    DEFF Research Database (Denmark)

    Stafford, Andrew C; Tenni, Peter C; Peterson, Gregory M

    2009-01-01

    OBJECTIVE: In Australia, accredited pharmacists perform medication reviews for patients to identify and resolve drug-related problems. We analysed the drug-related problems identified in reviews for both home-dwelling and residential care-facility patients. The objective of this study was to exam......OBJECTIVE: In Australia, accredited pharmacists perform medication reviews for patients to identify and resolve drug-related problems. We analysed the drug-related problems identified in reviews for both home-dwelling and residential care-facility patients. The objective of this study...... was to examine the number and nature of the drug-related problems identified and investigate differences between each type of review. SETTING: Australian patients living at home or in residential care-facilities. METHOD: We collected a nation-wide sample of medication reviews conducted between 1998 and 2005....... These reviews had been self-selected by pharmacists and submitted as part of the reaccreditation process to the primary body responsible for accrediting Australian pharmacists to perform medication reviews. The drug-related problems identified in each review were classified by type and drugs involved. MAIN...

  10. [Classic psychedelic drugs and their potential therapeutic effect].

    Science.gov (United States)

    Bayat, Michael

    2017-09-11

    Over the past decade we have witnessed a renewed scientific interest in the classic hallucinogens (psychedelic drugs). These are substances which exert their effects by an agonist action on the 5-HT2A receptors. The purpose of this paper is to provide a short review and discussion of the psychedelic drugs, their safety profile and their potential antidepressive, anxiolytic and antiaddictive effects. The article primarily focusses on the most recent clinical trials.

  11. Refining adverse drug reaction signals by incorporating interaction variables identified using emergent pattern mining

    OpenAIRE

    Reps, Jenna M.; Aickelin, Uwe; Hubbard, Richard B.

    2016-01-01

    Purpose: To develop a framework for identifying and incorporating candidate confounding interaction terms into a regularised cox regression analysis to refine adverse drug reaction signals obtained via longitudinal observational data. Methods: We considered six drug families that are commonly associated with myocardial infarction in observational healthcare data, but where the causal relationship ground truth is known (adverse drug reaction or not). We applied emergent pattern mining to fi...

  12. Cancer in silico drug discovery: a systems biology tool for identifying candidate drugs to target specific molecular tumor subtypes.

    Science.gov (United States)

    San Lucas, F Anthony; Fowler, Jerry; Chang, Kyle; Kopetz, Scott; Vilar, Eduardo; Scheet, Paul

    2014-12-01

    Large-scale cancer datasets such as The Cancer Genome Atlas (TCGA) allow researchers to profile tumors based on a wide range of clinical and molecular characteristics. Subsequently, TCGA-derived gene expression profiles can be analyzed with the Connectivity Map (CMap) to find candidate drugs to target tumors with specific clinical phenotypes or molecular characteristics. This represents a powerful computational approach for candidate drug identification, but due to the complexity of TCGA and technology differences between CMap and TCGA experiments, such analyses are challenging to conduct and reproduce. We present Cancer in silico Drug Discovery (CiDD; scheet.org/software), a computational drug discovery platform that addresses these challenges. CiDD integrates data from TCGA, CMap, and Cancer Cell Line Encyclopedia (CCLE) to perform computational drug discovery experiments, generating hypotheses for the following three general problems: (i) determining whether specific clinical phenotypes or molecular characteristics are associated with unique gene expression signatures; (ii) finding candidate drugs to repress these expression signatures; and (iii) identifying cell lines that resemble the tumors being studied for subsequent in vitro experiments. The primary input to CiDD is a clinical or molecular characteristic. The output is a biologically annotated list of candidate drugs and a list of cell lines for in vitro experimentation. We applied CiDD to identify candidate drugs to treat colorectal cancers harboring mutations in BRAF. CiDD identified EGFR and proteasome inhibitors, while proposing five cell lines for in vitro testing. CiDD facilitates phenotype-driven, systematic drug discovery based on clinical and molecular data from TCGA.

  13. Potential anti-cancer drugs commonly used for other indications.

    Science.gov (United States)

    Hanusova, Veronika; Skalova, Lenka; Kralova, Vera; Matouskova, Petra

    2015-01-01

    An increasing resistance of mammalian tumor cells to chemotherapy along with the severe side effects of commonly used cytostatics has raised the urgency in the search for new anti-cancer agents. Several drugs originally approved for indications other than cancer treatment have recently been found to have a cytostatic effect on cancer cells. These drugs could be expediently repurposed as anti-cancer agents, since they have already been tested for toxicity in humans and animals. The groups of newly recognized potential cytostatics discussed in this review include benzimidazole anthelmintics (albendazole, mebendazole, flubendazole), anti-hypertensive drugs (doxazosin, propranolol), psychopharmaceuticals (chlorpromazine, clomipramine) and antidiabetic drugs (metformin, pioglitazone). All these drugs have a definite potential to be used especially in combinations with other cytostatics; the chemotherapy targeting of multiple sites now represents a promising approach in cancer treatment. The present review summarizes recent information about the anti-cancer effects of selected drugs commonly used for other medical indications. Our aim is not to collect all the reported results, but to present an overview of various possibilities. Advantages, disadvantages and further perspectives regarding individual drugs are discussed and evaluated.

  14. Concomitant therapy in people with epilepsy: potential drug-drug interactions and patient awareness.

    Science.gov (United States)

    Eyal, Sara; Rasaby, Sivan; Ekstein, Dana

    2014-02-01

    People with epilepsy (PWE) may use prescription and over-the-counter (OTC) drugs for the treatment of concomitant diseases. Combinations of these drugs, as well as dietary supplements, with antiepileptic drugs (AEDs) may lead to reduced control of seizures and of coexisting medical conditions and increased risk of adverse drug reactions (ADRs). The aims of this study were to obtain comprehensive lists of medications, dietary supplements, botanicals, and specific food components used by adult PWE and to evaluate the potential for interactions involving AEDs and patients' awareness of such potential interactions. We conducted a prospective, questionnaire-based study of PWE attending the Hadassah-Hebrew University Epilepsy Clinic over a period of 7months. The questionnaire interview included the listing of medications, medicinal herbs, dietary supplements, and specific food components consumed and the knowledge of potential drug-drug interactions (DDIs), and it was conducted by a pharmacist. Drug-drug interactions were analyzed via the Micromedex online database. Out of 179 patients who attended the clinic over the study period, we interviewed 73 PWE, of which 71 were included in our final analysis. The mean number of AEDs consumed per subject was 1.7 (SD: 0.8, range: 1-4). Forty (56%) subjects were also treated with other prescription and/or OTC medications, and thirty-four (48%) took dietary supplements. Drug families most prone to DDIs involving AEDs included antipsychotic agents, selective serotonin reuptake inhibitors, and statins. Two-thirds of study participants (67%) knew that DDIs may lead to ADRs, but only half (56%) were aware of the potential for reduced seizure control. Only 44% always reported treatment with AEDs to medical professionals. This study provides for the first time a comprehensive picture of prescription and OTC drugs and food supplements used by PWE. Despite a considerable potential for DDIs involving AEDs, patient awareness is limited

  15. Prevalence and factors associated with potential drug interactions among elderly in a population-based study

    Directory of Open Access Journals (Sweden)

    Daniel Riani Gotardelo

    2014-04-01

    Full Text Available Objectives: The aim of this study was to determine the prevalence of potential drug interactions and the factors associated with them among elderly patients covered by the Family Health Strategy in the municipality of Timóteo, state of Minas Gerais, Brazil. Methods: Cross-sectional study, using stratified random sampling. A total of 273 household interviews were conducted in subjects aged 60 years or older, after obtaining informed consent, using a questionnaire containing questions related to identification, demography, health conditions and medication use. Drug interactions were identified and classified according to the software Micromedex®. Results: The overall prevalence of potential drug interactions was 55.6%, a total of 466 cases, of which 5.6% were mild, 81.6% moderate and 12.8% of greater severity. Therapeutic classes most frequently involved were anti-inflammatory drugs and especially drugs used in cardiovascular disease. The absence of hospitalization in the last four months was significantly associated with a lower chance of serious drug interactions and most patients who did not have any moderate drug interactions used only drugs prescribed by physicians. Conclusions: The prevalence of potential drug interactions was similar to that described in the literature, demonstrating the high frequency of this phenomenon among the elderly. The absence of prior hospitalization and drug prescription by physicians were associated with a lower frequency of interactions. The prescription of multiple drugs simultaneously to elderly patients can compromise the safety and health of this population, requiring, by caregivers, observation for the occurrence of potential drug interactions.

  16. Geospatial analysis identifies critical mineral-resource potential in Alaska

    Science.gov (United States)

    Karl, Susan; Labay, Keith; Jacques, Katherine; Landowski, Claire

    2017-03-03

    Alaska consists of more than 663,000 square miles (1,717,000 square kilometers) of land—more than a sixth of the total area of the United States—and large tracts of it have not been systematically studied or sampled for mineral-resource potential. Many regions of the State are known to have significant mineral-resource potential, and there are currently six operating mines in the State along with numerous active mineral exploration projects. The U.S. Geological Survey and the Alaska Division of Geological & Geophysical Surveys have developed a new geospatial tool that integrates and analyzes publicly available databases of geologic information and estimates the mineral-resource potential for critical minerals, which was recently used to evaluate Alaska. The results of the analyses highlight areas that have known mineral deposits and also reveal areas that were not previously considered to be prospective for these deposit types. These results will inform land management decisions by Federal, State, and private landholders, and will also help guide future exploration activities and scientific investigations in Alaska.

  17. Controllability analysis of the directed human protein interaction network identifies disease genes and drug targets.

    Science.gov (United States)

    Vinayagam, Arunachalam; Gibson, Travis E; Lee, Ho-Joon; Yilmazel, Bahar; Roesel, Charles; Hu, Yanhui; Kwon, Young; Sharma, Amitabh; Liu, Yang-Yu; Perrimon, Norbert; Barabási, Albert-László

    2016-05-03

    The protein-protein interaction (PPI) network is crucial for cellular information processing and decision-making. With suitable inputs, PPI networks drive the cells to diverse functional outcomes such as cell proliferation or cell death. Here, we characterize the structural controllability of a large directed human PPI network comprising 6,339 proteins and 34,813 interactions. This network allows us to classify proteins as "indispensable," "neutral," or "dispensable," which correlates to increasing, no effect, or decreasing the number of driver nodes in the network upon removal of that protein. We find that 21% of the proteins in the PPI network are indispensable. Interestingly, these indispensable proteins are the primary targets of disease-causing mutations, human viruses, and drugs, suggesting that altering a network's control property is critical for the transition between healthy and disease states. Furthermore, analyzing copy number alterations data from 1,547 cancer patients reveals that 56 genes that are frequently amplified or deleted in nine different cancers are indispensable. Among the 56 genes, 46 of them have not been previously associated with cancer. This suggests that controllability analysis is very useful in identifying novel disease genes and potential drug targets.

  18. Methodological framework to identify possible adverse drug reactions using population-based administrative data.

    Science.gov (United States)

    Sauer, Brian; Nebeker, Jonathan; Shen, Shuying; Rupper, Randall; West, Suzanne; Shinogle, Judith A; Xu, Wu; Lohr, Kathleen N; Samore, Matthew

    2014-01-01

    We present a framework for detecting possible adverse drug reactions (ADRs) using the Utah Medicaid administrative data. We examined four classes of ADRs associated with treatment of dementia by acetylcholinesterase inhibitors (AChEIs): known reactions (gastrointestinal, psychological disturbances), potential reactions (respiratory disturbance), novel reactions (hepatic, hematological disturbances), and death. Our cohort design linked drug utilization data to medical claims from Utah Medicaid recipients. We restricted the analysis to 50 years-old and older beneficiaries diagnosed with dementia-related diseases. We compared patients treated with AChEI to patients untreated with anti-dementia medication therapy. We attempted to remove confounding by establishing propensity-score-matched cohorts for each outcome investigated; we then evaluated the effects of drug treatment by conditional multivariable Cox-proportional-hazard regression. Acute and transient effects were evaluated by a crossover design using conditional logistic regression. Propensity-matched analysis of expected reactions revealed that AChEI treatment was associated with gastrointestinal episodes (Hazard Ratio [HR]: 2.02; 95%CI: 1.28-3.2), but not psychological episodes, respiratory disturbance, or death. Among the unexpected reactions, the risk of hematological episodes was higher (HR: 2.32; 95%CI: 1.47-3.6) in patients exposed to AChEI. AChEI exposure was not associated with an increase in hepatic episodes. We also noted a trend, identified in the case-crossover design, toward increase odds of experiencing acute hematological events during AChEI exposure (Odds Ratio: 3.0; 95% CI: 0.97 - 9.3). We observed an expected association between AChEIs treatment and gastrointestinal disturbances and detected a signal of possible hematological ADR after treatment with AChEIs in this pilot study. Using this analytic framework may raise awareness of potential ADEs and generate hypotheses for future investigations

  19. Computational Approach to Identify Enzymes That Are Potential Therapeutic Candidates for Psoriasis

    Directory of Open Access Journals (Sweden)

    Daeui Park

    2011-01-01

    Full Text Available Psoriasis is well known as a chronic inflammatory dermatosis. The disease affects persons of all ages and is a burden worldwide. Psoriasis is associated with various diseases such as arthritis. The disease is characterized by well-demarcated lesions on the skin of the elbows and knees. Various genetic and environmental factors are related to the pathogenesis of psoriasis. In order to identify enzymes that are potential therapeutic targets for psoriasis, we utilized a computational approach, combining microarray analysis and protein interaction prediction. We found 6,437 genes (3,264 upregulated and 3,173 downregulated that have significant differences in expression between regions with and without lesions in psoriasis patients. We identified potential candidates through protein-protein interaction predictions made using various protein interaction resources. By analyzing the hub protein of the networks with metrics such as degree and centrality, we detected 32 potential therapeutic candidates. After filtering these candidates through the ENZYME nomenclature database, we selected 5 enzymes: DNA helicase (RUVBL2, proteasome endopeptidase complex (PSMA2, nonspecific protein-tyrosine kinase (ZAP70, I-kappa-B kinase (IKBKE, and receptor protein-tyrosine kinase (EGFR. We adopted a computational approach to detect potential therapeutic targets; this approach may become an effective strategy for the discovery of new drug targets for psoriasis.

  20. Identifying Initial Condition in Degenerate Parabolic Equation with Singular Potential

    Directory of Open Access Journals (Sweden)

    K. Atifi

    2017-01-01

    Full Text Available A hybrid algorithm and regularization method are proposed, for the first time, to solve the one-dimensional degenerate inverse heat conduction problem to estimate the initial temperature distribution from point measurements. The evolution of the heat is given by a degenerate parabolic equation with singular potential. This problem can be formulated in a least-squares framework, an iterative procedure which minimizes the difference between the given measurements and the value at sensor locations of a reconstructed field. The mathematical model leads to a nonconvex minimization problem. To solve it, we prove the existence of at least one solution of problem and we propose two approaches: the first is based on a Tikhonov regularization, while the second approach is based on a hybrid genetic algorithm (married genetic with descent method type gradient. Some numerical experiments are given.

  1. Candidiasis drug discovery and development: new approaches targeting virulence for discovering and identifying new drugs

    Science.gov (United States)

    Pierce, Christopher G.; Lopez-Ribot, Jose L.

    2014-01-01

    Introduction Targeting pathogenetic mechanisms rather than essential processes represents a very attractive alternative for the development of new antibiotics. This may be particularly important in the case of antimycotics, due to the urgent need for novel antifungal drugs and the paucity of selective fungal targets. The opportunistic pathogenic fungus Candida albicans is the main etiological agent of candidiasis, the most common human fungal infection. These infections carry unacceptably high mortality rates, a clear reflection of the many shortcomings of current antifungal therapy, including the limited armamentarium of antifungal agents, their toxicity, and the emergence of resistance. Moreover the antifungal pipeline is mostly dry. Areas covered This review covers some of the most recent progress towards understanding C. albicans pathogenetic processes and how to harness this information for the development of anti-virulence agents. The two principal areas covered are filamentation and biofilm formation, as C. albicans pathogenicity is intimately linked to its ability to undergo morphogenetic conversions between yeast and filamentous morphologies and to its ability to form biofilms. Expert opinion We argue that filamentation and biofilm formation represent high value targets, yet clinically unexploited, for the development of novel anti-virulence approaches against candidiasis. Although this has proved a difficult task despite increasing understanding at the molecular level of C. albicans virulence, we highlight new opportunities and prospects for antifungal drug development targeting these two important biological processes. PMID:23738751

  2. Design of a score to identify hospitalized patients at risk of drug-related problems.

    Science.gov (United States)

    Urbina, Olatz; Ferrández, Olivia; Grau, Santiago; Luque, Sonia; Mojal, Sergi; Marin-Casino, Monica; Mateu-de-Antonio, Javier; Carmona, Alexia; Conde-Estévez, David; Espona, Merce; González, Elena; Riu, Marta; Salas, Esther

    2014-09-01

    The potential impact of drug-related problems (DRP) on morbidity and mortality is a serious concern in hospitalized patients. This study aimed to design a risk score to identify patients most at risk of a DRP. Data from patients admitted to a tertiary university hospital between January and August 2009 were used to design the risk score (training set). DRP were detected through a pharmacy warning system integrated in the computerized medical history. The variables associated with developing a DRP were identified through a binary multivariate logistic regression analysis and were used to compute the DRP risk score, which was subsequently validated in patients admitted between September and December 2009 (validation set). Of the 8713 patients included in the training set, at least one DRP was detected in 2425 (27.8%). Prescription of a higher number of drugs, higher comorbidity, advanced age, certain groups of the Anatomical Therapeutic Chemical classification system, and some major diagnostic categories were associated with risk of DRP. These variables were used to compute the DRP risk score. The area under the receiver operator characteristic curve was 0.778 (95%CI [0.768, 0.789]). Of the 4058 admissions included in the validation set, at least one DRP was detected in 876 (21.6%). The area under the receiver operator characteristic curve was 0.776 (95%CI [0.759, 0.792]). Knowledge of the variables associated with DRP could aid their early detection in at-risk patients. The use of an application that can be continually updated in daily clinical practice helps to optimize resources. Copyright © 2014 John Wiley & Sons, Ltd.

  3. A Topology Potential-Based Method for Identifying Essential Proteins from PPI Networks.

    Science.gov (United States)

    Li, Min; Lu, Yu; Wang, Jianxin; Wu, Fang-Xiang; Pan, Yi

    2015-01-01

    Essential proteins are indispensable for cellular life. It is of great significance to identify essential proteins that can help us understand the minimal requirements for cellular life and is also very important for drug design. However, identification of essential proteins based on experimental approaches are typically time-consuming and expensive. With the development of high-throughput technology in the post-genomic era, more and more protein-protein interaction data can be obtained, which make it possible to study essential proteins from the network level. There have been a series of computational approaches proposed for predicting essential proteins based on network topologies. Most of these topology based essential protein discovery methods were to use network centralities. In this paper, we investigate the essential proteins' topological characters from a completely new perspective. To our knowledge it is the first time that topology potential is used to identify essential proteins from a protein-protein interaction (PPI) network. The basic idea is that each protein in the network can be viewed as a material particle which creates a potential field around itself and the interaction of all proteins forms a topological field over the network. By defining and computing the value of each protein's topology potential, we can obtain a more precise ranking which reflects the importance of proteins from the PPI network. The experimental results show that topology potential-based methods TP and TP-NC outperform traditional topology measures: degree centrality (DC), betweenness centrality (BC), closeness centrality (CC), subgraph centrality (SC), eigenvector centrality (EC), information centrality (IC), and network centrality (NC) for predicting essential proteins. In addition, these centrality measures are improved on their performance for identifying essential proteins in biological network when controlled by topology potential.

  4. Finding potential drug targets against Shigella flexneri through druggable proteome exploration.

    Directory of Open Access Journals (Sweden)

    Mohammad Uzzal Hossain

    2016-11-01

    Full Text Available Abstract:Background: Shigella flexneri is a gram negative bacteria that causes the infectious disease ‘shigellosis’. Shigella flexneri (S. flexneri is responsible for developing diarrhea, fever and stomach cramps in human. Antibiotics are mostly given to patients infected with shigella. Resistance to antibiotics can hinder its treatment significantly. Upon identification of essential therapeutic targets, vaccine and drug could be effective therapy for the treatment of shigellosis. Methods: The study was designed for the identification and qualitative characterization for potential drug targets from S. flexneri by using the subtractive genome analysis. A set of computational tools were used to identify essential proteins those are required for the survival of S. flexneri. Total proteome (13503 proteins of S. flexneri was retrieved from NCBI and further analyzed by subtractive channel analysis. After identification of the metabolic proteins we have also performed its qualitative characterization to pave the way for the identification of promising drug targets. Results: Subtractive analysis revealed that a list of 53 targets of S. flexneri were human non-homologous essential metabolic proteins that might be used for potential drug targets. We have also found that 11 drug targets are involved in unique pathway. Most of these proteins are cytoplasmic, can be used as broad spectrum drug targets, can interact with other proteins and show the druggable properties. The functionality and drug binding site analysis suggest a promising effective way to design the new drugs against S. flexneri. Conclusion: We have identified 13 potential novel drug and one vaccine target(s against S. flexneri. The outcome might also be used as module as well as circuit design in systems biology. Keywords: S. flexneri, drug target, therapeutics, metabolic proteins, proteome

  5. Frequency of potential interactions between drugs in medical prescriptions in a city in southern Brazil

    Directory of Open Access Journals (Sweden)

    Genici Weyh Bleich

    Full Text Available CONTEXT AND OBJECTIVE: Drug interactions form part of current clinical practice and they affect between 3 and 5% of polypharmacy patients. The aim of this study was to identify the frequency of potential drug-drug interactions in prescriptions for adult and elderly patients. TYPE OF STUDY AND SETTING: Cross-sectional pharmacoepidemiological survey in the Parque Verde housing project, municipality of Cascavel, Paraná, Brazil, between December 2006 and February 2007. METHODS: Stratified cluster sampling, proportional to the total number of homes in the housing project, was used. The sample consisted of 95 homes and 96 male or female patients aged 19 or over, with medical prescriptions for at least two pharmaceutical drugs. Interactions were identified using DrugDigest, Medscape and Micromedex softwares. RESULTS: Most of the patients were female (69.8%, married (59.4% and in the age group of 60 years or over (56.3%, with an income less than or equal to three minimum monthly salaries (81.3% and less than eight years of schooling (69.8%; 90.6% of the patients were living with another person. The total number of pharmaceutical drugs was 406 (average of 4.2 medications per patient. The drugs most prescribed were antihypertensives (47.5%. The frequency of drug interactions was 66.6%. Among the 154 potential drug interactions, 4.6% were classified as major, 65.6% as moderate and 20.1% as minor. CONCLUSION: The high frequency of drug prescriptions with a potential for differentiated interactions indicates a situation that has so far been little explored, albeit a reality in household surveys.

  6. Potential drug interactions in patients given antiretroviral therapy.

    Science.gov (United States)

    Santos, Wendel Mombaque Dos; Secoli, Silvia Regina; Padoin, Stela Maris de Mello

    2016-11-21

    to investigate potential drug-drug interactions (PDDI) in patients with HIV infection on antiretroviral therapy. a cross-sectional study was conducted on 161 adults with HIV infection. Clinical, socio demographic, and antiretroviral treatment data were collected. To analyze the potential drug interactions, we used the software Micromedex(r). Statistical analysis was performed by binary logistic regression, with a p-value of ≤0.05 considered statistically significant. of the participants, 52.2% were exposed to potential drug-drug interactions. In total, there were 218 potential drug-drug interactions, of which 79.8% occurred between drugs used for antiretroviral therapy. There was an association between the use of five or more medications and potential drug-drug interactions (p = 0.000) and between the time period of antiretroviral therapy being over six years and potential drug-drug interactions (p antirretroviral. um estudo de corte transversal foi conduzido em 161 pessoas infectadas com o HIV. Dados de tratamentos clínicos, sociodemográficos e antirretrovirais foram coletados. Para analisar a possível interação medicamentosa, nós usamos o software Micromedex(r). A análise estatística foi feita por regressão logística binária, com um valor P de ≤0.05, considerado estatisticamente significativo. dos participantes, 52.2% foram expostos a potenciais interações droga-droga. No total, houve 218 interações droga-droga, das quais 79.8% ocorreram entre drogas usadas para a terapia antirretroviral. Houve uma associação entre o uso de cinco ou mais medicamentos e possíveis interações droga-droga (p = 0.000), e entre o período de tempo de terapia antirretroviral acima de seis anos e possíveis interações droga-droga (p VIH que reciben terapia antirretroviral. un estudio transversal se llevó a cabo en 161 adultos con infección por VIH. Se recogieron datos clínicos, socio demográficos, y de tratamiento antirretroviral. Para analizar las posibles

  7. Extent of poly-pharmacy, occurrence and associated factors of drug-drug interaction and potential adverse drug reactions in Gondar Teaching Referral Hospital, North West Ethiopia

    Directory of Open Access Journals (Sweden)

    Endalkachew Admassie

    2013-01-01

    Full Text Available The aim of this study was to assess the extent of poly-pharmacy, occurrence, and associated factors for the occurrence of drug-drug interaction (DDI and potential adverse drug reaction (ADR in Gondar University Teaching Referral Hospital. Institutional-based retrospective cross-sectional study. This study was conducted on prescriptions of both in and out-patients for a period of 3 months at Gondar University Hospital. Both bivariate analysis and multivariate logistic regression were used to identify risk factors for the occurrence of DDI and possible ADRs. All the statistical calculations were performed using SPSS; software. A total of 12,334 prescriptions were dispensed during the study period of which, 2,180 prescriptions were containing two or more drugs per prescription. A total of 21,210 drugs were prescribed and the average number of drugs per prescription was 1.72. Occurrences of DDI of all categories (Major, Moderate, and Minor were analyzed and DDI were detected in 711 (32.6% prescriptions. Sex was not found to be a risk factor for the occurrence of DDI and ADR, while age and number of medications per prescription were found to be significant risk factors for the occurrence of DDI and ADR. The mean number of drugs per prescription was 1.72 and hence with regard to the WHO limit of drugs per prescription, Gondar hospital was able to maintain the limit and prescriptions containing multiple drugs supposed to be taken systemically. Numbers of drugs per prescription as well as older age were found to be predisposing factors for the occurrence of DDI and potential ADRs while sex was not a risk factor.

  8. Prevalence of potential drug-drug interactions among internal medicine ward in University of Gondar Teaching Hospital, Ethiopia

    Institute of Scientific and Technical Information of China (English)

    Akshaya Srikanth Bhagavathula; Alemayehu Berhanie; Habtamu Tigistu; Yishak Abraham; Yosheph Getachew; Tahir Mehmood Khan; Chandrashekhar Unakal

    2014-01-01

    Objective: To determine the prevalence, clinical significance and the associated risk factors of potential drug-drug interactions (DDIs) at internal medicine ward of University of Gondar (UOG) hospital.Method:medicine ward of UOG hospital from April 29, 2013 to June 2, 2013. Data was collected from medical records and by interviewing the patients face to face. Descriptive analysis was conducted for back ground characteristics and logistic regression was used to determine the associated risk factors.Result:A prospective cross-sectional study was conducted on patients treated in internal interacting combinations with 4.13 potential DDIs per patient. Among 413 potential DDIs most were of moderate interactions 61.2% (n=253) followed by 26% (n=107) of minor interactions and 12.8% (n=53) of major interactions. There was significant association of occurrence of potential DDIs only with taking three or more medications.Conclusion:We have recorded a high rate of prevalence of potential DDI in the internal In our study, we have identified a total number of 413 potential DDIs and 184 types of medicine ward of UOG hospital and a high number of clinically significant DDIs which the most prevalent DDI were of moderate severity. Careful selection of drugs and active pharmaceutical care is encouraged in order to avoid negative consequences of these interactions.

  9. Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post-chemotherapy tissues.

    Science.gov (United States)

    Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng

    2015-12-01

    Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens.

  10. Scorpion peptides: potential use for new drug development.

    Science.gov (United States)

    Hmed, Bennasr; Serria, Hammami Turky; Mounir, Zeghal Khaled

    2013-01-01

    Several peptides contained in scorpion fluids showed diverse array of biological activities with high specificities to their targeted sites. Many investigations outlined their potent effects against microbes and showed their potential to modulate various biological mechanisms that are involved in immune, nervous, cardiovascular, and neoplastic diseases. Because of their important structural and functional diversity, it is projected that scorpion-derived peptides could be used to develop new specific drugs. This review summarizes relevant findings improving their use as valuable tools for new drugs development.

  11. Scorpion Peptides: Potential Use for New Drug Development

    Directory of Open Access Journals (Sweden)

    BenNasr Hmed

    2013-01-01

    Full Text Available Several peptides contained in scorpion fluids showed diverse array of biological activities with high specificities to their targeted sites. Many investigations outlined their potent effects against microbes and showed their potential to modulate various biological mechanisms that are involved in immune, nervous, cardiovascular, and neoplastic diseases. Because of their important structural and functional diversity, it is projected that scorpion-derived peptides could be used to develop new specific drugs. This review summarizes relevant findings improving their use as valuable tools for new drugs development.

  12. Carbon nanotubes: a potential concept for drug delivery applications.

    Science.gov (United States)

    Kumar, Rakesh; Dhanawat, Meenakshi; Kumar, Sudhir; Singh, Brahma N; Pandit, Jayant K; Sinha, Vivek R

    2014-04-01

    The unique properties of carbon nanotubes (CNTs) make them a highly interesting and demandable nanocarrier in the field of nanoscience. CNTs facilitate efficient delivery of therapeutics like drugs, proteins, genes, nucleic acids, vitamins and lot more. Even though highly beneficial, the biocompatibility of CNTs is a major issue in their questioning their potential application in targeting drug delivery. Studies confirmed subdued toxicity of CNTs following slight modifications like functionalization, controlled dimensions, purification etc. A well-established mechanism for cellular internalization is an insistent need to attain a more efficient and targeted delivery. Recent patents have been thoroughly discussed in the text below.

  13. Drug-induced acute myocardial infarction: identifying 'prime suspects' from electronic healthcare records-based surveillance system.

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    Preciosa M Coloma

    Full Text Available BACKGROUND: Drug-related adverse events remain an important cause of morbidity and mortality and impose huge burden on healthcare costs. Routinely collected electronic healthcare data give a good snapshot of how drugs are being used in 'real-world' settings. OBJECTIVE: To describe a strategy that identifies potentially drug-induced acute myocardial infarction (AMI from a large international healthcare data network. METHODS: Post-marketing safety surveillance was conducted in seven population-based healthcare databases in three countries (Denmark, Italy, and the Netherlands using anonymised demographic, clinical, and prescription/dispensing data representing 21,171,291 individuals with 154,474,063 person-years of follow-up in the period 1996-2010. Primary care physicians' medical records and administrative claims containing reimbursements for filled prescriptions, laboratory tests, and hospitalisations were evaluated using a three-tier triage system of detection, filtering, and substantiation that generated a list of drugs potentially associated with AMI. Outcome of interest was statistically significant increased risk of AMI during drug exposure that has not been previously described in current literature and is biologically plausible. RESULTS: Overall, 163 drugs were identified to be associated with increased risk of AMI during preliminary screening. Of these, 124 drugs were eliminated after adjustment for possible bias and confounding. With subsequent application of criteria for novelty and biological plausibility, association with AMI remained for nine drugs ('prime suspects': azithromycin; erythromycin; roxithromycin; metoclopramide; cisapride; domperidone; betamethasone; fluconazole; and megestrol acetate. LIMITATIONS: Although global health status, co-morbidities, and time-invariant factors were adjusted for, residual confounding cannot be ruled out. CONCLUSION: A strategy to identify potentially drug-induced AMI from electronic healthcare

  14. Genetic variations may help identify best candidates for preventive breast cancer drugs | Division of Cancer Prevention

    Science.gov (United States)

    Newly discovered genetic variations may help predict breast cancer risk in women who receive preventive breast cancer therapy with the selective estrogen receptor modulator drugs tamoxifen andraloxifene, a Mayo Clinic-led study has found. The study is published in the journal Cancer Discovery. "Our findings are important because we identified genetic factors that could eventually be used to select women who should be offered the drugs for prevention," said James Ingle, M.D., an oncologist at Mayo Clinic. |

  15. LIPOSOME AS A POTENTIAL DRUG DELIVERY SYSTEM: A REVIEW

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    Dash Tapaswi Rani

    2013-01-01

    Full Text Available Liposomes are microscopic phospholipid vescicles made of lipid bilayer which are the drug carrier for improving the delivery of therapeutic agents. Research on liposome technology has progressed from conventional vesicles (“first-generation liposomes” to “second-generation liposomes”, in which long-circulating liposomes are obtained by modulating the lipid composition, size, and charge of the vesicle. Liposomes with modified surfaces have also been developed using several molecules, such as glycolipids or sialic acid. A significant step in the development of long-circulating liposomes came with inclusion of the synthetic polymer poly-(ethylene glycol (PEG in liposome composition. Due to advancement in liposomal technology a number of liposomal formulations are available in market for clinical use, with gene delivery and cancer therapy and some formulations are under clinical trial. Reformulation of drugs in liposomes has provided an opportunity to enhance the therapeutic indices of various agents mainly through alteration in their biodistribution. This review discusses the basic principles of liposome structures and preparations, evaluation parameters of liposomal formulation, pharmacokinetics of liposomes and liposome-encapsulated drugs, the potential applications of liposomes in drug delivery with examples of formulations approved for clinical use, and the problems associated with further exploitation of this drug delivery system.

  16. Potential drug development candidates for human soil-transmitted helminthiases.

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    Piero Olliaro

    2011-06-01

    Full Text Available Few drugs are available for soil-transmitted helminthiasis (STH; the benzimidazoles albendazole and mebendazole are the only drugs being used for preventive chemotherapy as they can be given in one single dose with no weight adjustment. While generally safe and effective in reducing intensity of infection, they are contra-indicated in first-trimester pregnancy and have suboptimal efficacy against Trichuris trichiura. In addition, drug resistance is a threat. It is therefore important to find alternatives.We searched the literature and the animal health marketed products and pipeline for potential drug development candidates. Recently registered veterinary products offer advantages in that they have undergone extensive and rigorous animal testing, thus reducing the risk, cost and time to approval for human trials. For selected compounds, we retrieved and summarised publicly available information (through US Freedom of Information (FoI statements, European Public Assessment Reports (EPAR and published literature. Concomitantly, we developed a target product profile (TPP against which the products were compared.The paper summarizes the general findings including various classes of compounds, and more specific information on two veterinary anthelmintics (monepantel, emodepside and nitazoxanide, an antiprotozoal drug, compiled from the EMA EPAR and FDA registration files.Few of the compounds already approved for use in human or animal medicine qualify for development track decision. Fast-tracking to approval for human studies may be possible for veterinary compounds like emodepside and monepantel, but additional information remains to be acquired before an informed decision can be made.

  17. ETHOSOMES: A POTENTIAL CARRIES FOR TRANSDERMAL DRUG DELIVERY

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    RAJ KUMAR TIWARI

    2010-06-01

    Full Text Available The literature is abounding with attempts made to enhance the delivery of drugs into the deep layers of the skin and through the skin. Ethosomes are noninvasive delivery carriers that enable drugs to reach the deep skin layers and/or the systemic circulation. Although ethosomal systems are conceptually sophisticated, they are characterized by simplicity in their preparation, safety, and efficacy a combination that can highly expand their application. Ethosomes are soft, malleable vesicles tailored for enhanced delivery of active agents. This article reviews various aspect of ethosomes including their preparation, characterization, potential advantages and their applications in drug delivery. Because of their unique structure, ethosomes are able to encapsulate and deliver through the skin highly lipophilic molecules such as cannabinoids, testosterone, and minoxidil, as well as cationic drugs such as propranolol and trihexyphenidil. Ethosomes are provides a number of important benefits including improving the drug's efficacy, enhancing patient compliance and comfort and reducing the total cost of treatment. Enhanced delivery of bioactive molecules through the skin and cellular membranes by means of an ethosomal carrier opens numerous challenges and opportunities for the research and future development of novel improved therapies.

  18. Spermbots: potential impact for drug delivery and assisted reproductive technologies.

    Science.gov (United States)

    Magdanz, Veronika; Schmidt, Oliver G

    2014-08-01

    Micromotors and nanomotors are an emerging research field that aims at achieving locomotion on the microscale for a variety of applications such as drug delivery, single cell manipulation, microsensors and lab-on-a-chip devices, just to point out a few. The enthusiastic development of hybrid micromotors harnessing biological power sources for physiologically compatible nano/microdevices has recently brought a lot of attention to the international research community that is looking for a solution for the actuation and locomotion on the microscale. This article describes the potential of sperm-driven micro-bio-robots in the biomedical field such as drug delivery or single cell manipulation. Herein, a specific potential of the sperm-driven micro-bio-robot is described that might have impact on the development of assisted reproductive technologies.

  19. Preferred drug lists: Potential impact on healthcare economics

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    Kimberly Ovsag

    2008-04-01

    Full Text Available Kimberly Ovsag, Sabrina Hydery, Shaker A MousaPharmaceutical Research Institute at Albany College of Pharmacy, Albany, New York, USAObjectives: To analyze the implementation of Medicaid preferred drug lists (PDLs in a number of states and determine its impact on quality of care and cost relative to other segments of healthcare.Methods: We reviewed research and case studies found by searching library databases, primarily MEDLINE and EBSCOHost, and searching pertinent journals. Keywords initially included “drug lists,” “prior authorization,” “prior approval,” and “Medicaid.” We added terms such as “influence use of other healthcare services,” “quality of care,” and “overall economic impact.” We mainly used primary sources.Results: Based on our literature review, we determined that there are a number of issues regarding Medicaid PDLs that need to be addressed. Some issues include: (a the potential for PDLs to influence the utilization of other healthcare services, (b criteria used by Medicaid for determining acceptance of drugs onto a PDL, (c the effect of PDL implementation on compliance to new regimens, (d the potential effects of restricting medication availability on quality of care, (e administrative costs associated with PDLs, and (f satisfaction rates among patients and medical providers. This review highlighted expected short-term cost savings with limited degree of compromised quality of PDL implementation, but raised the concern about the potential long-term decline in quality of care and overall economic impact.Conclusions: The number of concerns raised indicates that further studies are warranted regarding both short-term cost benefits as well as potential long-term effects of Medicaid PDL implementation. Objective analysis of these effects is necessary to ensure cost-effectiveness and quality of care.Keywords: preferred drug lists, medicaid, healthcare costs, managed care

  20. Rapid Identification of Potential Drugs for Diabetic Nephropathy Using Whole-Genome Expression Profiles of Glomeruli

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    Jingsong Shi

    2016-01-01

    Full Text Available Objective. To investigate potential drugs for diabetic nephropathy (DN using whole-genome expression profiles and the Connectivity Map (CMAP. Methodology. Eighteen Chinese Han DN patients and six normal controls were included in this study. Whole-genome expression profiles of microdissected glomeruli were measured using the Affymetrix human U133 plus 2.0 chip. Differentially expressed genes (DEGs between late stage and early stage DN samples and the CMAP database were used to identify potential drugs for DN using bioinformatics methods. Results. (1 A total of 1065 DEGs (FDR 1.5 were found in late stage DN patients compared with early stage DN patients. (2 Piperlongumine, 15d-PGJ2 (15-delta prostaglandin J2, vorinostat, and trichostatin A were predicted to be the most promising potential drugs for DN, acting as NF-κB inhibitors, histone deacetylase inhibitors (HDACIs, PI3K pathway inhibitors, or PPARγ agonists, respectively. Conclusion. Using whole-genome expression profiles and the CMAP database, we rapidly predicted potential DN drugs, and therapeutic potential was confirmed by previously published studies. Animal experiments and clinical trials are needed to confirm both the safety and efficacy of these drugs in the treatment of DN.

  1. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets

    Science.gov (United States)

    Alexandrov, Ludmil B; Calderaro, Julien; Rebouissou, Sandra; Couchy, Gabrielle; Meiller, Clément; Shinde, Jayendra; Soysouvanh, Frederic; Calatayud, Anna-Line; Pinyol, Roser; Pelletier, Laura; Balabaud, Charles; Laurent, Alexis; Blanc, Jean-Frederic; Mazzaferro, Vincenzo; Calvo, Fabien; Villanueva, Augusto; Nault, Jean-Charles; Bioulac-Sage, Paulette; Stratton, Michael R; Llovet, Josep M; Zucman-Rossi, Jessica

    2015-01-01

    Genomic analyses promise to improve tumor characterization in order to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors revealed mutational signatures associated with specific risk factors, mainly combined alcohol/tobacco consumption, and aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrent pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (HBV), and AXIN1. Analyses according to tumor stage progression revealed TERT promoter mutation as an early event whereas FGF3, FGF4, FGF19/CCND1 amplification, TP53 and CDKN2A alterations, appeared at more advanced stages in aggressive tumors. In 28% of the tumors we identified genetic alterations potentially targetable by FDA-approved drugs. In conclusion, we identified risk factor-specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC which will be useful to design clinical trials for targeted therapy. PMID:25822088

  2. Potential drug-drug interactions in prescriptions to patients over 45 years of age in primary care, southern Brazil.

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    Jorge Juarez Vieira Teixeira

    Full Text Available BACKGROUND: Few cross-sectional studies involving adults and elderly patients with major DDIs have been conducted in the primary care setting. The study aimed to investigate the prevalence of potential drug-drug interactions (DDIs in patients treated in primary care. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional study involving patients aged 45 years or older was conducted at 25 Basic Health Units in the city of Maringá (southern Brazil from May to December 2010. The data were collected from prescriptions at the pharmacy of the health unit at the time of the delivery of medication to the patient. After delivery, the researcher checked the electronic medical records of the patient. A total of 827 patients were investigated (mean age: 64.1; mean number of medications: 4.4. DDIs were identified in the Micromedex® database. The prevalence of potential DDIs and major DDIs was 63.0% and 12.1%, respectively. In both the univariate and multivariate analyses, the number of drugs prescribed was significantly associated with potential DDIs, with an increasing risk from three to five drugs (OR = 4.74; 95% CI: 2.90-7.73 to six or more drugs (OR = 23.03; 95% CI: 10.42-50.91. Forty drugs accounted for 122 pairs of major DDIs, the most frequent of which involved simvastatin (23.8%, captopril/enalapril (16.4% and fluoxetine (16.4%. CONCLUSIONS/SIGNIFICANCE: This is the first large-scale study on primary care carried out in Latin America. Based on the findings, the estimated prevalence of potential DDIs was high, whereas clinically significant DDIs occurred in a smaller proportion. Exposing patients to a greater number of prescription drugs, especially three or more, proved to be a significant predictor of DDIs. Prescribers should be more aware of potential DDIs. Future studies should assess potential DDIs in primary care over a longer period of time.

  3. A Clinical Drug Library Screen Identifies Tosufloxacin as Being Highly Active against Staphylococcus aureus Persisters

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    Hongxia Niu

    2015-07-01

    Full Text Available To identify effective compounds that are active against Staphylococcus aureus (S. aureus persisters, we screened a clinical drug library consisting of 1524 compounds and identified six drug candidates that had anti-persister activity: tosufloxacin, clinafloxacin, sarafloxacin, doxycycline, thiostrepton, and chlorosalicylanilide. Among them, tosufloxacin had the highest anti-persister activity, which could completely eradicate S. aureus persisters within 2 days in vitro. Clinafloxacin ranked the second with very few persisters surviving the drug exposure. Interestingly, we found that both tosufloxacin and trovafloxacin that had high activity against persisters contained at the N-1 position the 2,4-difluorophenyl group, which is absent in other less active quinolones and may be associated with the high anti-persister activity. Further studies are needed to evaluate tosufloxacin in animal models and to explain its unique activity against bacterial persisters. Our findings may have implications for improved treatment of persistent bacterial infections.

  4. 76 FR 44593 - Identifying the Center for Drug Evaluation and Research's Science and Research Needs...

    Science.gov (United States)

    2011-07-26

    ... Science and Research Needs; Availability of a Draft Report; Request for Comments AGENCY: Food and Drug... announcing the availability of a draft report entitled ``Identifying CDER's Science and Research Needs... efforts. Through external communication of the science and research needs outlined in the report, CDER...

  5. Identifying Some Factors That Might Predispose Drug Abuse among Learners in a South African Township School

    Science.gov (United States)

    Grobler, R.; Khatite, M.

    2012-01-01

    This study inquires into some of the factors that might predispose the use and abuse of drugs among secondary school learners in a township school. The objective of this research is to identify these factors and to offer a few suggestions on how the abuse may be prevented. A quantitative research strategy is used and a document analysis technique…

  6. Potential and problems in ultrasound-responsive drug delivery systems

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    Zhao YZ

    2013-04-01

    Full Text Available Ying-Zheng Zhao,1,3 Li-Na Du,2 Cui-Tao Lu,1 Yi-Guang Jin,2 Shu-Ping Ge3 1Wenzhou Medical College, Wenzhou City, Zhejiang Province, 2Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People’s Republic of China; 3St Christopher’s Hospital for Children/Drexel University College of Medicine, Philadelphia, PA, USA Abstract: Ultrasound is an important local stimulus for triggering drug release at the target tissue. Ultrasound-responsive drug delivery systems (URDDS have become an important research focus in targeted therapy. URDDS include many different formulations, such as microbubbles, nanobubbles, nanodroplets, liposomes, emulsions, and micelles. Drugs that can be loaded into URDDS include small molecules, biomacromolecules, and inorganic substances. Fields of clinical application include anticancer therapy, treatment of ischemic myocardium, induction of an immune response, cartilage tissue engineering, transdermal drug delivery, treatment of Huntington’s disease, thrombolysis, and disruption of the blood–brain barrier. This review focuses on recent advances in URDDS, and discusses their formulations, clinical application, and problems, as well as a perspective on their potential use in the future. Keywords: ultrasound, targeted therapy, clinical application

  7. Bionanocomposites containing magnetic graphite as potential systems for drug delivery.

    Science.gov (United States)

    Ribeiro, Lígia N M; Alcântara, Ana C S; Darder, Margarita; Aranda, Pilar; Herrmann, Paulo S P; Araújo-Moreira, Fernando M; García-Hernández, Mar; Ruiz-Hitzky, Eduardo

    2014-12-30

    New magnetic bio-hybrid matrices for potential application in drug delivery are developed from the assembly of the biopolymer alginate and magnetic graphite nanoparticles. Ibuprofen (IBU) intercalated in a Mg-Al layered double hydroxide (LDH) was chosen as a model drug delivery system (DDS) to be incorporated as third component of the magnetic bionanocomposite DDS. For comparative purposes DDS based on the incorporation of pure IBU in the magnetic bio-hybrid matrices were also studied. All the resulting magnetic bionanocomposites were processed as beads and films and characterized by different techniques with the aim to elucidate the role of the magnetic graphite on the systems, as well as that of the inorganic brucite-like layers in the drug-loaded LDH. In this way, the influence of both inorganic components on the mechanical properties, the water uptake ability, and the kinetics of the drug release from these magnetic systems were determined. In addition, the possibility of modulating the levels of IBU release by stimulating the bionanocomposites with an external magnetic field was also evaluated in in vitro assays. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Potential drug-drug interactions in a Brazilian teaching hospital: age-related differences?

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    Daniela Oliveira Melo

    2016-07-01

    Full Text Available This study proposes to measure frequency and to characterize the profile of potential drug interactions (pDDI in a general medicine ward of a teaching hospital. Data about identification and clinical status of patients were extracted from medical records between March to August 2006. The occurrence of pDDI was analyzed using the database monographs Micromedex® DrugReax® System. From 5,336 prescriptions with two or more drugs, 3,097 (58.0% contained pDDI. The frequency of major and well document pDDI was 26.5%. Among 647 patients, 432 (66.8% were exposed to at least one pDDI and 283 (43.7% to major pDDI. The multivariate analysis identified that factors related to higher rates of major pDDI were the same age (p< 0.0001, length of stay (p< 0.0001, prevalence of hypertension [OR=3.42 (p< 0.0001] and diabetes mellitus [OR=2.1 (p< 0.0001], cardiovascular diseases (p< 0.0001 and the number of prescribed drugs (Spearman’s correlation=0.640622, p< 0.0001. Between major pDDI, the main risk was hemorrhage (50.3%, the most frequent major pDDI involved combination of anticoagulants and antiplatelet drugs. Among moderate pDDI, 3,866 (90.8% involved medicines for the treatment of chronic non-communicable diseases, mainly hypertension. In HU-USP, the profile of pDDI was similar among adults and elderly (the most frequent pDDI and major pDDI were same, the difference was only the frequency in either group. The efforts of the clinical pharmacists should be directed to elderly patients with cardiovascular compromise, mainly in use of anticoagulants and antiplatelet drugs. Furthermore, hospital managers should increase the integration between levels of health care to promote safety patient after discharge.Keywords: Drug interactions. Aged. Internal Medicine. Hospitals, University. RESUMOInterações medicamentosas potenciais em um hospital escolar brasileiro: diferenças relacionadas à idade?O estudo tem por objetivo descrever o perfil de intera

  9. Computational drug designing of fungal pigments as potential aromatase inhibitors

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    Nighat Fatima

    2014-12-01

    Full Text Available The existing aromatase inhibitors produced unwelcome effects impose the discovery of novel drugs with privileged selectivity, a reduced amount of toxicity and humanizing potency. In this study, we illuminate the binding mode of polyketide azaphilanoid pigments monascin, ankaflavin, monascorubrin and monascorubramine isolated from Monascus fungus to the aromatase by molecular docking. The 3-dimensional structure of aromatase enzyme (PDB: 4KQ8 was obtained from the Protein Data Bank. PatchDock docking software was used to analyze structural complexes of the aromatase with monascus pigments. Comparatively, the AutoGrid model presented the most briskly constructive binding mode of monascin to aromatase. Docked energies in kcal/mol are: monascin;-13.2; monascorubramine:-12.8, monascorubrin:-12.3; ankaflavin: -10.5. These outcomes exposed these ligands could be potential drugs to treat hormone dependent breast cancer.

  10. Corifungin, a new drug lead against Naegleria, identified from a high-throughput screen.

    Science.gov (United States)

    Debnath, Anjan; Tunac, Josefino B; Galindo-Gómez, Silvia; Silva-Olivares, Angélica; Shibayama, Mineko; McKerrow, James H

    2012-11-01

    Primary amebic meningoencephalitis (PAM) is a rapidly fatal infection caused by the free-living ameba Naegleria fowleri. The drug of choice in treating PAM is the antifungal antibiotic amphotericin B, but its use is associated with severe adverse effects. Moreover, few patients treated with amphotericin B have survived PAM. Therefore, fast-acting and efficient drugs are urgently needed for the treatment of PAM. To facilitate drug screening for this pathogen, an automated, high-throughput screening methodology was developed and validated for the closely related species Naegleria gruberi. Five kinase inhibitors and an NF-kappaB inhibitor were hits identified in primary screens of three compound libraries. Most importantly for a preclinical drug discovery pipeline, we identified corifungin, a water-soluble polyene macrolide with a higher activity against Naegleria than that of amphotericin B. Transmission electron microscopy of N. fowleri trophozoites incubated with different concentrations of corifungin showed disruption of cytoplasmic and plasma membranes and alterations in mitochondria, followed by complete lysis of amebae. In vivo efficacy of corifungin in a mouse model of PAM was confirmed by an absence of detectable amebae in the brain and 100% survival of mice for 17 days postinfection for a single daily intraperitoneal dose of 9 mg/kg of body weight given for 10 days. The same dose of amphotericin B did not reduce ameba growth, and mouse survival was compromised. Based on these results, the U.S. FDA has approved orphan drug status for corifungin for the treatment of PAM.

  11. Prevalence of potential drug interactions in patients in an intensive care unit of a university hospital in Brazil

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    Adriano Max Moreira Reis

    2011-01-01

    Full Text Available OBJECTIVES: To investigate the prevalence of potential drug interactions at the intensive care unit of a university hospital in Brazil and to analyze their clinical significance. METHODS: This cross-sectional retrospective study included 299 patients who had been hospitalized in the intensive care unit of the hospital. The drugs administered during the first 24 hours of hospitalization, in the 50th length-ofstay percentile and at the time of discharge were analyzed to identify potential drug-drug and drug-enteral nutrition interactions using DRUG-REAXH software. The drugs were classified according to the anatomical therapeutic chemical classification. RESULTS: The median number of medications per patient was smaller at the time of discharge than in the 50th length-of-stay percentile and in the first 24 hours of hospitalization. There was a 70% prevalence of potential drug interactions at the intensive care unit at the studied time points of hospitalization. Most of the drug interactions were either severe or moderate, and the scientific evidence for the interactions was, in general, either good or excellent. Pharmacodynamic interactions presented a subtle predominance in relation to pharmacokinetic interactions. The occurrence of potential drug interactions was associated with the number of medications administered and the length of stay. Medications that induced cytochrome P450, drugs that prolong the QT interval and cardiovascular drugs were pharmacotherapy factors associated with potential drug interactions. CONCLUSION: The study showed that potential drug interactions were prevalent in the intensive care unit due to the complexity of the pharmacotherapies administered. The interactions were associated with the number of drugs, the length of stay and the characteristics of the administered medications.

  12. New drug candidates for liposomal delivery identified by computer modeling of liposomes' remote loading and leakage.

    Science.gov (United States)

    Cern, Ahuva; Marcus, David; Tropsha, Alexander; Barenholz, Yechezkel; Goldblum, Amiram

    2017-02-16

    Remote drug loading into nano-liposomes is in most cases the best method for achieving high concentrations of active pharmaceutical ingredients (API) per nano-liposome that enable therapeutically viable API-loaded nano-liposomes, referred to as nano-drugs. This approach also enables controlled drug release. Recently, we constructed computational models to identify APIs that can achieve the desired high concentrations in nano-liposomes by remote loading. While those previous models included a broad spectrum of experimental conditions and dealt only with loading, here we reduced the scope to the molecular characteristics alone. We model and predict API suitability for nano-liposomal delivery by fixing the main experimental conditions: liposome lipid composition and size to be similar to those of Doxil® liposomes. On that basis, we add a prediction of drug leakage from the nano-liposomes during storage. The latter is critical for having pharmaceutically viable nano-drugs. The "load and leak" models were used to screen two large molecular databases in search of candidate APIs for delivery by nano-liposomes. The distribution of positive instances in both loading and leakage models was similar in the two databases screened. The screening process identified 667 molecules that were positives by both loading and leakage models (i.e., both high-loading and stable). Among them, 318 molecules received a high score in both properties and of these, 67 are FDA-approved drugs. This group of molecules, having diverse pharmacological activities, may be the basis for future liposomal drug development.

  13. Chemical screen identifies FDA-approved drugs and target pathways that induce precocious pancreatic endocrine differentiation.

    Science.gov (United States)

    Rovira, Meritxell; Huang, Wei; Yusuff, Shamila; Shim, Joong Sup; Ferrante, Anthony A; Liu, Jun O; Parsons, Michael J

    2011-11-29

    Pancreatic β-cells are an essential source of insulin and their destruction because of autoimmunity causes type I diabetes. We conducted a chemical screen to identify compounds that would induce the differentiation of insulin-producing β-cells in vivo. To do this screen, we brought together the use of transgenic zebrafish as a model of β-cell differentiation, a unique multiwell plate that allows easy visualization of lateral views of swimming larval fish and a library of clinical drugs. We identified six hits that can induce precocious differentiation of secondary islets in larval zebrafish. Three of these six hits were known drugs with a considerable background of published data on mechanism of action. Using pharmacological approaches, we have identified and characterized two unique pathways in β-cell differentiation in the zebrafish, including down-regulation of GTP production and retinoic acid biosynthesis.

  14. Managing potential drug-drug interactions between gastric acid-reducing agents and antiretroviral therapy: experience from a large HIV-positive cohort.

    Science.gov (United States)

    Lewis, J M; Stott, K E; Monnery, D; Seden, K; Beeching, N J; Chaponda, M; Khoo, S; Beadsworth, M B J

    2016-02-01

    Drug-drug interactions between antiretroviral therapy and other drugs are well described. Gastric acid-reducing agents are one such class. However, few data exist regarding the frequency of and indications for prescription, nor risk assessment in the setting of an HIV cohort receiving antiretroviral therapy. To assess prevalence of prescription of gastric acid-reducing agents and drug-drug interaction within a UK HIV cohort, we reviewed patient records for the whole cohort, assessing demographic data, frequency and reason for prescription of gastric acid-reducing therapy. Furthermore, we noted potential drug-drug interaction and whether risk had been documented and mitigated. Of 701 patients on antiretroviral therapy, 67 (9.6%) were prescribed gastric acid-reducing therapy. Of these, the majority (59/67 [88.1%]) were prescribed proton pump inhibitors. We identified four potential drug-drug interactions, which were appropriately managed by temporally separating the administration of gastric acid-reducing agent and antiretroviral therapy, and all four of these patients remained virally suppressed. Gastric acid-reducing therapy, in particular proton pump inhibitor therapy, appears common in patients prescribed antiretroviral therapy. Whilst there remains a paucity of published data, our findings are comparable to those in other European cohorts. Pharmacovigilance of drug-drug interactions in HIV-positive patients is vital. Education of patients and staff, and accurate data-gathering tools, will enhance patient safety.

  15. Nicotine and Nicotinic Receptor Drugs: Potential for Parkinson's Disease and Drug-Induced Movement Disorders.

    Science.gov (United States)

    Quik, Maryka; Bordia, Tanuja; Zhang, Danhui; Perez, Xiomara A

    2015-01-01

    Parkinson's disease is a progressive neurodegenerative disorder associated with tremor, rigidity, and bradykinesia, as well as nonmotor symptoms including autonomic impairments, olfactory dysfunction, sleep disturbances, depression, and dementia. Although the major neurological deficit is a loss of nigrostriatal dopaminergic neurons, multiple neurotransmitters systems are compromised in Parkinson's disease. Consistent with this observation, dopamine replacement therapy dramatically improves Parkinson's disease motor symptoms. Additionally, drugs targeting the serotonergic, glutamatergic, adenosine, and other neurotransmitter systems may be beneficial. Recent evidence also indicates that nicotinic cholinergic drugs may be useful for the management of Parkinson's disease. This possibility initially arose from the results of epidemiological studies, which showed that smoking was associated with a decreased incidence of Parkinson's disease, an effect mediated in part by the nicotine in smoke. Further evidence for this idea stemmed from preclinical studies which showed that nicotine administration reduced nigrostriatal damage in parkinsonian rodents and monkeys. In addition to a potential neuroprotective role, emerging work indicates that nicotinic receptor drugs improve the abnormal involuntary movements or dyskinesias that arise as a side effect of l-dopa treatment, the gold standard therapy for Parkinson's disease. Both nicotine and nicotinic receptor drugs reduced l-dopa-induced dyskinesias by over 50% in parkinsonian rodent and monkey models. Notably, nicotine also attenuated the abnormal involuntary movements or tardive dyskinesias that arise with antipsychotic treatment. These observations, coupled with reports that nicotinic receptor drugs have procognitive and antidepressant effects, suggest that central nervous system (CNS) nicotinic receptors may represent useful targets for the treatment of movement disorders.

  16. Disruptive Potential of the Internet to Transform Illicit Drug Markets and Impact on Future Patterns of Drug Consumption.

    Science.gov (United States)

    Griffiths, P; Mounteney, J

    2017-02-01

    The internet facilitates rapid and covert communication, knowledge transfer, and has the potential to disrupt and transform drug market models and associated consumption patterns. Innovation and new trends diffuse rapidly through this medium and new operational models are emerging. Although the online drug markets currently only account for a small share of all drug transactions, the potential of the surface and deep web to provide a new platform for drug sale and exchanges is considerable.

  17. Ethnobotanical bioprospection of candidates for potential antimicrobial drugs from Brazilian plants: state of art and perspectives.

    Science.gov (United States)

    Benko-Iseppon, Ana Maria; Crovella, Sergio

    2010-05-01

    Despite of the high biological diversity and traditional use of medicinal plants in Brazil, no comprehensive ethnobotanic review of plants with potential antimicrobial effects is available. In the present work own field information is aggregated with a literature review, identifying 433 Brazilian plant species potentially useful for identification of antimicrobial peptides. They included mainly woody species, distributed on 100 plant families (93 angiosperms and 7 pteridophytes) and 266 genera, covering all Brazilian regions and ecosystems. Main plant parts and indications for their use are presented and discussed, revealing the high potential that these plants present for the future planning strategies regarding the future development of antimicrobial drugs.

  18. The Possible Potential Therapeutic Targets for Drug Induced Gingival Overgrowth

    Directory of Open Access Journals (Sweden)

    Tamilselvan Subramani

    2013-01-01

    Full Text Available Gingival overgrowth is a side effect of certain medications. The most fibrotic drug-induced lesions develop in response to therapy with phenytoin, the least fibrotic lesions are caused by cyclosporin A, and the intermediate fibrosis occurs in nifedipine-induced gingival overgrowth. Fibrosis is one of the largest groups of diseases for which there is no therapy but is believed to occur because of a persistent tissue repair program. During connective tissue repair, activated gingival fibroblasts synthesize and remodel newly created extracellular matrix. Proteins such as transforming growth factor (TGF, endothelin-1 (ET-1, angiotensin II (Ang II, connective tissue growth factor (CCN2/CTGF, insulin-like growth factor (IGF, and platelet-derived growth factor (PDGF appear to act in a network that contributes to the development of gingival fibrosis. Since inflammation is the prerequisite for gingival overgrowth, mast cells and its protease enzymes also play a vital role in the pathogenesis of gingival fibrosis. Drugs targeting these proteins are currently under consideration as antifibrotic treatments. This review summarizes recent observations concerning the contribution of TGF-β, CTGF, IGF, PDGF, ET-1, Ang II, and mast cell chymase and tryptase enzymes to fibroblast activation in gingival fibrosis and the potential utility of agents blocking these proteins in affecting the outcome of drug-induced gingival overgrowth.

  19. Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment.

    Directory of Open Access Journals (Sweden)

    Adam A Friedman

    Full Text Available A newer generation of anti-cancer drugs targeting underlying somatic genetic driver events have resulted in high single-agent or single-pathway response rates in selected patients, but few patients achieve complete responses and a sizeable fraction of patients relapse within a year. Thus, there is a pressing need for identification of combinations of targeted agents which induce more complete responses and prevent disease progression. We describe the results of a combination screen of an unprecedented scale in mammalian cells performed using a collection of targeted, clinically tractable agents across a large panel of melanoma cell lines. We find that even the most synergistic drug pairs are effective only in a discrete number of cell lines, underlying a strong context dependency for synergy, with strong, widespread synergies often corresponding to non-specific or off-target drug effects such as multidrug resistance protein 1 (MDR1 transporter inhibition. We identified drugs sensitizing cell lines that are BRAFV600E mutant but intrinsically resistant to BRAF inhibitor PLX4720, including the vascular endothelial growth factor receptor/kinase insert domain receptor (VEGFR/KDR and platelet derived growth factor receptor (PDGFR family inhibitor cediranib. The combination of cediranib and PLX4720 induced apoptosis in vitro and tumor regression in animal models. This synergistic interaction is likely due to engagement of multiple receptor tyrosine kinases (RTKs, demonstrating the potential of drug- rather than gene-specific combination discovery approaches. Patients with elevated biopsy KDR expression showed decreased progression free survival in trials of mitogen-activated protein kinase (MAPK kinase pathway inhibitors. Thus, high-throughput unbiased screening of targeted drug combinations, with appropriate library selection and mechanistic follow-up, can yield clinically-actionable drug combinations.

  20. Potential therapeutic targets and the role of technology in developing novel cannabinoid drugs from cyanobacteria.

    Science.gov (United States)

    Vijayakumar, S; Manogar, P; Prabhu, S

    2016-10-01

    Cyanobacteria find several applications in pharmacology as potential candidates for drug design. The need for new compounds that can be used as drugs has always been on the rise in therapeutics. Cyanobacteria have been identified as promising targets of research in the quest for new pharmaceutical compounds as they can produce secondary metabolites with novel chemical structures. Cyanobacteria is now recognized as a vital source of bioactive molecules like Curacin A, Largazole and Apratoxin which have succeeded in reaching Phase II and Phase III into clinical trials. The discovery of several new clinical cannabinoid drugs in the past decade from diverse marine life should translate into a number of new drugs for cannabinoid in the years to come. Conventional cannabinoid drugs have high toxicity and as a result, they affect the efficacy of chemotherapy and patients' life very much. The present review focuses on how potential, safe and affordable drugs used for cannabinoid treatment could be developed from cyanobacteria. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  1. Potential drug–drug interactions in Alzheimer patients with behavioral symptoms

    OpenAIRE

    2015-01-01

    Giuseppe Pasqualetti, Sara Tognini, Valeria Calsolaro, Antonio Polini, Fabio Monzani Geriatrics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Abstract: The use of multi drug regimens among the elderly population has increased tremendously over the last decade although the benefits of medications are always accompanied by potential harm, even when prescribed at recommended doses. The elderly populations are particularly at an increased risk of adverse ...

  2. Characterization of drug-related problems identified by clinical pharmacy staff at Danish hospitals.

    Science.gov (United States)

    Kjeldsen, Lene Juel; Birkholm, Trine; Fischer, Hanne; Graabæk, Trine; Kibsdal, Karina Porsborg; Ravn-Nielsen, Lene Vestergaard; Truelshøj, Tania Holtum

    2014-08-01

    In 2010, a database of drug related problems (DRPs) was implemented to assist clinical pharmacy staff in documenting clinical pharmacy activities locally. A study of quality, reliability and generalisability showed that national analyses of the data could be conducted. Analyses at the national level may help identify and prevent DRPs by performing national interventions. The aim of the study was to explore the DRP characteristics as documented by clinical pharmacy staff at hospital pharmacies in the Danish DRP-database during a 3-year period. Danish hospital pharmacies. Data documented in the DRP-database during the initial 3 years after implementation were analyzed retrospectively. The DRP-database contains DRPs reported at hospitals by clinical pharmacy staff. The analyses focused on DRP categories, implementation rates and drugs associated with the DRPs. Characteristics of DRPs. In total, 72,044 DRPs were documented in the DRP-database during the first 3 years of implementation, and the number of documented DRPs increased every year. An overall stable implementation rate of approximately 58 % was identified. The DRPs identified were multi-facetted, however evenly distributed for each of the 3 years. The most frequently identified DRP categories were: "Dose", followed by "Nonadherence to guidelines" and "Supplement to treatment". The highest implementation rates were found for the following DRP categories: "Non-adherence to guidelines" (79 %) followed by "Therapeutic duplication" (73 %) and "Dosing time and interval" (70 %). Even though the top 25 drugs were involved in 58 % of all DRPs, multiple drugs were associated with DRPs. The drugs most frequently involved in DRPs were paracetamol (4.6 % of all DRPs), simvastatin (3.0 %), lansoprazole (2.7 %), morphine (2.6 %) and alendronic acid (2.4 %). The study found that a national database on DRPs contained multi-facetted DRPs, however evenly distributed for each of the 3 years. Even though the top 25 drugs were

  3. Role of transdermal potential difference during iontophoretic drug delivery.

    Science.gov (United States)

    Bandrivskyy, Andriy; Bernjak, Alan; McClintock, Peter V E; Stefanovska, Aneta

    2004-09-01

    Potential differences have been measured during transdermal iontophoresis in order to establish the effect of voltage, as opposed to current, on cutaneous blood flow. It is known that, even in the absence of drugs, the iontophoresis current can sometimes produce increased blood flow. The role of voltage in this process is studied through single-ended measurements (between electrode and body) of the potential difference during iontophoresis with 100-microA, 20-s current pulses through deionized water, saturated 20.4% NaCl solution, 1% acetylcholine, and 1% sodium nitroprusside. It is found that the voltage needed to deliver the current varied by orders of magnitudes less than the differences in the conductance of these different electrolytes, and it is concluded that, at least for the present current protocol, the voltage as such is not an important factor in increasing the blood flow.

  4. Fexinidazole: a potential new drug candidate for Chagas disease.

    Directory of Open Access Journals (Sweden)

    Maria Terezinha Bahia

    resistant T. cruzi. These findings illustrate the potential of fexinidazole as a drug candidate for the treatment of human CD.

  5. Fexinidazole: a potential new drug candidate for Chagas disease.

    Science.gov (United States)

    Bahia, Maria Terezinha; de Andrade, Isabel Mayer; Martins, Tassiane Assíria Fontes; do Nascimento, Álvaro Fernando da Silva; Diniz, Lívia de Figueiredo; Caldas, Ivo Santana; Talvani, André; Trunz, Bernadette Bourdin; Torreele, Els; Ribeiro, Isabela

    2012-01-01

    New safe and effective treatments for Chagas disease (CD) are urgently needed. Current chemotherapy options for CD have significant limitations, including failure to uniformly achieve parasitological cure or prevent the chronic phase of CD, and safety and tolerability concerns. Fexinidazole, a 2-subsituted 5-nitroimidazole drug candidate rediscovered following extensive compound mining by the Drugs for Neglected Diseases initiative and currently in Phase I clinical study for the treatment of human African trypanosomiasis, was evaluated in experimental models of acute and chronic CD caused by different strains of Trypanosoma cruzi. We investigated the in vivo activity of fexinidazole against T. cruzi, using mice as hosts. The T. cruzi strains used in the study were previously characterized in murine models as susceptible (CL strain), partially resistant (Y strain), and resistant (Colombian and VL-10 strains) to the drugs currently in clinical use, benznidazole and nifurtimox. Our results demonstrated that fexinidazole was effective in suppressing parasitemia and preventing death in infected animals for all strains tested. In addition, assessment of definitive parasite clearance (cure) through parasitological, PCR, and serological methods showed cure rates of 80.0% against CL and Y strains, 88.9% against VL-10 strain, and 77.8% against Colombian strain among animals treated during acute phase, and 70% (VL-10 strain) in those treated in chronic phase. Benznidazole had a similar effect against susceptible and partially resistant T. cruzi strains. Fexinidazole treatment was also shown to reduce myocarditis in all animals infected with VL-10 or Colombian resistant T. cruzi strains, although parasite eradication was not achieved in all treated animals at the tested doses. Fexinidazole is an effective oral treatment of acute and chronic experimental CD caused by benznidazole-susceptible, partially resistant, and resistant T. cruzi. These findings illustrate the potential

  6. Identifying and quantifying heterogeneity in high content analysis: application of heterogeneity indices to drug discovery.

    Directory of Open Access Journals (Sweden)

    Albert H Gough

    Full Text Available One of the greatest challenges in biomedical research, drug discovery and diagnostics is understanding how seemingly identical cells can respond differently to perturbagens including drugs for disease treatment. Although heterogeneity has become an accepted characteristic of a population of cells, in drug discovery it is not routinely evaluated or reported. The standard practice for cell-based, high content assays has been to assume a normal distribution and to report a well-to-well average value with a standard deviation. To address this important issue we sought to define a method that could be readily implemented to identify, quantify and characterize heterogeneity in cellular and small organism assays to guide decisions during drug discovery and experimental cell/tissue profiling. Our study revealed that heterogeneity can be effectively identified and quantified with three indices that indicate diversity, non-normality and percent outliers. The indices were evaluated using the induction and inhibition of STAT3 activation in five cell lines where the systems response including sample preparation and instrument performance were well characterized and controlled. These heterogeneity indices provide a standardized method that can easily be integrated into small and large scale screening or profiling projects to guide interpretation of the biology, as well as the development of therapeutics and diagnostics. Understanding the heterogeneity in the response to perturbagens will become a critical factor in designing strategies for the development of therapeutics including targeted polypharmacology.

  7. Systems Biology-Based Investigation of Cellular Antiviral Drug Targets Identified by Gene-Trap Insertional Mutagenesis.

    Science.gov (United States)

    Cheng, Feixiong; Murray, James L; Zhao, Junfei; Sheng, Jinsong; Zhao, Zhongming; Rubin, Donald H

    2016-09-01

    Viruses require host cellular factors for successful replication. A comprehensive systems-level investigation of the virus-host interactome is critical for understanding the roles of host factors with the end goal of discovering new druggable antiviral targets. Gene-trap insertional mutagenesis is a high-throughput forward genetics approach to randomly disrupt (trap) host genes and discover host genes that are essential for viral replication, but not for host cell survival. In this study, we used libraries of randomly mutagenized cells to discover cellular genes that are essential for the replication of 10 distinct cytotoxic mammalian viruses, 1 gram-negative bacterium, and 5 toxins. We herein reported 712 candidate cellular genes, characterizing distinct topological network and evolutionary signatures, and occupying central hubs in the human interactome. Cell cycle phase-specific network analysis showed that host cell cycle programs played critical roles during viral replication (e.g. MYC and TAF4 regulating G0/1 phase). Moreover, the viral perturbation of host cellular networks reflected disease etiology in that host genes (e.g. CTCF, RHOA, and CDKN1B) identified were frequently essential and significantly associated with Mendelian and orphan diseases, or somatic mutations in cancer. Computational drug repositioning framework via incorporating drug-gene signatures from the Connectivity Map into the virus-host interactome identified 110 putative druggable antiviral targets and prioritized several existing drugs (e.g. ajmaline) that may be potential for antiviral indication (e.g. anti-Ebola). In summary, this work provides a powerful methodology with a tight integration of gene-trap insertional mutagenesis testing and systems biology to identify new antiviral targets and drugs for the development of broadly acting and targeted clinical antiviral therapeutics.

  8. Systems Biology-Based Investigation of Cellular Antiviral Drug Targets Identified by Gene-Trap Insertional Mutagenesis.

    Directory of Open Access Journals (Sweden)

    Feixiong Cheng

    2016-09-01

    Full Text Available Viruses require host cellular factors for successful replication. A comprehensive systems-level investigation of the virus-host interactome is critical for understanding the roles of host factors with the end goal of discovering new druggable antiviral targets. Gene-trap insertional mutagenesis is a high-throughput forward genetics approach to randomly disrupt (trap host genes and discover host genes that are essential for viral replication, but not for host cell survival. In this study, we used libraries of randomly mutagenized cells to discover cellular genes that are essential for the replication of 10 distinct cytotoxic mammalian viruses, 1 gram-negative bacterium, and 5 toxins. We herein reported 712 candidate cellular genes, characterizing distinct topological network and evolutionary signatures, and occupying central hubs in the human interactome. Cell cycle phase-specific network analysis showed that host cell cycle programs played critical roles during viral replication (e.g. MYC and TAF4 regulating G0/1 phase. Moreover, the viral perturbation of host cellular networks reflected disease etiology in that host genes (e.g. CTCF, RHOA, and CDKN1B identified were frequently essential and significantly associated with Mendelian and orphan diseases, or somatic mutations in cancer. Computational drug repositioning framework via incorporating drug-gene signatures from the Connectivity Map into the virus-host interactome identified 110 putative druggable antiviral targets and prioritized several existing drugs (e.g. ajmaline that may be potential for antiviral indication (e.g. anti-Ebola. In summary, this work provides a powerful methodology with a tight integration of gene-trap insertional mutagenesis testing and systems biology to identify new antiviral targets and drugs for the development of broadly acting and targeted clinical antiviral therapeutics.

  9. Systems Biology-Based Investigation of Cellular Antiviral Drug Targets Identified by Gene-Trap Insertional Mutagenesis

    Science.gov (United States)

    Zhao, Junfei; Sheng, Jinsong; Rubin, Donald H.

    2016-01-01

    Viruses require host cellular factors for successful replication. A comprehensive systems-level investigation of the virus-host interactome is critical for understanding the roles of host factors with the end goal of discovering new druggable antiviral targets. Gene-trap insertional mutagenesis is a high-throughput forward genetics approach to randomly disrupt (trap) host genes and discover host genes that are essential for viral replication, but not for host cell survival. In this study, we used libraries of randomly mutagenized cells to discover cellular genes that are essential for the replication of 10 distinct cytotoxic mammalian viruses, 1 gram-negative bacterium, and 5 toxins. We herein reported 712 candidate cellular genes, characterizing distinct topological network and evolutionary signatures, and occupying central hubs in the human interactome. Cell cycle phase-specific network analysis showed that host cell cycle programs played critical roles during viral replication (e.g. MYC and TAF4 regulating G0/1 phase). Moreover, the viral perturbation of host cellular networks reflected disease etiology in that host genes (e.g. CTCF, RHOA, and CDKN1B) identified were frequently essential and significantly associated with Mendelian and orphan diseases, or somatic mutations in cancer. Computational drug repositioning framework via incorporating drug-gene signatures from the Connectivity Map into the virus-host interactome identified 110 putative druggable antiviral targets and prioritized several existing drugs (e.g. ajmaline) that may be potential for antiviral indication (e.g. anti-Ebola). In summary, this work provides a powerful methodology with a tight integration of gene-trap insertional mutagenesis testing and systems biology to identify new antiviral targets and drugs for the development of broadly acting and targeted clinical antiviral therapeutics. PMID:27632082

  10. Potential strategies for increasing drug-discovery productivity.

    Science.gov (United States)

    Cumming, John G; Finlay, M Raymond V; Giordanetto, Fabrizio; Hemmerling, Martin; Lister, Troy; Sanganee, Hitesh; Waring, Michael J

    2014-04-01

    The productivity challenge facing the pharmaceutical industry is well documented. Strategies to improve productivity have mainly focused on enhancing efficiency, such as the application of Lean Six Sigma process improvement methods and the introduction of modeling and simulation in place of 'wet' experiments. While these strategies have their benefits, the real challenge is to improve effectiveness by reducing clinical failure rates. We advocate redesigning the screening cascade to identify and optimize novel compounds with improved efficacy against disease, not just with improved potency against the target. There should be greater use of disease-relevant phenotypic screens in conjunction with target-based assays to drive medicinal chemistry optimization. An opportunistic approach to polypharmacology is recommended. There should also be more emphasis on optimization of the molecular mechanism of action incorporating understanding of binding kinetics, consideration of covalent drug strategies and targeting allosteric modulators.

  11. Transcriptome bioinformatic analysis identifies potential therapeutic mechanism of pentylenetetrazole in down syndrome

    Directory of Open Access Journals (Sweden)

    Sharma Abhay

    2010-10-01

    Full Text Available Abstract Background Pentylenetetrazole (PTZ has recently been found to ameliorate cognitive impairment in rodent models of Down syndrome (DS. The mechanism underlying PTZ's therapeutic effect in DS is however not clear. Microarray profiling has previously reported differential expression, both up- and down-regulation, of genes in DS. Given this, transcriptomic data related to PTZ treatment, if available, could be used to understand the drug's therapeutic mechanism in DS. No such mammalian data however exists. Nevertheless, a Drosophila model inspired by PTZ induced kindling plasticity in rodents has recently been described. Microarray profiling has shown PTZ's downregulatory effect on gene expression in the fly heads. Methods In a comparative transcriptomics approach, I have analyzed the available microarray data in order to identify potential therapeutic mechanism of PTZ in DS. In the analysis, summary data of up- and down-regulated genes reported in human DS studies and of down-regulated genes reported in the Drosophila model has been used. Results I find that transcriptomic correlate of chronic PTZ in Drosophila counteracts that of DS. Genes downregulated by PTZ significantly over-represent genes upregulated in DS and under-represent genes downregulated in DS. Further, the genes which are common in the downregulated and upregulated DS set show enrichment for MAP kinase pathway. Conclusion My analysis suggests that downregulation of MAP kinase pathway may mediate therapeutic effect of PTZ in DS. Existing evidence implicating MAP kinase pathway in DS supports this observation.

  12. Interdisciplinary researches for potential developments of drugs and natural products

    Directory of Open Access Journals (Sweden)

    Arunrat Chaveerach

    2017-04-01

    Full Text Available Developments of drugs or natural products from plants are possibly made, simple to use and lower cost than modern drugs. The development processes can be started with studying local wisdom and literature reviews to choose the plants which have long been used in diverse areas, such as foods, traditional medicine, fragrances and seasonings. Then those data will be associated with scientific researches, namely plant collection and identification, phytochemical screening by gas chromatography-mass spectrometry, pharmacological study/review for their functions, and finally safety and efficiency tests in human. For safety testing, in vitro cell toxicity by cell viability assessment and in vitro testing of DNA breaks by the comet assay in human peripheral blood mononuclear cells can be performed. When active chemicals and functions containing plants were chosen with safety and efficacy for human uses, then, the potential medicinal natural products will be produced. Based on these procedures, the producing cost will be cheaper and the products can be evaluated for their clinical properties. Thus, the best and lowest-priced medicines and natural products can be distributed worldwide.

  13. TRPV1: A Potential Drug Target for Treating Various Diseases

    Directory of Open Access Journals (Sweden)

    Rafael Brito

    2014-05-01

    Full Text Available Transient receptor potential vanilloid 1 (TRPV1 is an ion channel present on sensory neurons which is activated by heat, protons, capsaicin and a variety of endogenous lipids termed endovanilloids. As such, TRPV1 serves as a multimodal sensor of noxious stimuli which could trigger counteractive measures to avoid pain and injury. Activation of TRPV1 has been linked to chronic inflammatory pain conditions and peripheral neuropathy, as observed in diabetes. Expression of TRPV1 is also observed in non-neuronal sites such as the epithelium of bladder and lungs and in hair cells of the cochlea. At these sites, activation of TRPV1 has been implicated in the pathophysiology of diseases such as cystitis, asthma and hearing loss. Therefore, drugs which could modulate TRPV1 channel activity could be useful for the treatment of conditions ranging from chronic pain to hearing loss. This review describes the roles of TRPV1 in the normal physiology and pathophysiology of selected organs of the body and highlights how drugs targeting this channel could be important clinically.

  14. Bryostatin-1: pharmacology and therapeutic potential as a CNS drug.

    Science.gov (United States)

    Sun, Miao-Kun; Alkon, Daniel L

    2006-01-01

    Bryostatin-1 is a powerful protein kinase C (PKC) agonist, activating PKC isozymes at nanomolar concentrations. Pharmacological studies of bryostatin-1 have mainly been focused on its action in preventing tumor growth. Emerging evidence suggests, however, that bryostatin-1 exhibits additional important pharmacological activities. In preclinical studies bryostatin-1 has been shown at appropriate doses to have cognitive restorative and antidepressant effects. The underlying pharmacological mechanisms may involve an activation of PKC isozymes, induction of synthesis of proteins required for long-term memory, restoration of stress-evoked inhibition of PKC activity, and reduction of neurotoxic amyloid accumulation and tau protein hyperphosphorylation. The therapeutic potential of bryostatin-1 as a CNS drug should be further explored.

  15. A functional perspective of nitazoxanide as a potential anticancer drug

    Energy Technology Data Exchange (ETDEWEB)

    Di Santo, Nicola, E-mail: nico.disanto@duke.edu; Ehrisman, Jessie, E-mail: jessie.ehrisman@duke.edu

    2014-10-15

    Highlights: • Combination anti-cancer therapies are associated with increased toxicity and cross-resistance. • Some antiparasitic compounds may have anti-cancer potential. • Nitazoxanide interferes with metabolic and pro-death signaling. • Preclinical studies are needed to confirm anticancer ability of nitazoxanide. - Abstract: Cancer is a group of diseases characterized by uncontrolled cell proliferation, evasion of cell death and the ability to invade and disrupt vital tissue function. The classic model of carcinogenesis describes successive clonal expansion driven by the accumulation of mutations that eliminate restraints on proliferation and cell survival. It has been proposed that during cancer's development, the loose-knit colonies of only partially differentiated cells display some unicellular/prokaryotic behavior reminiscent of robust ancient life forms. The seeming “regression” of cancer cells involves changes within metabolic machinery and survival strategies. This atavist change in physiology enables cancer cells to behave as selfish “neo-endo-parasites” that exploit the tumor stromal cells in order to extract nutrients from the surrounding microenvironment. In this framework, it is conceivable that anti-parasitic compounds might serve as promising anticancer drugs. Nitazoxanide (NTZ), a thiazolide compound, has shown antimicrobial properties against anaerobic bacteria, as well as against helminths and protozoa. NTZ has also been successfully used to promote Hepatitis C virus (HCV) elimination by improving interferon signaling and promoting autophagy. More compelling however are the potential anti-cancer properties that have been observed. NTZ seems to be able to interfere with crucial metabolic and pro-death signaling such as drug detoxification, unfolded protein response (UPR), autophagy, anti-cytokine activities and c-Myc inhibition. In this article, we review the ability of NTZ to interfere with integrated survival mechanisms of

  16. The creative potential of the identified gifted students in the second triade of the primary school

    OpenAIRE

    Kavčič, Manca

    2016-01-01

    The purpose of the master thesis is a trial use of the EPoC, Evaluation of Potential Creativity, in primary school in Slovenia and identifying its potential contribution to improving teachers’ ability to evaluate creative potential and identifying gifted students in everyday situations in the future. The theoretical part captures the scientific findings about creativity, evaluation of creativity, relationship between creativity and giftedness and the influence of environment on creativity. Th...

  17. The creative potential of the identified gifted students in the second triade of the primary school

    OpenAIRE

    Kavčič, Manca

    2016-01-01

    The purpose of the master thesis is a trial use of the EPoC, Evaluation of Potential Creativity, in primary school in Slovenia and identifying its potential contribution to improving teachers’ ability to evaluate creative potential and identifying gifted students in everyday situations in the future. The theoretical part captures the scientific findings about creativity, evaluation of creativity, relationship between creativity and giftedness and the influence of environment on creativity. Th...

  18. High-throughput drug library screening identifies colchicine as a thyroid cancer inhibitor

    Science.gov (United States)

    Zhang, Le; Yang, Zhaoying; Granieri, Letizia; Pasculescu, Adrian; Datti, Alessandro; Asa, Sylvia L.; Xu, Zheli; Ezzat, Shereen

    2016-01-01

    We employed a high-throughput drug library screening platform to identify novel agents affecting thyroid cancer cells. We used human thyroid cancer cell lines to screen a collection of approximately 5200 small molecules with biological and/or pharmacologial properties. Parallel primary screens yielded a number of hits differentially active between thyroid and melanoma cells. Amongst compounds specifically targeting thyroid cancer cells, colchicine emerged as an effective candidate. Colchicine inhibited cell growth which correlated with G2 cell cycle arrest and apoptosis. These effects were hampered through inhibition of MEK1/2 and JNK. In contrast, inhibition of p38-MAPK had little effect, and AKT had no impact on colchicine action. Systemic colchicine inhibited thyroid cancer progression in xenografted mice. These findings demonstrate that our screening platform is an effective vehicle for drug reposition and show that colchicine warrants further attention in well-defined clinical niches such as thyroid cancer. PMID:26942566

  19. Identifying Liver Cancer and Its Relations with Diseases, Drugs, and Genes: A Literature-Based Approach

    Science.gov (United States)

    Song, Min

    2016-01-01

    In biomedicine, scientific literature is a valuable source for knowledge discovery. Mining knowledge from textual data has become an ever important task as the volume of scientific literature is growing unprecedentedly. In this paper, we propose a framework for examining a certain disease based on existing information provided by scientific literature. Disease-related entities that include diseases, drugs, and genes are systematically extracted and analyzed using a three-level network-based approach. A paper-entity network and an entity co-occurrence network (macro-level) are explored and used to construct six entity specific networks (meso-level). Important diseases, drugs, and genes as well as salient entity relations (micro-level) are identified from these networks. Results obtained from the literature-based literature mining can serve to assist clinical applications. PMID:27195695

  20. High-throughput drug library screening identifies colchicine as a thyroid cancer inhibitor.

    Science.gov (United States)

    Zhang, Le; Yang, Zhaoying; Granieri, Letizia; Pasculescu, Adrian; Datti, Alessandro; Asa, Sylvia L; Xu, Zheli; Ezzat, Shereen

    2016-04-12

    We employed a high-throughput drug library screening platform to identify novel agents affecting thyroid cancer cells. We used human thyroid cancer cell lines to screen a collection of approximately 5200 small molecules with biological and/or pharmacologial properties. Parallel primary screens yielded a number of hits differentially active between thyroid and melanoma cells. Amongst compounds specifically targeting thyroid cancer cells, colchicine emerged as an effective candidate. Colchicine inhibited cell growth which correlated with G2 cell cycle arrest and apoptosis. These effects were hampered through inhibition of MEK1/2 and JNK. In contrast, inhibition of p38-MAPK had little effect, and AKT had no impact on colchicine action. Systemic colchicine inhibited thyroid cancer progression in xenografted mice. These findings demonstrate that our screening platform is an effective vehicle for drug reposition and show that colchicine warrants further attention in well-defined clinical niches such as thyroid cancer.

  1. Identifying drug risk perceptions in Danish youths: Ranking exercises in focus groups

    DEFF Research Database (Denmark)

    Demant, Jakob; Ravn, Signe

    2010-01-01

    and provides a relatively efficient way of investigating normative risk perceptions at a national or subcultural level. The paper develops this methodology in relation to a Danish case with 12 focus group interviews with youths aged from 17 to 22. Results: The analysis identifies five discourses articulated......Abstract: Background: This paper develops an analytical approach for understanding the perceptions of risks associated with drugs among youths in general. These perceptions are central in order to understand how certain drugs become popular, leading to increasing prevalence of use, while others do...... not. As such, this approach can become an efficient policy tool. Methods: Focus groups are used to investigate risk perceptions. We develop a specific methodology that combines a ranking exercise with discourse theory as an analytical approach. This methodology produces detailed information...

  2. Potential Impact of Diet on Treatment Effect from Anti-TNF Drugs in Inflammatory Bowel Disease

    DEFF Research Database (Denmark)

    Andersen, Vibeke; Hansen, Axel Kornerup; Heitmann, Berit Lilienthal

    2017-01-01

    We wanted to investigate the current knowledge on the impact of diet on anti-TNF response in inflammatory bowel diseases (IBD), to identify dietary factors that warrant further investigations in relation to anti-TNF treatment response, and, finally, to discuss potential strategies......% CI: 1.73-4.31, p TNF treatment response for clinical use is scarce. Here we propose a mechanism by which Western style diet high in meat and low in fibre may promote colonic...... inflammation and potentially impact treatment response to anti-TNF drugs. Further studies using hypothesis-driven and data-driven strategies in prospective observational, animal and interventional studies are warranted....

  3. Predict potential drug targets from the ion channel proteins based on SVM.

    Science.gov (United States)

    Huang, Chen; Zhang, Ruijie; Chen, Zhiqiang; Jiang, Yongshuai; Shang, Zhenwei; Sun, Peng; Zhang, Xuehong; Li, Xia

    2010-02-21

    The identification of molecular targets is a critical step in the drug discovery and development process. Ion channel proteins represent highly attractive drug targets implicated in a diverse range of disorders, in particular in the cardiovascular and central nervous systems. Due to the limits of experimental technique and low-throughput nature of patch-clamp electrophysiology, they remain a target class waiting to be exploited. In our study, we combined three types of protein features, primary sequence, secondary structure and subcellular localization to predict potential drug targets from ion channel proteins applying classical support vector machine (SVM) method. In addition, our prediction comprised two stages. In stage 1, we predicted ion channel target proteins based on whole-genome target protein characteristics. Firstly, we performed feature selection by Mann-Whitney U test, then made predictions to identify potential ion channel targets by SVM and designed a new evaluating indicator Q to prioritize results. In stage 2, we made a prediction based on known ion channel target protein characteristics. Genetic algorithm was used to select features and SVM was used to predict ion channel targets. Then, we integrated results of two stages, and found that five ion channel proteins appeared in both prediction results including CGMP-gated cation channel beta subunit and Gamma-aminobutyric acid receptor subunit alpha-5, etc., and four of which were relative to some nerve diseases. It suggests that these five proteins are potential targets for drug discovery and our prediction strategies are effective.

  4. Linkage disequilibrium mapping identifies a 390 kb region associated with CYP2D6 poor drug metabolising activity.

    Science.gov (United States)

    Hosking, L K; Boyd, P R; Xu, C F; Nissum, M; Cantone, K; Purvis, I J; Khakhar, R; Barnes, M R; Liberwirth, U; Hagen-Mann, K; Ehm, M G; Riley, J H

    2002-01-01

    The cytochrome p450 enzyme, CYP2D6, metabolises approximately 20% of marketed drugs. CYP2D6 multiple variants are associated with altered enzyme activities. Genotyping 1018 Caucasians for CYP2D6 polymorphisms (G1846A, delT1707, delA2549 and A2935C), known to result in the recessive CYP2D6 poor drug metaboliser (PM) phenotype, identified 41 individuals with predicted PM phenotype. These 41 individuals were classified as 'cases'. Single nucleotide polymorphisms (SNPs) mapping within an 880 kb region flanking CYP2D6, were identified to evaluate potential association between genetic variation and the CYP2D6 PM phenotype. The 41 PM cases and 977 controls were genotyped and analysed for 27 SNPs. Associations were observed across a 390 kb region between 14 SNPs and the PM phenotype (P values from 6.20 x 10(-4) to 4.54 x 10(-35)). Haplotype analysis revealed more significant levels of association (P = 3.54 x 10(-56)). Strong (D' > 0.7) linkage disequilibrium (LD) between SNPs was observed across the same 390 kb region associated with the CYP2D6 phenotype. The observed phenotype:genotype association reached genome-wide levels of significance, and supports the strategy for potential application of LD mapping and whole genome association scans to pharmacogenetic studies.

  5. Identifying New Drug Targets for Potent Phospholipase D Inhibitors: Combining Sequence Alignment, Molecular Docking, and Enzyme Activity/Binding Assays.

    Science.gov (United States)

    Djakpa, Helene; Kulkarni, Aditya; Barrows-Murphy, Scheneque; Miller, Greg; Zhou, Weihong; Cho, Hyejin; Török, Béla; Stieglitz, Kimberly

    2016-05-01

    Phospholipase D enzymes cleave phospholipid substrates generating choline and phosphatidic acid. Phospholipase D from Streptomyces chromofuscus is a non-HKD (histidine, lysine, and aspartic acid) phospholipase D as the enzyme is more similar to members of the diverse family of metallo-phosphodiesterase/phosphatase enzymes than phospholipase D enzymes with active site HKD repeats. A highly efficient library of phospholipase D inhibitors based on 1,3-disubstituted-4-amino-pyrazolopyrimidine core structure was utilized to evaluate the inhibition of purified S. chromofuscus phospholipase D. The molecules exhibited inhibition of phospholipase D activity (IC50 ) in the nanomolar range with monomeric substrate diC4 PC and micromolar range with phospholipid micelles and vesicles. Binding studies with vesicle substrate and phospholipase D strongly indicate that these inhibitors directly block enzyme vesicle binding. Following these compelling results as a starting point, sequence searches and alignments with S. chromofuscus phospholipase D have identified potential new drug targets. Using AutoDock, inhibitors were docked into the enzymes selected from sequence searches and alignments (when 3D co-ordinates were available) and results analyzed to develop next-generation inhibitors for new targets. In vitro enzyme activity assays with several human phosphatases demonstrated that the predictive protocol was accurate. The strategy of combining sequence comparison, docking, and high-throughput screening assays has helped to identify new drug targets and provided some insight into how to make potential inhibitors more specific to desired targets.

  6. Transmission of extensively drug-resistant and multidrug resistant Mycobacterium tuberculosis in families identified by genotyping

    Institute of Scientific and Technical Information of China (English)

    YAN Li-ping; QIN Lian-hua; ZHANG Qing; SUN Hua; HAN Min; XIAO He-ping

    2013-01-01

    Background Diagnosis and appropriate treatment of multidrug-resistant tuberculosis (MDR-TB) remain major challenges.We sought to elucidate that persons who share a household with drug resistance tuberculosis patients are at high risk for primary drug resistance tuberculosis and how to prevent these outbreaks.Methods We used 12-locus mycobacterial interspersed repetitive unit and 7-locus variable-number tandem repeat to identify household transmission of extensively drug resistant and multiple drug resistant Mycobacterium tuberculosis in three families admitted in Shanghai Pulmonary Hospital affiliated with Tongji University.Drug susceptibility tests were done by the modified proportion method in the MGIT 960 system in the same time.Clinical data were also obtained from the subjects' medical records.Results All of the six strains were defined as Beijing genotype by the deletion-targeted multiplex PCR (DTM-PCR) identification on the genomic deletion RD105.Strains from family-1 had the same minisatellite interspersed repetitive unit (MIRU) pattem (232225172531) and the same MIRU pattern (3677235).Strains from family-2 had the same MIRU pattern (2212261553323) and the same MIRU pattern (3685134).Strains from family-3 did not have the same MIRU pattern and they differed at only one locus (223326173533,223325173533),and did not have the same VNTR pattern with two locus differed (3667233,3677234).Conclusions Household transmission exists in the three families.A clear chain of tuberculosis transmission within family exists.Tuberculosis susceptibility should be considered when there is more than one tuberculosis patients in a family.Household tuberculosis transmission could be prevented with adequate treatment of source patients.

  7. A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions

    Directory of Open Access Journals (Sweden)

    Robert Kraft

    2013-01-01

    The actin-bundling protein fascin is a key mediator of tumor invasion and metastasis and its activity drives filopodia formation, cell-shape changes and cell migration. Small-molecule inhibitors of fascin block tumor metastasis in animal models. Conversely, fascin deficiency might underlie the pathogenesis of some developmental brain disorders. To identify fascin-pathway modulators we devised a cell-based assay for fascin function and used it in a bidirectional drug screen. The screen utilized cultured fascin-deficient mutant Drosophila neurons, whose neurite arbors manifest the ‘filagree’ phenotype. Taking a repurposing approach, we screened a library of 1040 known compounds, many of them FDA-approved drugs, for filagree modifiers. Based on scaffold distribution, molecular-fingerprint similarities, and chemical-space distribution, this library has high structural diversity, supporting its utility as a screening tool. We identified 34 fascin-pathway blockers (with potential anti-metastasis activity and 48 fascin-pathway enhancers (with potential cognitive-enhancer activity. The structural diversity of the active compounds suggests multiple molecular targets. Comparisons of active and inactive compounds provided preliminary structure-activity relationship information. The screen also revealed diverse neurotoxic effects of other drugs, notably the ‘beads-on-a-string’ defect, which is induced solely by statins. Statin-induced neurotoxicity is enhanced by fascin deficiency. In summary, we provide evidence that primary neuron culture using a genetic model organism can be valuable for early-stage drug discovery and developmental neurotoxicity testing. Furthermore, we propose that, given an appropriate assay for target-pathway function, bidirectional screening for brain-development disorders and invasive cancers represents an efficient, multipurpose strategy for drug discovery.

  8. Heparin-based nanocapsules as potential drug delivery systems.

    Science.gov (United States)

    Baier, Grit; Winzen, Svenja; Messerschmidt, Claudia; Frank, Daniela; Fichter, Michael; Gehring, Stephan; Mailänder, Volker; Landfester, Katharina

    2015-06-01

    Herein, the synthesis and characterization of heparin-based nanocapsules (NCs) as potential drug delivery systems is described. For the synthesis of the heparin-based NCs, the versatile method of miniemulsion polymerization at the droplets interface was achieved resulting in narrowly distributed NCs with 180 nm in diameter. Scanning and transmission electron microscopy images showed clearly NC morphology. A highly negative charge density for the heparin-based NCs was determined by measuring the electro-kinetic potential. Measuring the activated clotting time demonstrated the biological intactness of the polymeric shell. The ability of heparin-based NCs to bind to antithrombin (AT III) was investigated using isothermal titration calorimetry and dynamic light scattering experiments. The chemical stability of the NCs was studied in physiological protein-containing solutions and also in medically interesting fluids such as sodium chloride 0.9%, Ringer's solution, and phosphate buffer saline using dynamic light scattering and measuring the fluorescence intensity. The impressive uptake of NCs in different cells was confirmed by fluorescence-activated cell sorting, confocal laser scanning microscopy, and transmission electron microscopy. The low toxicity of all types of NCs was demonstrated.

  9. [Drug or plant substances which antagonize venoms or potentiate antivenins].

    Science.gov (United States)

    Chippaux, J P; Rakotonirina, V S; Rakotonirina, A; Dzikouk, G

    1997-01-01

    Dendroaspis jamesoni (Elapidae) and Echis oceliatus (Viperidae) are responsible for most of severe evenomation in Cameroon. Toxicity of venoms of these two species has been measured using mice according to the method of Spearman & Kàrber. The effect on experimental envenomation of various drugs (atropine, promethazine, neostigmine, hydrocortisone, pentosane sulfuric polyester, heparin, tranexamic acid and aminocaproic acid) and plant extracts (Schumanniophyton magnificum, Bidens pilosa, Securidaca longepedunculata and Garcinia lucida) has been observed associated or not with the antivenom lpser Afrique (SAV). The venom of D. jamesoni contains neurotoxins agonizing and antagonising acetylcholine. The toxicity of the venom did not depend on the route of injection. Atropine, promethazine, neostigmine and hydrocortisone protected animals against a venom dose up to 2 LD50. Moreover, atropine and promethazine potentiated the SAV. Similar results have been obtained with extracts from S. magnificum and B. pilosa. The venom of E. ocellatus induces haemorrhage and necrosis. The toxicity increased by 3-fold when the venom was injected through intravenous or intraperitoneal route, compared to intramuscular route. Pentosane sulfuric polyester and tranexamic acid protected mice against doses up to 3 LD50. Pentosane sulfuric polyester, hydrocortisone, heparin and aminocaproic acid increased the SAV protective titre by 50%. However, tried plant extracts weakly antagonised the venom and did not potentiate the SAV.

  10. Natural Products Towards the Discovery of Potential Future Antithrombotic Drugs.

    Science.gov (United States)

    Islam, Md Asiful; Alam, Fahmida; Khalil, Md Ibrahim; Sasongko, Teguh Haryo; Gan, Siew Hua

    2016-01-01

    Globally, thrombosis-associated disorders are one of the main contributors to fatalities. Besides genetic influences, there are some acquired and environmental risk factors dominating thrombotic diseases. Although standard regimens have been used for a long time, many side effects still occur which can be life threatening. Therefore, natural products are good alternatives. Although the quest for antithrombotic natural products came to light only since the end of last century, in the last two decades, a considerable number of natural products showing antithrombotic activities (antiplatelet, anticoagulant and fibrinolytic) with no or minimal side effects have been reported. In this review, several natural products used as antithrombotic agents including medicinal plants, vegetables, fruits, spices and edible mushrooms which have been discovered in the last 15 years and their target sites (thrombogenic components, factors and thrombotic pathways) are described. In addition, the side effects, limitations and interactions of standard regimens with natural products are also discussed. The active compounds could serve as potential sources for future research on antithrombotic drug development. As a future direction, more advanced researches (in quest of the target cofactor or component involved in antithrombotic pathways) are warranted for the development of potential natural antithrombotic medications (alone or combined with standard regimens) to ensure maximum safety and efficacy.

  11. Comparison of two databases to detect potential drug-drug interactions between prescriptions of HIV/AIDS patients in critical care.

    Science.gov (United States)

    Ramos, G V; Guaraldo, L; Japiassú, A M; Bozza, F A

    2015-02-01

    Adverse drug events (ADE), common and underestimated in ICU patients, have direct consequences on length of stay, mortality and hospital costs. Critically ill patients with HIV/AIDS are at a high risk of ADE because of their need for multiple drug therapies. ADE can be prevented, especially by the identification of potentially harmful drug-drug interactions (DDIs). Electronic databases are useful tools for the investigation of DDIs to avoid potential ADEs, thereby increasing patient safety. The purpose of this study was to compare the classification and severity rating of potential adverse drug interactions seen in the prescriptions for patients with HIV/AIDS in two databases, one with free access (Drugs.com(™)) and another requiring payment for access (Micromedex(®)). A cross-sectional retrospective study of the prescriptions issued for 40 ICU HIV/AIDS patients on mechanical ventilation, admitted for more than 48 h, in a referral hospital for infectious diseases in Rio de Janeiro, Brazil, was undertaken. One prescription was reviewed each week for each patient from the second day after admission. A list of all drug-drug interactions was generated for each patient using the two drug-drug interactions databases. The weighted kappa index was estimated to assess the agreement between the classifications of DDIs identified by both databases and qualitative assessment made of any discordant classification of recorded drug-drug interactions. Of the 106 prescriptions analysed, Micromedex(®) and Drugs.com identified 347 and 615 potential DDIs, respectively. A predominance of moderate interactions and pharmacokinetic interactions was observed. The agreement between the databases regarding the severity rating was only 68.3%. The weighted kappa of 0.44 is considered moderate. Better agreement (82.4%) was observed in the classification of mechanism of interaction, with a weighted kappa of 0.61. DDIs are common between the prescriptions of patients with HIV/AIDS admitted to

  12. Pediatric psychopharmacology and local anesthesia: potential adverse drug reactions with vasoconstrictor use in dental practice.

    Science.gov (United States)

    Waits, Joe; Cretton-Scott, Erika; Childers, Noel K; Sims, Pamela J

    2014-01-01

    Pain management is important when dealing with pediatric dental patients. The use of local anesthetics can be especially challenging for children taking psychotropic medications. The purpose of this paper was to identify pertinent information regarding drug interactions between vasoconstrictor/local anesthetic combinations and medications for the management of psychiatric or behavior disorders in children. Many of the reported interactions are controversial, largely theoretical with very limited clinical evidence, and not well defined. However, when considering the potential for significant increased blood pressure when local anesthesia containing a vasoconstrictor is used, a thorough under standing of the pharmacological actions of medications used to treat psychiatric or behavioral disorders and vasoconstrictors can help dental professionals minimize the potential risk of drug interactions in their practice.

  13. Potential for treating tuberculosis with nano drug delivery system

    CSIR Research Space (South Africa)

    Swai, H

    2006-11-01

    Full Text Available easily within the body. Once Optimised for TB - NDDS can be applied for treatment of anti-Malaria drugs, anti-Cancer drugs, anti-Retrovirus Antibiotics and long term pain killers just to name a few....

  14. Identifying high-risk medication

    DEFF Research Database (Denmark)

    Sædder, Eva; Brock, Birgitte; Nielsen, Lars Peter

    2014-01-01

    salicylic acid, and beta-blockers; 30 drugs or drug classes caused 82 % of all serious MEs. The top ten drugs involved in fatal events accounted for 73 % of all drugs identified. CONCLUSION: Increasing focus on seven drugs/drug classes can potentially reduce hospitalizations, extended hospitalizations...

  15. Reimbursed Price of Orphan Drugs: Current Strategies and Potential Improvements.

    Science.gov (United States)

    Mincarone, Pierpaolo; Leo, Carlo Giacomo; Sabina, Saverio; Sarriá-Santamera, Antonio; Taruscio, Domenica; Serrano-Aguilar, Pedro Guillermo; Kanavos, Panos

    2017-01-01

    The pricing and reimbursement policies for pharmaceuticals are relevant to balance timely and equitable access for all patients, financial sustainability, and reward for valuable innovation. The proliferation of high-cost specialty medicines is particularly true in rare diseases (RDs) where the pricing mechanism is characterised by a lack of transparency. This work provides an overall picture of current strategies for the definition of the reimbursed prices of orphan drugs (ODs) and highlights some potential improvements. Current strategies and suggestions are presented along 4 dimensions: (1) comprehensive value assessment, (2) early dialogs among relevant stakeholders, (3) innovative reimbursement approaches, and (4) societal participation in producing ODs. Comprehensive value assessment could be achieved by clarifying the approach of distributive justice to adopt, ensuring a representative participation of stakeholders, and with a broad consideration of value-bearing factors. With respect to early dialogs, cross-border cooperation can be determinant to companies and agencies. The cost-benefit ratio of early dialogs needs to be demonstrated and the "regulatory capture" effect should be monitored. Innovative reimbursement approaches were developed to balance the need for evidence-based decisions with the timely access to innovative drugs. The societal participation in producing ODs needs to be recognised in a collaborating framework where adaptive agreements can be developed with mutual satisfaction. Such agreements could also impact on coverage and reimbursement decisions as additional elements for the determination of a comprehensive societal value of ODs. Further research is needed to investigate the highlighted open challenges so that RDs will not remain, in practical terms, orphan diseases. © 2017 S. Karger AG, Basel.

  16. In vitro metabolism and drug-drug interaction potential of UTL-5g, a novel chemo- and radioprotective agent.

    Science.gov (United States)

    Wu, Jianmei; Shaw, Jiajiu; Dubaisi, Sarah; Valeriote, Frederick; Li, Jing

    2014-12-01

    N-(2,4-dichlorophenyl)-5-methyl-1,2-oxazole-3-carboxamide (UTL-5g), a potential chemo- and radioprotective agent, acts as a prodrug requiring bioactivation to the active metabolite 5-methylisoxazole-3-carboxylic acid (ISOX). UTL-5g hydrolysis to ISOX and 2,4-dichloroaniline (DCA) has been identified in porcine and rabbit liver esterases. The purpose of this study was to provide insights on the metabolism and drug interaction potential of UTL-5g in humans. The kinetics of UTL-5g hydrolysis was determined in human liver microsomes (HLM) and recombinant human carboxylesterases (hCE1b and hCE2). The potential of UTL-5g and its metabolites for competitive inhibition and time-dependent inhibition of microsomal cytochrome P450 (P450) was examined in HLM. UTL-5g hydrolysis to ISOX and DCA in HLM were NADPH-independent, with a maximum rate of reaction (Vmax) of 11.1 nmol/min per mg and substrate affinity (Km) of 41.6 µM. Both hCE1b and hCE2 effectively catalyzed UTL-5g hydrolysis, but hCE2 exhibited ∼30-fold higher catalytic efficiency (Vmax/Km) than hCE1b. UTL-5g and DCA competitively inhibited microsomal CYP1A2, CYP2B6, and CYP2C19 (IC50 values 5g. Factors influencing carboxylesterase activities may have a significant impact on the pharmacological and therapeutic effects of UTL-5g. UTL-5g has the potential to inhibit P450-mediated metabolism through competitive inhibition or time-dependent inhibition. Caution is particularly needed for potential drug interactions involving competitive inhibition or time-dependent inhibition of CYP1A2 in the future clinical development of UTL-5g. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

  17. Genome-wide approaches to identify pharmacogenetic contributions to adverse drug reactions.

    Science.gov (United States)

    Nelson, M R; Bacanu, S-A; Mosteller, M; Li, L; Bowman, C E; Roses, A D; Lai, E H; Ehm, M G

    2009-02-01

    Adverse drug reactions (ADRs) have a major impact on patients, physicians, health care providers, regulatory agencies and pharmaceutical companies. Identifying the genetic contributions to ADR risk may lead to a better understanding of the underlying mechanisms, identification of patients at risk and a decrease in the number of events. Technological advances have made the routine monitoring and investigation of the genetic basis of ADRs during clinical trials possible. We demonstrate through simulation that genome-wide genotyping, coupled with the use of clinically matched or population controls, can yield sufficient statistical power to permit the identification of strong genetic predictors of ADR risk in a prospective manner with modest numbers of ADR cases. The results of a 500,000 single nucleotide polymorphism analysis of abacavir-associated hypersensitivity reaction suggest that the known HLA-B gene region could be identified with as few as 15 cases and 200 population controls in a sequential analysis.

  18. MONITORING POTENTIAL DRUG INTERACTIONS AND REACTIONS VIA NETWORK ANALYSIS OF INSTAGRAM USER TIMELINES.

    Science.gov (United States)

    Correia, Rion Brattig; Li, Lang; Rocha, Luis M

    2016-01-01

    Much recent research aims to identify evidence for Drug-Drug Interactions (DDI) and Adverse Drug reactions (ADR) from the biomedical scientific literature. In addition to this "Bibliome", the universe of social media provides a very promising source of large-scale data that can help identify DDI and ADR in ways that have not been hitherto possible. Given the large number of users, analysis of social media data may be useful to identify under-reported, population-level pathology associated with DDI, thus further contributing to improvements in population health. Moreover, tapping into this data allows us to infer drug interactions with natural products-including cannabis-which constitute an array of DDI very poorly explored by biomedical research thus far. Our goal is to determine the potential of Instagram for public health monitoring and surveillance for DDI, ADR, and behavioral pathology at large. Most social media analysis focuses on Twitter and Facebook, but Instagram is an increasingly important platform, especially among teens, with unrestricted access of public posts, high availability of posts with geolocation coordinates, and images to supplement textual analysis. Using drug, symptom, and natural product dictionaries for identification of the various types of DDI and ADR evidence, we have collected close to 7000 user timelines spanning from October 2010 to June 2015.We report on 1) the development of a monitoring tool to easily observe user-level timelines associated with drug and symptom terms of interest, and 2) population-level behavior via the analysis of co-occurrence networks computed from user timelines at three different scales: monthly, weekly, and daily occurrences. Analysis of these networks further reveals 3) drug and symptom direct and indirect associations with greater support in user timelines, as well as 4) clusters of symptoms and drugs revealed by the collective behavior of the observed population. This demonstrates that Instagram

  19. Metabolomics has the potential to improve drug therapy

    DEFF Research Database (Denmark)

    Stage, Claus; Jürgens, Gesche; Dalhoff, Kim Peder

    2014-01-01

    Until now drug therapy has primarily been controlled by dose titration on the basis of effects and side effects. However, a lot of people being treated with a drug experience too little effect or too many side effects. Therefore it will be advantageous to improve drug therapy and make it even mor...... "individualized". In this chase metabolomics is a hot topic. The aim of this paper is to review the concepts of metabolomics and the possible applications in regard to drug development, drug therapy and diagnosis, prognosis and monitoring of diseases....

  20. A practical Bayesian design to identify the maximum tolerated dose contour for drug combination trials.

    Science.gov (United States)

    Zhang, Liangcai; Yuan, Ying

    2016-11-30

    Drug combination therapy has become the mainstream approach to cancer treatment. One fundamental feature that makes combination trials different from single-agent trials is the existence of the maximum tolerated dose (MTD) contour, that is, multiple MTDs. As a result, unlike single-agent phase I trials, which aim to find a single MTD, it is often of interest to find the MTD contour for combination trials. We propose a new dose-finding design, the waterfall design, to find the MTD contour for drug combination trials. Taking the divide-and-conquer strategy, the waterfall design divides the task of finding the MTD contour into a sequence of one-dimensional dose-finding processes, known as subtrials. The subtrials are conducted sequentially in a certain order, such that the results of each subtrial will be used to inform the design of subsequent subtrials. Such information borrowing allows the waterfall design to explore the two-dimensional dose space efficiently using a limited sample size and decreases the chance of overdosing and underdosing patients. To accommodate the consideration that doses on the MTD contour may have very different efficacy or synergistic effects because of drug-drug interaction, we further extend our approach to a phase I/II design with the goal of finding the MTD with the highest efficacy. Simulation studies show that the waterfall design is safer and has higher probability of identifying the true MTD contour than some existing designs. The R package "BOIN" to implement the waterfall design is freely available from CRAN. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  1. Potential utility of data-mining algorithms for early detection of potentially fatal/disabling adverse drug reactions: a retrospective evaluation.

    Science.gov (United States)

    Hauben, Manfred; Reich, Lester

    2005-04-01

    The objective of this study was to apply 2 data-mining algorithms to a drug safety database to determine if these methods would have flagged potentially fatal/disabling adverse drug reactions that triggered black box warnings/drug withdrawals in advance of initial identification via "traditional" methods. Relevant drug-event combinations were identified from a journal publication. Data-mining algorithms using commonly cited disproportionality thresholds were then applied to the US Food and Drug Administration database. Seventy drug-event combinations were considered sufficiently specific for retrospective data mining. In a minority of instances, potential signals of disproportionate reporting were provided clearly in advance of initial identification via traditional pharmacovigilance methods. Data-mining algorithms have the potential to improve pharmacovigilance screening; however, for the majority of drug-event combinations, there was no substantial benefit of either over traditional methods. They should be considered as potential supplements to, and not substitutes for, traditional pharmacovigilance strategies. More research and experience will be needed to optimize deployment of data-mining algorithms in pharmacovigilance.

  2. Potential interactions of central nervous system drugs used in the elderly population

    Directory of Open Access Journals (Sweden)

    Fernanda Bueno Morrone

    2009-06-01

    Full Text Available OBJECTIVE: To describe the use of CNS drugs and to identify the most frequently observed potential drug interactions in the elderly living in Southern Brazil. METHODS: A population-based, transversal and observational study was carried out during 2006-2007. Four hundred and eighty elderly individuals of both genders were randomly recruited and interviewed. A validated pharmacotherapeutic questionnaire and the Micromedex® Healthcare Series were utilized to analyze potential drug interactions. A severity rating scale employing the categories of "mild", "moderate" and "severe" was used to describe the interactions. RESULTS: A population of elderly living in Southern Brazil was interviewed and 98 reported using CNS drugs, 74.5% female and 25.5% male. Out of these patients, 32.0% reported severe or moderate pharmacological interactions related to the use of other drugs. Alprazolam and imipramine were reported to potentially interact with tobacco. Twenty potential moderate drug/ethanol interactions were found. The potential drug/caffeine interactions were classified as mild on the severity scale. CONCLUSION: Elderly being prescribed drugs that act on the CNS should be closely monitored, and furthermore, should be warned against potential drug-drug, drug-ethanol, and drug-tobacco interactions.OBJETIVO: Descrever o uso de medicamentos que atuam no sistema nervoso central (SNC e identificar as possíveis interações mais frequentes com esses medicamentos em idosos do sul do Brasil. MÉTODOS: Estudo de base populacional, transversal e observacional, realizado durante 2006-2007. Quatrocentos e oitenta idosos de ambos os sexos foram randomizados e entrevistados. Foram utilizados um questionário farmacoterapêutico validado e o programa Micromedex® Healthcare Series para analisar as potenciais interações com os medicamentos. Foi utilizada uma escala para descrever a gravidade das interações nas categorias de "leve", "moderada" e "grave". RESULTADOS

  3. Identifying drug-induced repolarization abnormalities from distinct ECG patterns in congenital long QT syndrome: a study of sotalol effects on T-wave morphology

    DEFF Research Database (Denmark)

    Graff, Claus; Andersen, Mads P; Xue, Joel Q

    2009-01-01

    BACKGROUND: The electrocardiographic QT interval is used to identify drugs with potential harmful effects on cardiac repolarization in drug trials, but the variability of the measurement can mask drug-induced ECG changes. The use of complementary electrocardiographic indices of abnormal repolariz......BACKGROUND: The electrocardiographic QT interval is used to identify drugs with potential harmful effects on cardiac repolarization in drug trials, but the variability of the measurement can mask drug-induced ECG changes. The use of complementary electrocardiographic indices of abnormal...... are typical ECG patterns in LQT2. Blinded to labels, the new morphology measures were tested in a third group of 39 healthy subjects receiving sotalol. Over 3 days the sotalol group received 0, 160 and 320 mg doses, respectively, and a 12-lead Holter ECG was recorded for 22.5 hours each day. Drug...... with QTcF, p ECG patterns in LQT2 carriers effectively quantified repolarization changes induced by sotalol. Further studies are needed to validate whether this measure has...

  4. Visual Evoked Potential Response Among Drug Abusers- A Cross Sectional Study

    Science.gov (United States)

    Sharma, Rajeev; Thapar, Satish; Mittal, Shilekh

    2016-01-01

    Introduction There is important preclinical evidence that substance abuse may produce neurophysiological disturbances particularly in relation to altered neural synchronization in Visual Evoked Potentials (VEP). Aim The purpose of current study was to compare the latencies and amplitudes of different waveforms of VEP among different drug abusers and controls and also to identify early neurological damage so that proper counseling and timely intervention can be undertaken. Materials and Methods VEP was assessed by Data Acquisition and Analysis system in a sample of 58 drug abusers, all males, within age group of 15-45 years as well as in age matched 30 healthy controls. The peak latencies and peak to peak amplitudes of different waveforms were measured by applying one-way Anova test and unpaired t-test using SPSS version 16. Results In between drug abusers and controls, the difference in the duration of N75 and P100 waveform of VEP was found to be statistically highly significant (pdrug abusers in both eyes. Conclusion Chronic intoxication by different drugs has been extensively associated with amplitude reduction of P100 and prolonged latency of N75 and P100 reflecting an adverse effects of drug dependence on neural transmission within primary visual areas of brain. PMID:27042456

  5. Computer-aided identification of potential TYK2 inhibitors from drug database

    Science.gov (United States)

    Zhang, Wei; Li, Jianzong; Huang, Zhixin; Wang, Haiyang; Luo, Hao; Wang, Xin; Zhou, Nan; Wu, Chuanfang; Bao, Jinku

    2016-10-01

    TYK2 is a member of JAKs family protein tyrosine kinase activated in response to various cytokines. It plays a crucial role in transducing signals downstream of various cytokine receptors, which are involved in proinflammatory responses associated with immunological diseases. Thus, the study of selective TYK2 inhibitors is one of the most popular fields in anti-inflammation drug development. Herein, we adopted molecular docking, molecular dynamics simulation and MM-PBSA binding free energy calculation to screen potential TYK2-selective inhibitors from ZINC Drug Database. Finally, three small molecule drugs ZINC12503271 (Gemifloxacin), ZINC05844792 (Nebivolol) and ZINC00537805 (Glyburide) were selected as potential TYK2-selective inhibitors. Compared to known inhibitor 2,6-dichloro-N-{2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}benzamide, these three candidates had better Grid score and Amber score from molecular docking and preferable results from binding free energy calculation as well. What's more, the ATP-binding site and A-loop motif had been identified to play key roles in TYK2-targeted inhibitor discovery. It is expected that our study will pave the way for the design of potent TYK2 inhibitors of new drugs to treat a wide variety of immunological diseases such as inflammatory diseases, multiple sclerosis, psoriasis inflammatory bowel disease (IBD) and so on.

  6. Identification of potential therapeutic drugs for huntington's disease using Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Cindy Voisine

    Full Text Available BACKGROUND: The prolonged time course of Huntington's disease (HD neurodegeneration increases both the time and cost of testing potential therapeutic compounds in mammalian models. An alternative is to initially assess the efficacy of compounds in invertebrate models, reducing time of testing from months to days. METHODOLOGY/PRINCIPAL FINDINGS: We screened candidate therapeutic compounds that were identified previously in cell culture/animal studies in a C. elegans HD model and found that two FDA approved drugs, lithium chloride and mithramycin, independently and in combination suppressed HD neurotoxicity. Aging is a critical contributor to late onset neurodegenerative diseases. Using a genetic strategy and a novel assay, we demonstrate that lithium chloride and mithramycin remain neuroprotective independent of activity of the forkhead transcription factor DAF-16, which mediates the effects of the insulin-like signaling pathway on aging. CONCLUSIONS/SIGNIFICANCE: These results suggest that pathways involved in polyglutamine-induced degeneration are distinct from specific aging pathways. The assays presented here will be useful for rapid and inexpensive testing of other potential HD drugs and elucidating pathways of drug action. Additionally, the neuroprotection conferred by lithium chloride and mithramycin suggests that these drugs may be useful for polyglutamine disease therapy.

  7. 75 FR 4400 - Draft Guidance for Industry on Assessment of Abuse Potential of Drugs; Availability

    Science.gov (United States)

    2010-01-27

    ... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Assessment of Abuse Potential... and Drug Administration (FDA) is announcing the availability of a draft guidance for industry entitled... availability of a draft guidance for industry entitled ``Assessment of Abuse Potential of Drugs.'' Under...

  8. Altered protein S-glutathionylation identifies a potential mechanism of resistance to acetaminophen-induced hepatotoxicity.

    Science.gov (United States)

    McGarry, David J; Chakravarty, Probir; Wolf, C Roland; Henderson, Colin J

    2015-11-01

    Acetaminophen (APAP) is the most commonly used over-the-counter analgesic. However, hepatotoxicity induced by APAP is a major clinical issue, and the factors that define sensitivity to APAP remain unclear. We have previously demonstrated that mice nulled for glutathione S-transferase Pi (GSTP) are resistant to APAP-induced hepatotoxicity. This study aims to exploit this difference to delineate pathways of importance in APAP toxicity. We used mice nulled for GSTP and heme oxygenase-1 oxidative stress reporter mice, together with a novel nanoflow liquid chromatography-tandem mass spectrometry methodology to investigate the role of oxidative stress, cell signaling, and protein S-glutathionylation in APAP hepatotoxicity. We provide evidence that the sensitivity difference between wild-type and Gstp1/2(-/-) mice is unrelated to the ability of APAP to induce oxidative stress, despite observing significant increases in c-Jun N-terminal kinase and extracellular signal-regulated kinase phosphorylation in wild-type mice. The major difference in response to APAP was in the levels of protein S-glutathionylation: Gstp1/2(-/-) mice exhibited a significant increase in the number of S-glutathionylated proteins compared with wild-type animals. Remarkably, these S-glutathionylated proteins are involved in oxidative phosphorylation, respiratory complexes, drug metabolism, and mitochondrial apoptosis. Furthermore, we found that S-glutathionylation of the rate-limiting glutathione-synthesizing enzyme, glutamate cysteine ligase, was markedly increased in Gstp1/2(-/-) mice in response to APAP. The data demonstrate that S-glutathionylation provides an adaptive response to APAP and, as a consequence, suggest that this is an important determinant in APAP hepatotoxicity. This work identifies potential novel avenues associated with cell survival for the treatment of chemical-induced hepatotoxicity.

  9. Closantel; a veterinary drug with potential severe morbidity in humans.

    Science.gov (United States)

    Tabatabaei, Seyed Ali; Soleimani, Mohammad; Mansouri, Mohammad Reza; Mirshahi, Ahmad; Inanlou, Bahman; Abrishami, Mojtaba; Pakrah, Ahmad Reza; Masarat, Hamideh

    2016-11-29

    Closantel is a halogenated salicylanilide with a potent anti parasitic activity. It is widely used in management of parasitic infestation in animals, but is contraindicated in humans. A 34-year-old man with depression was referred to our center with progressive loss of vision in both eyes 10 days after unintentional ingestion of three 500 mg tablets of Closantel. On fundus examination, left optic disc margin was blurred. His bilateral visual acuity was no light perception (NLP) despite prescribed IV erythropoietin injections 20,000 units daily for 3 days and 1gr intravenous methylprednisolone acetate for 3 days followed by 1 mg/kg oral prednisolone. On macular optical coherence tomography (OCT), a disruption in outer retina was observed. Electroretinogram and visual evoked potential tests showed visual pathway involvement. Destruction of neurosensory retina and visual pathways after accidental Closantel use is related to severe visual loss. This case alerts us about the destructive effect of this drug on humans even in low dosage which necessitates preventive efforts to reduce the chance of this morbid side effect.

  10. Computational Identification of Potential Multi-drug Combinations for Reduction of Microglial Inflammation in Alzheimer Disease

    Directory of Open Access Journals (Sweden)

    Thomas J. Anastasio

    2015-06-01

    Full Text Available Like other neurodegenerative diseases, Alzheimer Disease (AD has a prominent inflammatory component mediated by brain microglia. Reducing microglial inflammation could potentially halt or at least slow the neurodegenerative process. A major challenge in the development of treatments targeting brain inflammation is the sheer complexity of the molecular mechanisms that determine whether microglia become inflammatory or take on a more neuroprotective phenotype. The process is highly multifactorial, raising the possibility that a multi-target/multi-drug strategy could be more effective than conventional monotherapy. This study takes a computational approach in finding combinations of approved drugs that are potentially more effective than single drugs in reducing microglial inflammation in AD. This novel approach exploits the distinct advantages of two different computer programming languages, one imperative and the other declarative. Existing programs written in both languages implement the same model of microglial behavior, and the input/output relationships of both programs agree with each other and with data on microglia over an extensive test battery. Here the imperative program is used efficiently to screen the model for the most efficacious combinations of 10 drugs, while the declarative program is used to analyze in detail the mechanisms of action of the most efficacious combinations. Of the 1024 possible drug combinations, the simulated screen identifies only 7 that are able to move simulated microglia at least 50% of the way from a neurotoxic to a neuroprotective phenotype. Subsequent analysis shows that of the 7 most efficacious combinations, 2 stand out as superior both in strength and reliability. The model offers many experimentally testable and therapeutically relevant predictions concerning effective drug combinations and their mechanisms of action.

  11. Assessment of potential drug–drug interactions and its associated factors in the hospitalized cardiac patients

    Directory of Open Access Journals (Sweden)

    Ghulam Murtaza

    2016-03-01

    Full Text Available Drug–drug interactions (DDIs may result in the alteration of therapeutic response. Sometimes they may increase the untoward effects of many drugs. Hospitalized cardiac patients need more attention regarding drug–drug interactions due to complexity of their disease and therapeutic regimen. This research was performed to find out types, prevalence and association between various predictors of potential drug–drug interactions (pDDIs in the Department of Cardiology and to report common interactions. This study was performed in the hospitalized cardiac patients at Ayub Teaching Hospital, Abbottabad, Pakistan. Patient charts of 2342 patients were assessed for pDDIs using Micromedex® Drug Information. Logistic regression was applied to find predictors of pDDIs. The main outcome measure in the study was the association of the potential drug–drug interactions with various factors such as age, gender, polypharmacy, and hospital stay of the patients. We identified 53 interacting-combinations that were present in total 5109 pDDIs with median number of 02 pDDIs per patient. Overall, 91.6% patients had at least one pDDI; 86.3% were having at least one major pDDI, and 84.5% patients had at least one moderate pDDI. Among 5109 identified pDDIs, most were of moderate (55% or major severity (45%; established (24.2%, theoretical (18.8% or probable (57% type of scientific evidence. Top 10 common pDDIs included 3 major and 7 moderate interactions. Results obtained by multivariate logistic regression revealed a significant association of the occurrence of pDDIs in patient with age of 60 years or more (p < 0.001, hospital stay of 7 days or longer (p < 0.001 and taking 7 or more drugs (p < 0.001. We found a high prevalence for pDDIs in the Department of Cardiology, most of which were of moderate severity. Older patients, patients with longer hospital stay and with elevated number of prescribed drugs were at higher risk of pDDIs.

  12. Natural Compounds from Mexican Medicinal Plants as Potential Drug Leads for Anti-Tuberculosis Drugs

    Directory of Open Access Journals (Sweden)

    ROCIO GÓMEZ-CANSINO

    Full Text Available ABSTRACT In Mexican Traditional Medicine 187 plant species are used in the treatment of respiratory conditions that may be associated with tuberculosis. In this contribution, we review the ethnobotany, chemistry and pharmacology of 63 species whose extracts have been assayed for antimycobacterial activity in vitro. Among these, the most potent is Aristolochia brevipes (MIC= 12.5 µg/mL, followed by Aristolochia taliscana, Citrus sinensis, Chrysactinia mexicana, Persea americana, and Olea europaea (MIC 95%, 50 µg/mL include: Amphipterygium adstringens, Larrea divaricata, and Phoradendron robinsoni. Several active compounds have been identified, the most potent are: Licarin A (isolated from A. taliscana, and 9-amino-9-methoxy-3,4-dihydro-2H-benzo[h]-chromen-2-one (transformation product of 9-methoxytariacuripyrone isolated from Aristolochia brevipes, both with MIC= 3.125 µg/mL, that is 8-fold less potent than the reference drug Rifampicin (MIC= 0.5 µg/mL. Any of the compounds or extracts here reviewed has been studied in clinical trials or with animal models; however, these should be accomplished since several are active against strains resistant to common drugs.

  13. Natural Compounds from Mexican Medicinal Plants as Potential Drug Leads for Anti-Tuberculosis Drugs.

    Science.gov (United States)

    Gómez-Cansino, Rocio; Guzmán-Gutiérrez, Silvia Laura; Campos-Lara, María Guadalupe; Espitia-Pinzón, Clara Ines; Reyes-Chilpa, Ricardo

    2017-02-09

    In Mexican Traditional Medicine 187 plant species are used in the treatment of respiratory conditions that may be associated with tuberculosis. In this contribution, we review the ethnobotany, chemistry and pharmacology of 63 species whose extracts have been assayed for antimycobacterial activity in vitro. Among these, the most potent is Aristolochia brevipes (MIC= 12.5 µg/mL), followed by Aristolochia taliscana, Citrus sinensis, Chrysactinia mexicana, Persea americana, and Olea europaea (MIC 95%, 50 µg/mL) include: Amphipterygium adstringens, Larrea divaricata, and Phoradendron robinsoni. Several active compounds have been identified, the most potent are: Licarin A (isolated from A. taliscana), and 9-amino-9-methoxy-3,4-dihydro-2H-benzo[h]-chromen-2-one (transformation product of 9-methoxytariacuripyrone isolated from Aristolochia brevipes), both with MIC= 3.125 µg/mL, that is 8-fold less potent than the reference drug Rifampicin (MIC= 0.5 µg/mL). Any of the compounds or extracts here reviewed has been studied in clinical trials or with animal models; however, these should be accomplished since several are active against strains resistant to common drugs.

  14. Drugging the Undruggable: Therapeutic Potential of Targeting Protein Tyrosine Phosphatases.

    Science.gov (United States)

    Zhang, Zhong-Yin

    2017-01-17

    Protein tyrosine phosphatases (PTPs) are essential signaling enzymes that, together with protein tyrosine kinases, regulate tyrosine phosphorylation inside the cell. Proper level of tyrosine phosphorylation is important for a diverse array of cellular processes, such as proliferation, metabolism, motility, and survival. Aberrant tyrosine phosphorylation, resulting from alteration of PTP expression, misregulation, and mutation, has been linked to the etiology of many human ailments including cancer, diabetes/obesity, autoimmune disorders, and infectious diseases. However, despite the fact that PTPs have been garnering attention as compelling drug targets, they remain a largely underexploited resource for therapeutic intervention. Indeed, PTPs have been widely dismissed as "undruggable", due to concerns that (1) the highly conserved active site (i.e., pTyr-binding pocket) makes it difficult to achieve inhibitor selectivity among closely related family members, and (2) the positive-charged active site prefers negatively charged molecules, which usually lack cell permeability. To address the issue of selectivity, we advanced a novel paradigm for the acquisition of highly potent and selective PTP inhibitors through generation of bivalent ligands that interact with both PTP active site and adjacent unique peripheral pockets. To overcome the bioavailability issue, we have identified nonhydrolyzable pTyr mimetics that are sufficiently polar to bind the PTP active site, yet still capable of efficiently penetrating cell membranes. We show that these pTyr mimetics interact in the desired inhibitory fashion with the PTP active site and tethering them to appropriate molecular fragments to engage less conserved interactions outside of PTP active site can increase PTP inhibitor potency and selectivity. We demonstrate through three pTyr mimetics fragment-based approaches that it is completely feasible to obtain highly potent and selective PTP inhibitors with robust in vivo

  15. Emory University: MEDICI (Mining Essentiality Data to Identify Critical Interactions) for Cancer Drug Target Discovery and Development | Office of Cancer Genomics

    Science.gov (United States)

    The CTD2 Center at Emory University has developed a computational methodology to combine high-throughput knockdown data with known protein network topologies to infer the importance of protein-protein interactions (PPIs) for the survival of cancer cells.  Applying these data to the Achilles shRNA results, the CCLE cell line characterizations, and known and newly identified PPIs provides novel insights for potential new drug targets for cancer therapies and identifies important PPI hubs.

  16. Potential drug-drug interactions in prescriptions dispensed in community and hospital pharmacies in East of Iran

    OpenAIRE

    Dirin, Mandana Moradi; Mousavi, Sarah; Afshari, Amir Reza; Tabrizian, Kaveh; Ashrafi, Mohammad Hossein

    2014-01-01

    Objective: This study aim to evaluate and compare type and prevalence of drug-drug interactions (DDIs) in prescriptions dispensed in both community and hospital setting in Zabol, Iran. Methods: A total of 2796 prescriptions were collected from community and inpatient and outpatient pharmacy of Amir-al-momenin only current acting hospital in Zabol, Iran. The prescriptions were processed using Lexi-Comp drug interaction software. The identified DDIs were categorized into five classes (A, B, C, ...

  17. 78 FR 57859 - Draft Guidance for Industry on Endocrine Disruption Potential of Drugs: Nonclinical Evaluation...

    Science.gov (United States)

    2013-09-20

    ... entitled ``Endocrine Disruption Potential of Drugs: Nonclinical Evaluation.'' Endocrine disruptors are... its progeny. Any component of the endocrine system can be a target of endocrine disruptors, although... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Endocrine...

  18. Coronary side-effect potential of current and prospective antimigraine drugs

    NARCIS (Netherlands)

    A. Maassen van den Brink (Antoinette); M. Reekers; W.A. Bax (Willem); M.D. Ferrari (Michel); P.R. Saxena (Pramod Ranjan)

    1998-01-01

    textabstractBACKGROUND: The antimigraine drugs ergotamine and sumatriptan may cause angina-like symptoms, possibly resulting from coronary artery constriction. We compared the coronary vasoconstrictor potential of a number of current and prospective antimigraine drugs (

  19. Erosive and cariogenicity potential of pediatric drugs: study of physicochemical parameters.

    Science.gov (United States)

    Xavier, Alidianne Fábia C; Moura, Eline F F; Azevedo, Waldeneide F; Vieira, Fernando F; Abreu, Mauro H N G; Cavalcanti, Alessandro L

    2013-12-10

    Pediatric medications may possess a high erosive potential to dental tissues due to the existence of acid components in their formulations. The purpose was to determine the erosive and cariogenic potential of pediatric oral liquid medications through the analysis of their physicochemical properties in vitro. A total of 59 substances were selected from the drug reference list of the National Health Surveillance Agency (ANVISA), which belong to 11 therapeutic classes, as follows: analgesics, non-steroidal anti-inflammatory, corticosteroids, antihistamines, antitussives, bronchodilators, antibacterials, antiparasitics, antiemetics, anticonvulsants and antipsychotics. Measurement of pH was performed by potentiometry, using a digital pH meter. For the Total Titratable Acidity (TTA) chemical assay, a 0.1 N NaOH standard solution was used, which was titrated until drug pH was neutralized. The Total Soluble Solids Contents (TSSC) quantification was carried out by refractometry using Brix scale and the analysis of Total Sugar Content was performed according to Fehling's method. In addition, it was analyzed the information contained in the drug inserts with regard to the presence of sucrose and type of acid and sweetener added to the formulations. All drug classes showed acidic pH, and the lowest mean was found for antipsychotics (2.61 ± 0.08). There was a large variation in the TTA (0.1% - 1.18%) and SST (10.44% - 57.08%) values. High total sugar contents were identified in the antitussives (53.25%) and anticonvulsants (51.75%). As described in the drug inserts, sucrose was added in 47.5% of the formulations, as well as citric acid (39.0%), sodium saccharin (36.4%) and sorbitol (34.8%). The drugs analyzed herein showed physicochemical characteristics indicative of a cariogenic and erosive potential on dental tissues. Competent bodies' strategies should be implemented in order to broaden the knowledge of health professionals, drug manufacturers and general consuming public

  20. Small molecule screening in zebrafish: an in vivo approach to identifying new chemical tools and drug leads

    Directory of Open Access Journals (Sweden)

    Patton E Elizabeth

    2010-06-01

    Full Text Available Abstract In the past two decades, zebrafish genetic screens have identified a wealth of mutations that have been essential to the understanding of development and disease biology. More recently, chemical screens in zebrafish have identified small molecules that can modulate specific developmental and behavioural processes. Zebrafish are a unique vertebrate system in which to study chemical genetic systems, identify drug leads, and explore new applications for known drugs. Here, we discuss some of the advantages of using zebrafish in chemical biology, and describe some important and creative examples of small molecule screening, drug discovery and target identification.

  1. Electrical potential difference across the stomach wall and gastric morphology in anaesthetized pigs after intravenous administration of cytotoxic drugs

    DEFF Research Database (Denmark)

    Fabrin, B.; Højgaard, L.; Olesen, H.P.;

    1991-01-01

    Oncologi, cytotoxic drugs, electrical potential difference, medicin, cander, gastric, side effects, chemotherapy......Oncologi, cytotoxic drugs, electrical potential difference, medicin, cander, gastric, side effects, chemotherapy...

  2. Surveillance methods for identifying, characterizing, and monitoring tobacco products: potential reduced exposure products as an example

    Science.gov (United States)

    O’Connor, Richard J.; Cummings, K. Michael; Rees, Vaughan W.; Connolly, Gregory N.; Norton, Kaila J.; Sweanor, David; Parascandola, Mark; Hatsukami, Dorothy K.; Shields, Peter G.

    2015-01-01

    Tobacco products are widely sold and marketed, yet integrated data systems for identifying, tracking, and characterizing products are lacking. Tobacco manufacturers recently have developed potential reduction exposure products (PREPs) with implied or explicit health claims. Currently, a systematic approach for identifying, defining, and evaluating PREPs sold at the local, state or national levels in the US has not been developed. Identifying, characterizing, and monitoring new tobacco products could be greatly enhanced with a responsive surveillance system. This paper critically reviews available surveillance data sources for identifying and tracking tobacco products, including PREPs, evaluating strengths and weaknesses of potential data sources in light of their reliability and validity. Absent regulations mandating disclosure of product-specific information, it is likely that public health officials will need to rely on a variety of imperfect data sources to help identify, characterize, and monitor tobacco products, including PREPs. PMID:19959680

  3. New imidazolidinic bioisosters: potential candidates for antischistosomal drugs

    Directory of Open Access Journals (Sweden)

    Maira GR Pitta

    2006-10-01

    Full Text Available The emergence of strains of Schistosoma resistant to praziquantel has drawn attention to the search for new schistosomacide drugs. Imidazolidinic derivatives have performed outstandingly against adult S. mansoni worms when evaluated in vitro. The molecular modification of imidazolidine by way of bioisosteric replacement gives rise to variations in its biological response. This study verifies the potential of substituent groups in the derivatives (Z3-benzyl-5-(2-fluoro-benzylidene-imidazolidine-2,4-dione NE4, 3-benzyl-5-(4-chloro-arylazo-4-thioxo-imidazolidin -2-ona PT5, 3-benzyl-5-(3-fluoro-benzylidene-1-methyl-2-thioxo-imidazolidin-4-one JT53; 3-benzyl-1-methyl-5-(4-methyl-benzylidene-2-thioxo-imidazolidin-4-one JT63; 3-benzyl-1-methyl-5-(4-methoxi-benzylidene-2-thioxo -imidazolidin-4-one JT68; 3-(4-chloro-benzyl-1-methyl-5-(4-methoxi-benzylidene-2-thioxo-imidazolidin-4-one JT69; 3-(4-phenyl-benzyl-1-methyl-5-(4-methoxi-benzylidene-2-thioxo-imidazolidin-4-one JT72 by determining the viability in vitro of adult S. mansoni worms in the presence of these derivatives. The susceptibility of the worms obtained from mice and kept in culture in the presence of different concentrations was determined by way of schistosomacide kinetic, observed every 24 h over a period of eight days. The results show that the worms were more sensitive to the PT5 derivative at a concentration of 58 µM which killed 100% of the worms after 24 h of contact, also giving rise to alterations in the tegument surface of the worms with the formation of bubbles and peeling. These observations suggest a strong electronic contribution of the arylazo grouping in the biological response.

  4. Can the genotype or phenotype of two polymorphic drug metabolising cytochrome P450-enzymes identify oral lichenoid drug eruptions?

    DEFF Research Database (Denmark)

    Kragelund, Camilla; Hansen, Claus; Reibel, Jesper

    2010-01-01

    Lichenoid drug eruptions (LDE) in the oral cavity are adverse drug reactions (ADR) that are impossible to differentiate from oral lichen planus (OLP) as no phenotypic criteria exist. Impaired function of polymorphic cytochrome 450-enzymes (CYPs) may cause increased plasma concentration of some dr...

  5. The potential drug-drug interaction between proton pump inhibitors and warfarin

    DEFF Research Database (Denmark)

    Henriksen, Daniel Pilsgaard; Stage, Tore Bjerregaard; Hansen, Morten Rix

    2015-01-01

    BACKGROUND: Proton pump inhibitors (PPIs) have been suggested to increase the effect of warfarin, and clinical guidelines recommend careful monitoring of international normalized ratio (INR) when initiating PPI among warfarin users. However, this drug-drug interaction is sparsely investigated...

  6. Membrane-Protein Crystallography and Potentiality for Drug Design

    Science.gov (United States)

    Yamashita, Atsuko

    Structure-based drug design for membrane proteins is far behind that for soluble proteins due to difficulty in crystallographic structure determination, despite the fact that about 60% of FDA-approved drugs target membrane proteins located at the cell surface. Stable homologs for a membrane protein of interest, such as prokaryotic neurotransmitter transporter homolog LeuT, might enable cooperative analyses by crystallography and functional assays, provide useful information for functional mechanisms, and thus serve as important probes for drug design based on mechanisms as well as structures.

  7. ETHOSOMES: A POTENTIAL CARRIES FOR TRANSDERMAL DRUG DELIVERY

    OpenAIRE

    RAJ KUMAR TIWARI; NITESH S CHAUHAN,; YOGESH H S,

    2010-01-01

    The literature is abounding with attempts made to enhance the delivery of drugs into the deep layers of the skin and through the skin. Ethosomes are noninvasive delivery carriers that enable drugs to reach the deep skin layers and/or the systemic circulation. Although ethosomal systems are conceptually sophisticated, they are characterized by simplicity in their preparation, safety, and efficacy a combination that can highly expand their application. Ethosomes are soft, malleable vesicles tai...

  8. Identifying and assessing highly hazardous drugs within quality risk management programs.

    Science.gov (United States)

    Sussman, Robert G; Schatz, Anthony R; Kimmel, Tracy A; Ader, Allan; Naumann, Bruce D; Weideman, Patricia A

    2016-08-01

    Historically, pharmaceutical industry regulatory guidelines have assigned certain active pharmaceutical ingredients (APIs) to various categories of concern, such as "cytotoxic", "hormones", and "steroids". These categories have been used to identify APIs requiring segregation or dedication in order to prevent cross-contamination and protect the quality and safety of drug products. Since these terms were never defined by regulatory authorities, and many novel pharmacological mechanisms challenge these categories, there is a recognized need to modify the historical use of these terms. The application of a risk-based approach using a health-based limit, such as an acceptable daily exposure (ADE), is more appropriate for the development of a Quality Risk Management Program (QRMP) than the use of categories of concern. The toxicological and pharmacological characteristics of these categories are discussed to help identify and prioritize compounds requiring special attention. Controlling airborne concentrations and the contamination of product contact surfaces in accordance with values derived from quantitative risk assessments can prevent adverse effects in workers and patients, regardless of specific categorical designations to which these APIs have been assigned. The authors acknowledge the movement away from placing compounds into categories and, while not yet universal, the importance of basing QRMPs on compound-specific ADEs and risk assessments. Based on the results of a risk assessment, segregation and dedication may also be required for some compounds to prevent cross contamination during manufacture of APIs. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma.

    Directory of Open Access Journals (Sweden)

    Eveline Barbieri

    Full Text Available Chemotherapy induces apoptosis and tumor regression primarily through activation of p53-mediated transcription. Neuroblastoma is a p53 wild type malignancy at diagnosis and repression of p53 signaling plays an important role in its pathogenesis. Recently developed small molecule inhibitors of the MDM2-p53 interaction are able to overcome this repression and potently activate p53 dependent apoptosis in malignancies with intact p53 downstream signaling. We used the small molecule MDM2 inhibitor, Nutlin-3a, to determine the p53 drug response signature in neuroblastoma cells. In addition to p53 mediated apoptotic signatures, GSEA and pathway analysis identified a set of p53-repressed genes that were reciprocally over-expressed in neuroblastoma patients with the worst overall outcome in multiple clinical cohorts. Multifactorial regression analysis identified a subset of four genes (CHAF1A, RRM2, MCM3, and MCM6 whose expression together strongly predicted overall and event-free survival (p<0.0001. The expression of these four genes was then validated by quantitative PCR in a large independent clinical cohort. Our findings further support the concept that oncogene-driven transcriptional networks opposing p53 activation are essential for the aggressive behavior and poor response to therapy of high-risk neuroblastoma.

  10. Selecting for neurogenic potential as an alternative for Alzheimer's disease drug discovery.

    Science.gov (United States)

    Prior, Marguerite; Goldberg, Joshua; Chiruta, Chandramouli; Farrokhi, Catherine; Kopynets, Mariya; Roberts, Amanda J; Schubert, David

    2016-06-01

    Neurons die in Alzheimer's disease (AD) and are not effectively replaced. An alternative approach to maintain nerve cell number is to identify compounds that stimulate the proliferation of endogenous neural stem cells in old individuals to replace lost neurons. However, unless a neurogenic drug is also neuroprotective, the replacement of lost neurons will not be sufficient to stop disease progression. The neuroprotective AD drug candidate J147 is shown to enhance memory, improve dendritic structure, and stimulate cell division in germinal regions of the brains of very old mice. Based on the potential neurogenic potential of J147, a neuronal stem cell screening assay was developed to optimize derivatives of J147 for human neurogenesis. The best derivative of J147, CAD-031, maintains the neuroprotective and memory enhancing properties of J147, yet is more active in the human neural stem cell assays. The combined properties of neuroprotection, neurogenesis, and memory enhancement in a single drug are more likely to be effective for the treatment of age-associated neurodegenerative disorders than any individual activity alone. Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  11. Robust global identifiability theory using potentials--Application to compartmental models.

    Science.gov (United States)

    Wongvanich, N; Hann, C E; Sirisena, H R

    2015-04-01

    This paper presents a global practical identifiability theory for analyzing and identifying linear and nonlinear compartmental models. The compartmental system is prolonged onto the potential jet space to formulate a set of input-output equations that are integrals in terms of the measured data, which allows for robust identification of parameters without requiring any simulation of the model differential equations. Two classes of linear and non-linear compartmental models are considered. The theory is first applied to analyze the linear nitrous oxide (N2O) uptake model. The fitting accuracy of the identified models from differential jet space and potential jet space identifiability theories is compared with a realistic noise level of 3% which is derived from sensor noise data in the literature. The potential jet space approach gave a match that was well within the coefficient of variation. The differential jet space formulation was unstable and not suitable for parameter identification. The proposed theory is then applied to a nonlinear immunological model for mastitis in cows. In addition, the model formulation is extended to include an iterative method which allows initial conditions to be accurately identified. With up to 10% noise, the potential jet space theory predicts the normalized population concentration infected with pathogens, to within 9% of the true curve. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. MEDICI: Mining Essentiality Data to Identify Critical Interactions for Cancer Drug Target Discovery and Development.

    Science.gov (United States)

    Harati, Sahar; Cooper, Lee A D; Moran, Josue D; Giuste, Felipe O; Du, Yuhong; Ivanov, Andrei A; Johns, Margaret A; Khuri, Fadlo R; Fu, Haian; Moreno, Carlos S

    2017-01-01

    Protein-protein interactions (PPIs) mediate the transmission and regulation of oncogenic signals that are essential to cellular proliferation and survival, and thus represent potential targets for anti-cancer therapeutic discovery. Despite their significance, there is no method to experimentally disrupt and interrogate the essentiality of individual endogenous PPIs. The ability to computationally predict or infer PPI essentiality would help prioritize PPIs for drug discovery and help advance understanding of cancer biology. Here we introduce a computational method (MEDICI) to predict PPI essentiality by combining gene knockdown studies with network models of protein interaction pathways in an analytic framework. Our method uses network topology to model how gene silencing can disrupt PPIs, relating the unknown essentialities of individual PPIs to experimentally observed protein essentialities. This model is then deconvolved to recover the unknown essentialities of individual PPIs. We demonstrate the validity of our approach via prediction of sensitivities to compounds based on PPI essentiality and differences in essentiality based on genetic mutations. We further show that lung cancer patients have improved overall survival when specific PPIs are no longer present, suggesting that these PPIs may be potentially new targets for therapeutic development. Software is freely available at https://github.com/cooperlab/MEDICI. Datasets are available at https://ctd2.nci.nih.gov/dataPortal.

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

    Science.gov (United States)

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

    2014-03-01

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

  14. Potential of magnetic nanoparticles for targeted drug delivery

    Directory of Open Access Journals (Sweden)

    Yang HW

    2012-08-01

    Full Text Available Hung-Wei Yang,1,2 Mu-Yi Hua,1 Hao-Li Liu,3 Chiung-Yin Huang,2 Kuo-Chen Wei21Molecular Medicine Research Center, Department of Chemical and Materials Engineering, Chang Gung University, 2Department of Neurosurgery, Chang Gung University and Memorial Hospital, 3Department of Electrical Engineering, Chang Gung University, Taoyuan, TaiwanAbstract: Nanoparticles (NPs play an important role in the molecular diagnosis, treatment, and monitoring of therapeutic outcomes in various diseases. Their nanoscale size, large surface area, unique capabilities, and negligible side effects make NPs highly effective for biomedical applications such as cancer therapy, thrombolysis, and molecular imaging. In particular, nontoxic superparamagnetic magnetic NPs (MNPs with functionalized surface coatings can conjugate chemotherapeutic drugs or be used to target ligands/proteins, making them useful for drug delivery, targeted therapy, magnetic resonance imaging, transfection, and cell/protein/DNA separation. To optimize the therapeutic efficacy of MNPs for a specific application, three issues must be addressed. First, the efficacy of magnetic targeting/guidance is dependent on particle magnetization, which can be controlled by adjusting the reaction conditions during synthesis. Second, the tendency of MNPs to aggregate limits their therapeutic use in vivo; surface modifications to produce high positive or negative charges can reduce this tendency. Finally, the surface of MNPs can be coated with drugs which can be rapidly released after injection, resulting in targeting of low doses of the drug. Drugs therefore need to be conjugated to MNPs such that their release is delayed and their thermal stability enhanced. This chapter describes the creation of nanocarriers with a high drug-loading capacity comprised of a high-magnetization MNP core and a shell of aqueous, stable, conducting polyaniline derivatives and their applications in cancer therapy. It further summarizes some

  15. Reverse screening approach to identify potential anti-cancer targets of dipyridamole

    Science.gov (United States)

    Ge, Shu-Min; Zhan, Dong-Ling; Zhang, Shu-Hua; Song, Li-Qiang; Han, Wei-Wei

    2016-01-01

    Dipyridamole (DIP) inhibits thrombus formation when given chronically, and causes vasodilation over a short time. To date, DIP can increase the anticancer drugs (5-fluorouracil, methotrexate, piperidine, vincristine) concentration in cancer cells and hence enhance the efficacy of treatment cancer. The inhibition of DIP may result in increased 5-fluorouracil efficacy and diminish the drug side effects. But the actual molecular targets remain unknown. In this study, reverse protein-ligands docking, and quantum mechanics were used to search for the potential molecular targets of DIP. The quantum mechanics calculation was performed by using Gaussian 03 program package. Reverse pharmacophore mapping was used to search for potential molecular target candidates for a given small molecule. The docking study was used for exploring the potential anti-cancer targets of dipyridamole. The two predicted binders with the statistically significant prediction are dihydropyrimidine dehydrogenase (DPD) (PDB Id: 1GTE) and human spindle checkpoint kinase Bub1 (PDB Id: 3E7E). Structure analysis suggests that electrostatic interaction and hydrogen bonding play an important role in their binding process. The strong functional linkage of DIP and 5FU supports our prediction. In conclusion, these results generate a tractable set of anticancer proteins. The exploration of polypharmacology will provide us new opportunities in treating systematic diseases, such as the cancers. The results would generate a tractable set of anticancer target proteins for future experimental validations. PMID:28077994

  16. Identifying the mechanisms of drug release from amorphous solid dispersions using MRI and ATR-FTIR spectroscopic imaging.

    Science.gov (United States)

    Punčochová, Kateřina; Ewing, Andrew V; Gajdošová, Michaela; Sarvašová, Nina; Kazarian, Sergei G; Beránek, Josef; Štěpánek, František

    2015-04-10

    The dissolution mechanism of a poorly aqueous soluble drug from amorphous solid dispersions was investigated using a combination of two imaging methods: attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopic imaging and magnetic resonance imaging (MRI). The rates of elementary processes such as water penetration, polymer swelling, growth and erosion of gel layer, and the diffusion, release and in some cases precipitation of drug were evaluated by image analysis. The results from the imaging methods were compared with drug release profiles obtained by classical dissolution tests. The study was conducted using three polymeric excipients (soluplus, polyvinylpyrrolidone - PVP K30, hydroxypropylmethyl cellulose - HPMC 100M) alone and in combination with a poorly soluble drug, aprepitant. The imaging methods were complementary: ATR-FTIR imaging enabled a qualitative observation of all three components during the dissolution experiments, water, polymer and drug, including identifying structural changes from the amorphous form of drug to the crystalline form. The comparison of quantitative MRI data with drug release profiles enabled the different processes during dissolution to be established and the rate-limiting step to be identified, which - for the drug-polymer combinations investigated in this work - was the drug diffusion through the gel layer rather than water penetration into the tablet.

  17. Leishmaniasis:Current status of available drugs and new potential drug targets

    Institute of Scientific and Technical Information of China (English)

    Nisha Singh; Manish Kumar; Rakesh Kumar Singh

    2012-01-01

    The control ofLeishmania infection relies primarily on chemotherapy till date. Resistance to pentavalent antimonials, which have been the recommended drugs to treat cutaneous and visceral leishmaniasis, is now widespread in Indian subcontinents. New drug formulations like amphotericinB, its lipid formulations, and miltefosine have shown great efficacy to treat leishmaniasis but their high cost and therapeutic complications limit their usefulness. In addition, irregular and inappropriate uses of these second line drugs in endemic regions like state of Bihar, India threaten resistance development in the parasite. In context to the limited drug options and unavailability of either preventive or prophylactic candidates, there is a pressing need to develop true antileishmanial drugs to reduce the disease burden of this debilitating endemic disease. Notwithstanding significant progress of leishmanial research during last few decades, identification and characterization of novel drugs and drug targets are far from satisfactory. This review will initially describe current drug regimens and later will provide an overview on few important biochemical and enzymatic machineries that could be utilized as putative drug targets for generation of true antileishmanial drugs.

  18. FAMILY HEALTH PROGRAM: CHALLENGES AND POTENTIALITIES REGARDING DRUGS USE

    Directory of Open Access Journals (Sweden)

    Marcelle Aparecida de Barros

    2006-04-01

    Full Text Available ABSTRACT: Epidemiological studies on drugs use point towards this phenomenon as a public health problem. Nowadays, the Family Health Program (FHP is presented by the Health Ministry as a model to restructure primary health care and aims to offer family-centered care, permeated by integrality, problem solving and community bonds. This article aims to discuss action possibilities of Family Health Care professionals involving drugs patients. It is evident that, as opposed to other actions already developed by FHP professionals in other health care areas, which has appeared clearly and objectively. This fact is observed in the daily activities of FHP professionals, which give little attention to drugs-related problems. However, research emphasizes that there exists a broad range of action possibilities for FHP professionals. Although other studies evidence this team’s fragilities in terms of care for drugs users, these can be overcome by investing in the training and valuation of these professionals. KEY WORDS: Family Health Program; Street drugs; Health Knowledge, Attitudes, Practice.

  19. Potentially inappropriate prescribing and the risk of adverse drug reactions in critically ill older adults

    Directory of Open Access Journals (Sweden)

    Galli TB

    2016-12-01

    Full Text Available Background: Potentially inappropriate medication (PIM use in the elderly is associated with increased risk of adverse drug reactions (ADRs, but there is limited information regarding PIM use in the intensive care unit (ICU setting. Objective: The aim of the study is to describe the prevalence and factors associated with the use of PIM and the occurrence of PIM-related adverse reactions in the critically ill elderly. Methods: This study enrolled all critically ill older adults (60 years or more admitted to medical or cardiovascular ICUs between January and December 2013, in a large tertiary teaching hospital. For all patients, clinical pharmacists listed the medications given during the ICU stay and data on drugs were analyzed using 2012 Beers Criteria, to identify the prevalence of PIM. For each identified PIM the medical records were analyzed to evaluate factors associated with its use. The frequency of ADRs and, the causal relationship between PIM and the ADRs identified were also evaluated through review of medical records. Results: According to 2012 Beers Criteria, 98.2% of elderly patients used at least one PIM (n=599, of which 24.8% were newly started in the ICUs. In 29.6% of PIMs, there was a clinical circumstance that justified their prescription. The number of PIMs was associated with ICU length of stay and total number of medications. There was at least one ADR identified in 17.8% of patients; more than 40% were attributed to PIM, but there was no statistical association. Conclusions: There is a high prevalence of PIM used in acutely ill older people, but they do not seem to be the major cause of adverse drug reactions in this population. Although many PIMs had a clinical circumstance that led to their prescription during the course of ICU hospitalization, many were still present upon hospital discharge. Therefore, prescription of PIMs should be minimized to improve the safety of elderly patients.

  20. FUNCTIONAL GENOMICS IDENTIFIES TIS21-DEPENDENT MECHANISMS AND PUTATIVE CANCER DRUG TARGETS UNDERLYING MEDULLOBLASTOMA SHH-TYPE DEVELOPMENT

    Directory of Open Access Journals (Sweden)

    Giulia Gentile

    2016-11-01

    Full Text Available We have recently generated a novel medulloblastoma (MB mouse model with activation of the Shh pathway and lacking the MB suppressor Tis21 (Patched1+-Tis21KO.ts main phenotype is a defect of migration of the cerebellar granule precursor cells (GCPs. By genomic analysis of GCPs in vivo, we identified as drug target and major responsible of this defect the down-regulation of the promigratory chemokine Cxcl3. Consequently, the GCPs remain longer in the cerebellum proliferative area, and the MB frequency is enhanced. Here, we further analyzed the genes deregulated in a Tis21-dependent manner (Patched1+-is21 wild-type versus Ptch1+-Tis21 knockout, among which are a number of down-regulated tumor inhibitors and up-regulated tumor facilitators, focusing on pathways potentially involved in the tumorigenesis and on putative new drug targets.The data analysis using bioinformatic tools revealed: i a link between the Shh signaling and the Tis21-dependent impairment of the GCPs migration, through a Shh-dependent deregulation of the clathrin-mediated chemotaxis operating in the primary cilium through the Cxcl3-Cxcr2 axis; ii a possible lineage shift of Shh-type GCPs toward retinal precursor phenotype the neural cell type involved in group 3 MB; iii the identification of a subset of putative drug targets for MB, involved, among the others, in the regulation of Hippo signaling and centrosome assembly. Finally, our findings define also the role of Tis21 in the regulation of gene expression, through epigenetic and RNA processing mechanisms, influencing the fate of the GCPs.

  1. Transdermal Delivery of Drugs with Microneedles—Potential and Challenges

    Directory of Open Access Journals (Sweden)

    Kevin Ita

    2015-06-01

    Full Text Available Transdermal drug delivery offers a number of advantages including improved patient compliance, sustained release, avoidance of gastric irritation, as well as elimination of pre-systemic first-pass effect. However, only few medications can be delivered through the transdermal route in therapeutic amounts. Microneedles can be used to enhance transdermal drug delivery. In this review, different types of microneedles are described and their methods of fabrication highlighted. Microneedles can be fabricated in different forms: hollow, solid, and dissolving. There are also hydrogel-forming microneedles. A special attention is paid to hydrogel-forming microneedles. These are innovative microneedles which do not contain drugs but imbibe interstitial fluid to form continuous conduits between dermal microcirculation and an attached patch-type reservoir. Several microneedles approved by regulatory authorities for clinical use are also examined. The last part of this review discusses concerns and challenges regarding microneedle use.

  2. Transdermal Delivery of Drugs with Microneedles—Potential and Challenges

    Science.gov (United States)

    Ita, Kevin

    2015-01-01

    Transdermal drug delivery offers a number of advantages including improved patient compliance, sustained release, avoidance of gastric irritation, as well as elimination of pre-systemic first-pass effect. However, only few medications can be delivered through the transdermal route in therapeutic amounts. Microneedles can be used to enhance transdermal drug delivery. In this review, different types of microneedles are described and their methods of fabrication highlighted. Microneedles can be fabricated in different forms: hollow, solid, and dissolving. There are also hydrogel-forming microneedles. A special attention is paid to hydrogel-forming microneedles. These are innovative microneedles which do not contain drugs but imbibe interstitial fluid to form continuous conduits between dermal microcirculation and an attached patch-type reservoir. Several microneedles approved by regulatory authorities for clinical use are also examined. The last part of this review discusses concerns and challenges regarding microneedle use. PMID:26131647

  3. Wzy-dependent bacterial capsules as potential drug targets.

    Science.gov (United States)

    Ericsson, Daniel J; Standish, Alistair; Kobe, Bostjan; Morona, Renato

    2012-10-01

    The bacterial capsule is a recognized virulence factor in pathogenic bacteria. It likely works as an antiphagocytic barrier by minimizing complement deposition on the bacterial surface. With the continual rise of bacterial pathogens resistant to multiple antibiotics, there is an increasing need for novel drugs. In the Wzy-dependent pathway, the biosynthesis of capsular polysaccharide (CPS) is regulated by a phosphoregulatory system, whose main components consist of bacterial-tyrosine kinases (BY-kinases) and their cognate phosphatases. The ability to regulate capsule biosynthesis has been shown to be vital for pathogenicity, because different stages of infection require a shift in capsule thickness, making the phosphoregulatory proteins suitable as drug targets. Here, we review the role of regulatory proteins focusing on Streptococcus pneumoniae, Staphylococcus aureus, and Escherichia coli and discuss their suitability as targets in structure-based drug design.

  4. Odorranalectin is a small peptide lectin with potential for drug delivery and targeting.

    Directory of Open Access Journals (Sweden)

    Jianxu Li

    Full Text Available BACKGROUND: Lectins are sugar-binding proteins that specifically recognize sugar complexes. Based on the specificity of protein-sugar interactions, different lectins could be used as carrier molecules to target drugs specifically to different cells which express different glycan arrays. In spite of lectin's interesting biological potential for drug targeting and delivery, a potential disadvantage of natural lectins may be large size molecules that results in immunogenicity and toxicity. Smaller peptides which can mimic the function of lectins are promising candidates for drug targeting. PRINCIPAL FINDINGS: Small peptide with lectin-like behavior was screened from amphibian skin secretions and its structure and function were studied by NMR, NMR-titration, SPR and mutant analysis. A lectin-like peptide named odorranalectin was identified from skin secretions of Odorrana grahami. It was composed of 17 aa with a sequence of YASPKCFRYPNGVLACT. L-fucose could specifically inhibit the haemagglutination induced by odorranalectin. (125I-odorranalectin was stable in mice plasma. In experimental mouse models, odorranalectin was proved to mainly conjugate to liver, spleen and lung after i.v. administration. Odorranalectin showed extremely low toxicity and immunogenicity in mice. The small size and single disulfide bridge of odorranalectin make it easy to manipulate for developing as a drug targeting system. The cyclic peptide of odorranalectin disclosed by solution NMR study adopts a beta-turn conformation stabilized by one intramolecular disulfide bond between Cys6-Cys16 and three hydrogen bonds between Phe7-Ala15, Tyr9-Val13, Tyr9-Gly12. Residues K5, C6, F7, C16 and T17 consist of the binding site of L-fucose on odorranalectin determined by NMR titration and mutant analysis. The structure of odorranalectin in bound form is more stable than in free form. CONCLUSION: These findings identify the smallest lectin so far, and show the application potential of

  5. Characterization of drug-related problems identified by clinical pharmacy staff at Danish hospitals

    DEFF Research Database (Denmark)

    Kjeldsen, Lene Juel; Birkholm, Trine; Fischer, Hanne

    2014-01-01

    -adherence to guidelines" (79 %) followed by "Therapeutic duplication" (73 %) and "Dosing time and interval" (70 %). Even though the top 25 drugs were involved in 58 % of all DRPs, multiple drugs were associated with DRPs. The drugs most frequently involved in DRPs were paracetamol (4.6 % of all DRPs), simvastatin (3.......0 %), lansoprazole (2.7 %), morphine (2.6 %) and alendronic acid (2.4 %). Conclusions The study found that a national database on DRPs contained multi-facetted DRPs, however evenly distributed for each of the 3 years. Even though the top 25 drugs were involved in 58 % of all DRPs, multiple drugs were associated...

  6. Potential adverse effects of discontinuing psychotropic drugs. Part 3: Antipsychotic, dopaminergic, and mood-stabilizing drugs.

    Science.gov (United States)

    Howland, Robert H

    2010-08-01

    Abrupt discontinuation of antipsychotic drugs in patients with schizophrenia is associated with earlier, and often more severe, illness episodes than are seen with gradual discontinuation. Antipsychotic drugs can cause various abnormal motor syndromes, but abruptly stopping them has been associated with the seemingly paradoxical development of similar motor syndromes, such as withdrawal dyskinesias, parkinsonian symptoms, dystonias, and neuroleptic malignant syndrome. Dopamine-releasing and dopamine-agonist drugs are used to treat some of the motor syndromes caused by antipsychotic drugs, but their abrupt discontinuation can also be associated with abnormal syndromes. When antipsychotic drugs, lithium, or certain anticonvulsant drugs are used for treatment of bipolar disorder, rapid versus gradual discontinuation is more likely to lead to greater mood instability and manic relapse. If necessary, these medications should be gradually tapered to minimize all types of adverse discontinuation effects. Patients should be educated about the possible adverse effects of abrupt medication discontinuation.

  7. Antimicrobial potential of Pakistani medicinal plants against multi-drug resistance Staphylococcus aureus

    Directory of Open Access Journals (Sweden)

    Rahat Ejaz

    2014-09-01

    Full Text Available Objective: To determine resistance patterns of Staphylococcus aureus (S. aureus isolated from different areas of Pakistan and to identify antimicrobial agents against multi-drug resistant S. aureus strains. Methods: A total of 67 samples (sewerage, nasal and milk were collected from different farm areas of Pakistan to identify local strains of S. aureus. Sixteen out of 67 samples were positive for S. aureus. Only 6 out of 16 S. aureus strains showed resistance to antibiotics. Then the antibacterial effect of 29 medicinal plants was evaluated on these S. aureus isolates and a standard S. aureus strain ATCC 25923. The solvents used for the extraction of plants were acetone, dimethyl sulfoxide and methanol. The in vitro antibacterial activity was performed using agar disc diffusion method. Moreover, minimum inhibitory concentration of effective medicinal plant extracts was identified through micro-dilution method to find out their 50% inhibitory concentration. Results: Plant extracts of 5 medicinal plants (Psidium guajava, Nigella sativa, Piper nigrum, Valeriana jatamansi, and Cucurbita pepo exhibited antibacterial activity against locally isolated multidrug resistant strains of S. aureus. The minimum inhibitory concentration of these extracts was ranged from 0.328 to 5.000 mg/mL. Conclusions: Plant extracts of Psidium guajava, Piper nigrum seed, Valeriana jatamansi, Cucurbita pepo and Nigella sativa showed significant in vitro antibacterial activity and thus, such findings may serve as valuable contribution in the treatment of infection and may contribute to the development of potential antimicrobial agents against multi drug resistant strains of S. aureus

  8. Antimicrobial potential of Pakistani medicinal plants against multi-drug resistance Staphylococcus aureus

    Institute of Scientific and Technical Information of China (English)

    Rahat Ejaz; Usman A Ashfaq; Sobia Idrees

    2014-01-01

    Objective: To determine resistance patterns of Staphylococcus aureus (S. aureus) isolated from different areas of Pakistan and to identify antimicrobial agents against multi-drug resistant S.aureus strains. Methods: A total of 67 samples (sewerage, nasal and milk) were collected from different farm areas of Pakistan to identify local strains of S. aureus. Sixteen out of 67 samples were positive for S.aureus. Only 6 out of 16 S. aureus strains showed resistance to antibiotics. Then the antibacterial effect of 29 medicinal plants was evaluated on these S. aureus isolates and a standard S. aureus strain ATCC 25923. The solvents used for the extraction of plants were acetone, dimethyl sulfoxide and methanol. The in vitro antibacterial activity was performed using agar disc diffusion method. Moreover, minimum inhibitory concentration of effective medicinal plant extracts was identified through micro-dilution method to find out their 50% inhibitory concentration.Results:Plant extracts of 5 medicinal plants (Psidium guajava, Nigella sativa, Piper nigrum, Valeriana jatamansi, and Cucurbita pepo) exhibited antibacterial activity against locally isolated multidrug resistant strains of S. aureus. The minimum inhibitory concentration of these extracts was ranged from 0.328 to 5.000 mg/mL. Conclusions: Plant extracts of Psidium guajava, Piper nigrum seed, Valeriana jatamansi, Cucurbita pepo and Nigella sativa showed significant in vitro antibacterial activity and thus, such findings may serve as valuable contribution in the treatment of infection and may contribute to the development of potential antimicrobial agents against multi drug resistant strains of S. aureus.

  9. Metabonomic analysis of potential biomarkers and drug targets involved in diabetic nephropathy mice.

    Science.gov (United States)

    Wei, Tingting; Zhao, Liangcai; Jia, Jianmin; Xia, Huanhuan; Du, Yao; Lin, Qiuting; Lin, Xiaodong; Ye, Xinjian; Yan, Zhihan; Gao, Hongchang

    2015-07-07

    Diabetic nephropathy (DN) is one of the lethal manifestations of diabetic systemic microvascular disease. Elucidation of characteristic metabolic alterations during diabetic progression is critical to understand its pathogenesis and identify potential biomarkers and drug targets involved in the disease. In this study, (1)H nuclear magnetic resonance ((1)H NMR)-based metabonomics with correlative analysis was performed to study the characteristic metabolites, as well as the related pathways in urine and kidney samples of db/db diabetic mice, compared with age-matched wildtype mice. The time trajectory plot of db/db mice revealed alterations, in an age-dependent manner, in urinary metabolic profiles along with progression of renal damage and dysfunction. Age-dependent and correlated metabolite analysis identified that cis-aconitate and allantoin could serve as biomarkers for the diagnosis of DN. Further correlative analysis revealed that the enzymes dimethylarginine dimethylaminohydrolase (DDAH), guanosine triphosphate cyclohydrolase I (GTPCH I), and 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase) were involved in dimethylamine metabolism, ketogenesis and GTP metabolism pathways, respectively, and could be potential therapeutic targets for DN. Our results highlight that metabonomic analysis can be used as a tool to identify potential biomarkers and novel therapeutic targets to gain a better understanding of the mechanisms underlying the initiation and progression of diseases.

  10. Use of Pregabalin - A Nationwide Pharmacoepidemiological Drug Utilization Study with Focus on Abuse Potential

    DEFF Research Database (Denmark)

    Schjerning, O; Pottegård, A; Damkier, P

    2016-01-01

    in dosages that exceed the approved therapeutic range. METHODS: To identify predictors of pregabalin use above recommended dosage, we conducted a pharmacoepidemological drug utilization study using the Danish nationwide registers. We deployed 4 measures of abuse: high use (≥600 mg/day) or very high use (≥1......INTRODUCTION: Pregabalin is currently approved for the treatment of epilepsy, generalized anxiety disorder and neuropathic pain with a licensed dosage range of 150 mg to 600 mg/day. Growing concern about the abuse potential of pregabalin is partly based on reports of pregabalin being used...... 200 mg/day) over a 6- or 12-month period, respectively. Multiple logistic regression was used to identify patient and treatment characteristics that were associated with either abuse marker. RESULTS: Out of 42 520 pregabalin users 4 090 (9.6%) were treated with more than 600 mg/day for 6 months and 2...

  11. Serine Proteases of Malaria Parasite Plasmodium falciparum: Potential as Antimalarial Drug Targets

    OpenAIRE

    Asrar Alam

    2014-01-01

    Malaria is a major global parasitic disease and a cause of enormous mortality and morbidity. Widespread drug resistance against currently available antimalarials warrants the identification of novel drug targets and development of new drugs. Malarial proteases are a group of molecules that serve as potential drug targets because of their essentiality for parasite life cycle stages and feasibility of designing specific inhibitors against them. Proteases belonging to various mechanistic classes...

  12. Methotrexate and epirubicin conjugates as potential antitumor drugs

    Directory of Open Access Journals (Sweden)

    Szymon Wojciech Kmiecik

    2017-07-01

    Full Text Available Introduction: The use of hybrid molecules has become one of the most significant approaches in new cytotoxic drug design. This study describes synthesis and characterization of conjugates consisting of two well-known and characterized chemotherapeutic agents: methotrexate (MTX and epirubicin (EPR. The synthesized conjugates combine two significant anticancer strategies: combinatory therapy and targeted therapy. These two drugs were chosen because they have different mechanisms of action, which can increase the anticancer effect of the obtained conjugates. MTX, which is a folic acid analog, has high cytotoxic properties and can serve as a targeting moiety that can reach folate receptors (FRs overexpresing tumor cells. Combination of nonselective drugs such as EPR with MTX can increase the selectivity of the obtained conjugates, while maintaining the high cytotoxic properties.Materials and methods: Conjugates were purified by RP-HPLC and the structure was investigated by MS and MS/MS methods. The effect of the conjugates on proliferation of LoVo, LoVo/Dx, MCF-7 and MV-4-11 human cancer cell lines was determined by SRB or MTT assay.Results: The conjugation reaction results in the formation of monosubstituted (α, γ and disubstituted MTX derivatives. In vitro proliferation data demonstrate that the conjugates synthesized in our study show lower cytotoxic properties than both chemotherapeutics used alone.Discussion: Epirubicin cytotoxicity was not observed in obtained conjugates. Effective drugs release after internalization needs further investigation.

  13. Extraction and identification of exosomes from drug-resistant breast cancer cells and their potential role in cell-to-cell drug-resistance transfer

    Institute of Scientific and Technical Information of China (English)

    许金金

    2014-01-01

    Objective To explore whether docetaxel-resistant cells(MCF-7/Doc)and doxorubicin-resistant cells(MCF-7/ADM)can secrete Exosomes and their potential role in cell-cell drug-resistance transfer.Methods Exosomes were extracted from the cell culture supernatants of MCF-7/Doc and MCF-7/ADM cells by fractionation ultracentrifugation,and were identified by transmission

  14. Identifying prospective antifouling coatings for venturis: Zeta potential measurements of oxides at elevated temperatures

    Energy Technology Data Exchange (ETDEWEB)

    Jayaweera, P.; Hettiarachchi, S.; Pound, B.G. (SRI International, Menlo Park, CA (United States))

    1992-10-01

    This report describes the results of research to determine the zeta potential of oxides responsible for fouling of heat transfer, venturi, and other flow measurement device surfaces. Fouling deposits formed on these surfaces reduce mass flow rates of water, causing power reductions of as much as 3 to 4%. There is considerable evidence that deposit formation can be prevented by coating the critical surfaces with a coating material that electrostatically repels the suspended fouling particulates. The zeta potential can be used as a parameter to identify and determine the best coating material to be employed for fouling prevention. The research entailed the development of the equipment necessary for zeta potential measurements, measurement of zeta potentials of oxides and coatings of interest to nuclear power plant applications, and evaluation of candidate coating materials to prevent fouling of surfaces. By this approach, numerous metals and oxides have been identified as potential coating materials. Fouling studies revealed that magnetite does not deposit on tungsten and palladium surfaces, indicating the potential use of these metals for coating venturi surfaces used in nuclear power plants.

  15. An overview of anthrax infection including the recently identified form of disease in injection drug users

    Science.gov (United States)

    Hicks, Caitlin W.; Sweeney, Daniel A.; Cui, Xizhong; Li, Yan

    2012-01-01

    Purpose Bacillus anthracis infection (anthrax) can be highly lethal. Two recent outbreaks related to contaminated mail in the USA and heroin in the UK and Europe and its potential as a bioterrorist weapon have greatly increased concerns over anthrax in the developed world. Methods This review summarizes the microbiology, pathogenesis, diagnosis, and management of anthrax. Results and conclusions Anthrax, a gram-positive bacterium, has typically been associated with three forms of infection: cutaneous, gastrointestinal, and inhalational. However, the anthrax outbreak among injection drug users has emphasized the importance of what is now considered a fourth disease form (i.e., injectional anthrax) that is characterized by severe soft tissue infection. While cutaneous anthrax is most common, its early stages are distinct and prompt appropriate treatment commonly produces a good outcome. However, early symptoms with the other three disease forms can be nonspecific and mistaken for less lethal conditions. As a result, patients with gastrointestinal, inhalational, or injectional anthrax may have advanced infection at presentation that can be highly lethal. Once anthrax is suspected, the diagnosis can usually be made with gram stain and culture from blood or tissue followed by confirmatory testing (e.g., PCR). While antibiotics are the mainstay of anthrax treatment, use of adjunctive therapies such as anthrax toxin antagonists are a consideration. Prompt surgical therapy appears to be important for successful management of injectional anthrax. PMID:22527064

  16. Incidence rate and pattern of clinically relevant potential drug-drug interactions in a large outpatient population of a developing country

    Directory of Open Access Journals (Sweden)

    Ehsan Nabovati

    2016-01-01

    Full Text Available The objective of this study was to determine incidence rate, type, and pattern of clinically relevant potential drug-drug interactions (pDDIs in a large outpatient population of a developing country. A retrospective, descriptive cross-sectional study was conducted on outpatients’ prescriptions in Khorasan Razavi province, Iran, over 12 months. A list of 25 clinically relevant DDIs, which are likely to occur in the outpatient setting, was used as the reference. Most frequent clinically relevant pDDIs, most common drugs contributing to the pDDIs, and the pattern of pDDIs for each medical specialty were determined. Descriptive statistics were used to report the results. In total, out of 8,169,142 prescriptions, 6,096 clinically relevant pDDIs were identified. The most common identified pDDIs were theophyllines-quinolones, warfarin-nonsteroidal anti-inflammatory drugs, benzodiazepines-azole antifungal agents, and anticoagulants-thyroid hormones. The most common drugs contributing to the identified pDDIs were ciprofloxacin, theophylline, warfarin, aminophylline, alprazolam, levothyroxine, and selegiline. While the incidence rate of clinically relevant pDDIs in prescriptions of general practitioners, internists, and cardiologists was the highest, the average pDDI incidence per 10,000 prescriptions of pulmonologists, infectious disease specialists, and cardiologists was highest. Although a small proportion of the analyzed prescriptions contained drug pairs with potential for clinically relevant DDIs, a significant number of outpatients have been exposed to the adverse effects associated with these interactions. It is recommended that in addition to training physicians and pharmacists, other effective interventions such as computerized alerting systems and electronic prescribing systems be designed and implemented.

  17. A universal meteorological method to identify potential risk of wind erosion on heavy-textured soils

    Directory of Open Access Journals (Sweden)

    Středová Hana

    2015-06-01

    Full Text Available The climate of Central Europe, mainly winter seasons with no snow cover at lower altitudes and a spring drought as well, might cause erosion events on heavy-textured soils. The aim of this paper is to define a universal method to identify the potential risk of wind erosion on heavy-textured soils. The categorization of potential wind erosion risk due to meteorological conditions is based on: (i an evaluation of the number of freeze-thaw episodes forming bare soil surfaces during the cold period of year; and (ii, an evaluation of the number of days with wet soil surfaces during the cold period of year. In the period 2001–2012 (from November to March, episodes with temperature changes from positive to negative and vice versa (thaw-freeze and freeze-thaw cycles and the effects of wet soil surfaces in connection with aggregate disintegration, are identified. The data are spatially interpolated by GIS tools for areas in the Czech Republic with heavy-textured soils. Blending critical categories is used to locate potential risks. The level of risk is divided into six classes. Those areas identified as potentially most vulnerable are the same localities where the highest number of erosive episodes on heavy-textured soils was documented.

  18. Pityriasis rosea like drug rash - a need to identify the disease in childhood.

    Science.gov (United States)

    Panda, Maitreyee; Patro, Nibedita; Jena, Monalisa; Dash, Mrutunjay; Mishra, Swati

    2014-08-01

    Pityriasis rosea is a common dermatosis named by Gibert in 1860. It is an acute self limiting papulosquamous disease, probably infective in origin affecting healthy adolescents and young adults. It is characterized by distinctive skin eruptions and minimal constitutional symptoms. Drug induced pityriasis rosea tend to occur in older generation and resolution seen only after withdrawal of the offending drug. We report a case of 12-year-old boy with erythematous papules distributed over trunk and proximal arms after nimesulide therapy consistent with a clinical diagnosis of atypical pityriasis rosea. The relation of drug and development of pityriasis rosea is confirmed by dechallenge test of the suspected drug.

  19. Pityriasis Rosea Like Drug Rash – A Need to Identify the Disease in Childhood

    Science.gov (United States)

    Patro, Nibedita; Jena, Monalisa; Dash, Mrutunjay; Mishra, Swati

    2014-01-01

    Pityriasis rosea is a common dermatosis named by Gibert in 1860. It is an acute self limiting papulosquamous disease, probably infective in origin affecting healthy adolescents and young adults. It is characterized by distinctive skin eruptions and minimal constitutional symptoms. Drug induced pityriasis rosea tend to occur in older generation and resolution seen only after withdrawal of the offending drug. We report a case of 12-year-old boy with erythematous papules distributed over trunk and proximal arms after nimesulide therapy consistent with a clinical diagnosis of atypical pityriasis rosea. The relation of drug and development of pityriasis rosea is confirmed by dechallenge test of the suspected drug. PMID:25302254

  20. Identifying potential indicators of conservation value using natural heritage occurrence data.

    Science.gov (United States)

    Pearman, Peter B; Penskar, Michael R; Schools, Edward H; Enander, Helen D

    2006-02-01

    Conservation planning based on the occurrence of rare species has been criticized as being too limited in scope to conserve biodiversity as a whole. Conversely, planning based on indicator taxa may lack sufficient focus to conserve those species in greatest need of conservation. An alternative approach is to identify a variety of species at risk that are associated with areas of conservation value, which is defined based on species-independent characteristics. We identified potential indicators of conservation value using occurrence data on species at risk and independent information on conservation value that incorporated indices of ecosystem integrity. We propose a taxonomically diverse group of indicator species that are strongly associated with areas of exceptional ecosystem integrity, to serve as a focus for further research and in planning for biodiversity conservation. We identify potential indicator species by defining a null model in which species at risk are equally associated with areas of high ecosystem integrity, then by conducting randomization tests to identify noncompliant species in the state of Michigan, USA. Areas of high ecosystem integrity are selected using criteria to flag (1) secure biotic communities with structural integrity and few exotic species, (2) natural areas subjected to expert review, (3) contiguous relict areas of forest interior, (4) contiguous areas of unmodified wetland, and (5) all these areas combined. We determine the spatial occurrence of species at risk using data from Michigan's statewide Natural Heritage database. The potential indicators include plants, insects, and birds. Their species identity and distribution of occurrences varies with the five scenarios, and together the species broadly cover the entire state. These species at risk, many of which occur throughout the Great Lakes region, may be used to identify additional areas potentially high in conservation value and to monitor their conservation. The ecological

  1. Potential applications of boron nitride nanotubes as drug delivery systems.

    Science.gov (United States)

    Ciofani, Gianni

    2010-08-01

    In recent years, there has been an explosion of research in the 'bio-nano' field, with the discovery and introduction of ever more fascinating materials for applications as drug delivery systems, sensors, transducers, and so on. The author's group, for the first time in the literature, proposed boron nitride nanotubes as a valid alternative to carbon nanotubes and other kinds of inorganic materials, because of their improved chemical properties that theoretically guarantee better stability and compatibility in a biological context. In this paper, the bio-applications of boron nitride nanotubes that have emerged in the literature are summarized, with special attention given to their exploitation as safe drug delivery and targeting carriers. Finally, the possibility of combining their physical and chemical properties is approached, highlighting the features that render these innovative nanovectors unique and exceptional candidates for many bio-applications.

  2. Life-threatening hyperkalemia: a potentially lethal drug combination.

    Science.gov (United States)

    Juvet, Tristan; Gourineni, Venkata C; Ravi, Sandeep; Zarich, Stuart W

    2013-09-01

    Hyperkalemia is commonly seen in the elderly and is occasionally fatal. Inadvertently combining potassium sparing medications can result in profound hyperkalemia which may result in cardiac dysrhythmias, especially in the setting of chronic kidney disease. An 85 year-old woman on a drug regimen of sotalol, valsartan, spironolactone, and trimethoprim-sulfamethoxazole presented to the emergency department with hypotension and bradycardia. Presumptive treatment for hyperkalemia was started based on her initial electrocardiogram. This diagnosis was later confirmed with a serum potassium value of 10.1 mmol/L. Following pharmacologic treatment, emergency hemodialysis was performed and the patient subsequently recovered. It is known that several drug classes can cause hyperkalemia, with elderly patients at a higher risk of developing this side effect. It is believed that this was a major contributor to the degree of hyperkalemia seen in this patient.

  3. An Antifungal Combination Matrix Identifies a Rich Pool of Adjuvant Molecules that Enhance Drug Activity against Diverse Fungal Pathogens

    Directory of Open Access Journals (Sweden)

    Nicole Robbins

    2015-11-01

    Full Text Available There is an urgent need to identify new treatments for fungal infections. By combining sub-lethal concentrations of the known antifungals fluconazole, caspofungin, amphotericin B, terbinafine, benomyl, and cyprodinil with ∼3,600 compounds in diverse fungal species, we generated a deep reservoir of chemical-chemical interactions termed the Antifungal Combinations Matrix (ACM. Follow-up susceptibility testing against a fluconazole-resistant isolate of C. albicans unveiled ACM combinations capable of potentiating fluconazole in this clinical strain. We used chemical genetics to elucidate the mode of action of the antimycobacterial drug clofazimine, a compound with unreported antifungal activity that synergized with several antifungals. Clofazimine induces a cell membrane stress for which the Pkc1 signaling pathway is required for tolerance. Additional tests against additional fungal pathogens, including Aspergillus fumigatus, highlighted that clofazimine exhibits efficacy as a combination agent against multiple fungi. Thus, the ACM is a rich reservoir of chemical combinations with therapeutic potential against diverse fungal pathogens.

  4. α1-Syntrophin Variant Identified in Drug-Induced Long QT Syndrome Increases Late Sodium Current.

    Science.gov (United States)

    Choi, Jong-Il; Wang, Chaojian; Thomas, Matthew J; Pitt, Geoffrey S

    2016-01-01

    Drug-induced long-QT syndrome (diLQTS) is often due to drug block of IKr, especially in genetically susceptible patients with subclinical mutations in the IKr-encoding KCHN2. Few variants in the cardiac NaV1.5 Na+ channel complex have been associated with diLQTS. We tested whether a novel SNTA1 (α1-syntrophin) variant (p.E409Q) found in a patient with diLQTS increases late sodium current (INa-L), thereby providing a disease mechanism. Electrophysiological studies were performed in HEK293T cells co-expressing human NaV1.5/nNOS/PMCA4b with either wild type (WT) or SNTA1 variants (A390V-previously reported in congenital LQTS; and E409Q); and in adult rat ventricular cardiomyocytes infected with SNTA1 expressing adenoviruses (WT or one of the two SNTA1 variants). In HEK293T cells and in cardiomyocytes, there was no significant difference in the peak INa densities among the SNTA1 WT and variants. However, both variants increased INa-L (% of peak current) in HEK293T cells (0.58 ± 0.10 in WT vs. 0.90 ± 0.11 in A390V, p = 0.048; vs. 0.88 ± 0.07 in E409Q, p = 0.023). In cardiomyocytes, INa-L was significantly increased by E409Q, but not by A390V compared to WT (0.49 ± 0.14 in WT vs.0.94 ± 0.23 in A390V, p = 0.099; vs. 1.12 ± 0.24 in E409Q, p = 0.019). We demonstrated that a novel SNTA1 variant is likely causative for diLQTS by augmenting INa-L. These data suggest that variants within the NaV1.5-interacting α1-syntrophin are a potential mechanism for diLQTS, thereby expanding the concept that variants within congenital LQTS loci can cause diLQTS.

  5. α1-Syntrophin Variant Identified in Drug-Induced Long QT Syndrome Increases Late Sodium Current.

    Directory of Open Access Journals (Sweden)

    Jong-Il Choi

    Full Text Available Drug-induced long-QT syndrome (diLQTS is often due to drug block of IKr, especially in genetically susceptible patients with subclinical mutations in the IKr-encoding KCHN2. Few variants in the cardiac NaV1.5 Na+ channel complex have been associated with diLQTS. We tested whether a novel SNTA1 (α1-syntrophin variant (p.E409Q found in a patient with diLQTS increases late sodium current (INa-L, thereby providing a disease mechanism. Electrophysiological studies were performed in HEK293T cells co-expressing human NaV1.5/nNOS/PMCA4b with either wild type (WT or SNTA1 variants (A390V-previously reported in congenital LQTS; and E409Q; and in adult rat ventricular cardiomyocytes infected with SNTA1 expressing adenoviruses (WT or one of the two SNTA1 variants. In HEK293T cells and in cardiomyocytes, there was no significant difference in the peak INa densities among the SNTA1 WT and variants. However, both variants increased INa-L (% of peak current in HEK293T cells (0.58 ± 0.10 in WT vs. 0.90 ± 0.11 in A390V, p = 0.048; vs. 0.88 ± 0.07 in E409Q, p = 0.023. In cardiomyocytes, INa-L was significantly increased by E409Q, but not by A390V compared to WT (0.49 ± 0.14 in WT vs.0.94 ± 0.23 in A390V, p = 0.099; vs. 1.12 ± 0.24 in E409Q, p = 0.019. We demonstrated that a novel SNTA1 variant is likely causative for diLQTS by augmenting INa-L. These data suggest that variants within the NaV1.5-interacting α1-syntrophin are a potential mechanism for diLQTS, thereby expanding the concept that variants within congenital LQTS loci can cause diLQTS.

  6. The Smart Drug Delivery System and Its Clinical Potential.

    Science.gov (United States)

    Liu, Dong; Yang, Fang; Xiong, Fei; Gu, Ning

    2016-01-01

    With the unprecedented progresses of biomedical nanotechnology during the past few decades, conventional drug delivery systems (DDSs) have been involved into smart DDSs with stimuli-responsive characteristics. Benefiting from the response to specific internal or external triggers, those well-defined nanoplatforms can increase the drug targeting efficacy, in the meantime, reduce side effects/toxicities of payloads, which are key factors for improving patient compliance. In academic field, variety of smart DDSs have been abundantly demonstrated for various intriguing systems, such as stimuli-responsive polymeric nanoparticles, liposomes, metals/metal oxides, and exosomes. However, these nanoplatforms are lack of standardized manufacturing method, toxicity assessment experience, and clear relevance between the pre-clinical and clinical studies, resulting in the huge difficulties to obtain regulatory and ethics approval. Therefore, such relatively complex stimulus-sensitive nano-DDSs are not currently approved for clinical use. In this review, we highlight the recent advances of smart nanoplatforms for targeting drug delivery. Furthermore, the clinical translation obstacles faced by these smart nanoplatforms have been reviewed and discussed. We also present the future directions and perspectives of stimuli-sensitive DDS in clinical applications.

  7. Type I methionine aminopeptidase from Saccharomyces cerevisiae is a potential target for antifungal drug screening

    Institute of Scientific and Technical Information of China (English)

    Ling-ling CHEN; Jia LI; Jing-ya LI; Qun-li LUO; Wei-feng MAO; Qiang SHEN; Fa-jun NAN; Qi-zhuang YE

    2004-01-01

    AIM: To screen antifungal drug candidates using in vitro and in vivo assays based on type I methionine aminopeptidase from Saccharomyces cerevisiae (ScMetAP1). METHODS: A colorimetric assay suitable for high throughput screening (HTS) using recombinant ScMetAP1 protein expressed in Escherichia coli was established for antifungal lead discovery. A series of pyridine-2-carboxylic acid derivatives were characterized and a chemical library of 12 800 pure organic compounds was screened with the in vitro ScMetAP1 assay. Active compounds from the in vitro assay were further evaluated by a growth inhibition assay on yeast strain with deletion of ScMetAP1 gene mapl in comparison with the wild-type yeast strain and the yeast strain with deletion of type II enzyme (ScMetAP2)gene map2. RESULTS: Active ScMetAP1 inhibitors were identified from HTS. Some of the pyridine-2-carboxylic acid derivatives (compound 2 and 3) had selective inhibition of the growth of map2 deletion yeast and weak inhibition on wild-type yeast growth, while no inhibition on mapl deletion yeast. CONCLUSION: ScMetAP1 is a novel potential target for developing antifungal drugs. The in vitro and in vivo ScMetAP1 assays can serve as tools in discovering antifungal drug candidates.

  8. Preventing, Identifying, and Treating Prescription Drug Misuse Among Active-Duty Service Members

    Science.gov (United States)

    2017-01-04

    actions, includ- ing courts martial or administrative separation for drug use. Prior to 1981, random drug testing existed but with the primary purpose...Life Course,” Epidemiology Research International, Vol. 2012, January 2012, art . 520894. Paulozzi, Leonard J., Christopher M. Jones, Karin A. Mack

  9. Usability Validation of Medical Devices: Issues in Identifying Potential Use Errors.

    Science.gov (United States)

    Schiro, Jessica; Pelayo, Sylvia; Weinhold, Thomas; Del Zotto, Marzia; Marcilly, Romaric

    2017-01-01

    In order to prevent use errors with their medical devices, manufacturers have to integrate a safety-oriented usability engineering process in their product development lifecycle. A critical step of this process is the identification of potential use-errors. Standards and guidelines recommend to triangulate several sources of information e.g. scientific literature, incident reports, manufacturer's files and user's feedbacks. This paper presents lessons learned from applying these recommendations during an international project. We identify issues with (i) searching literature and databases, and (ii) interpreting collected data. Nevertheless triangulation of information sources allows to identify different types of use errors therefore providing valuable lists of potential use errors. Issuing recommendations aim at making easier this critical task.

  10. Impact of educational intervention on the pattern and incidence of potential drug-drug interactions in Nepal

    Directory of Open Access Journals (Sweden)

    Shankar PR

    2009-12-01

    Full Text Available Objective: To study the impact of educational intervention on the pattern and incidence of potential drug-drug interactions (DDIs. Method: All patients admitted to Internal Medicine wards of Manipal Teaching Hospital during the study period were included. Patient details were collected using a patient profile form and the datum from the filled forms was analyzed using Micromedex electronic database. An intervention was carried out through a presentation during clinical meeting and personal discussion. The target groups for the intervention included doctors and the nurses. Results: Altogether 435 patients during preintervention and 445 during postintervention were studied. The incidence of potential DDIs was 53% (preintervention and 41% (postintervention [chi-square =11.27, p=0.001]. The average number of drugs per patient was 8.53 (pre-intervention and 7.32 (post-intervention [t=3.493, p=0.001]. Sixty-four percent of the potential DDIs were of ‘Moderate’ type and 58% had a ‘Delayed’ onset in both the phases. Seventy percent of the potential DDIs during the pre-intervention phase and 61% during post-intervention phase had a ‘Good’ documentation status. Pharmacokinetic mechanism accounted for 45% of the potential DDIs during pre-intervention and 36% in the post-intervention phase. Cardiovascular drugs accounted for 36% of the potential DDIs during pre-intervention and 33.2% during post-intervention phase. Furosemide was the high risk drug responsible for DDIs in both phases. The most common potential DDIs observed were between amlodipine and atenolol (4.82% (preintervention and frusemide and aspirin (5.20% (postintervention. Conclusion: There was an association between potential DDIs and age, sex, and polypharmacy.

  11. Triangulation of the human, chimpanzee and Neanderthal genome sequences identifies potentially compensated mutations

    OpenAIRE

    Zhang, Guojie; Zhang,Pei; Krawczak, Michael; Ball, Edward V.; Mort, Matthew; Kehrer-Sawatzki, Hildegard; Cooper, David N.

    2010-01-01

    Abstract Triangulation of the human, chimpanzee and Neanderthal genome sequences with respect to 44,348 disease-causing or disease-associated missense mutations and 1,712 putative regulatory mutations listed in the Human Gene Mutation Database was employed to identify genetic variants that are apparently pathogenic in humans but which may represent a `compensated? wild-type state in at least one of the other two species. Of 122 such `potentially compensated mutations? (PCMs) identi...

  12. Identifying Multiple Potential Metabolic Cycles in Time-Series from Biolog Experiments

    OpenAIRE

    Shubin, Mikhail; Schaufler, Katharina; Tedin, Karsten; Vehkala, Minna; Corander, Jukka

    2016-01-01

    Biolog Phenotype Microarray (PM) is a technology allowing simultaneous screening of the metabolic behaviour of bacteria under a large number of different conditions. Bacteria may often undergo several cycles of metabolic activity during a Biolog experiment. We introduce a novel algorithm to identify these metabolic cycles in PM experimental data, thus increasing the potential of PM technology in microbiology. Our method is based on a statistical decomposition of the time-series measurements i...

  13. PS1-31: Assessing the Potential for Research on Genetics of Drug Induced Liver Injury in the HMORN

    Science.gov (United States)

    Pawloski, Pamala; Hedblom, Brita; Hitz, Paul; Owens, Brian; Anderson, Chris; McCarty, Catherine; Yale, Steven; Davis, Robert; Hemmes, Mia; Schmelzer, John

    2011-01-01

    Background/Aims Drug Induced Liver Injury (DILI) is a major cause of liver failure in the US and the leading reason for failure of investigational drugs in clinical trials, lack of drug approval, and post-market withdrawal of approved drugs. Recent genome-wide association studies have identified variations within the major histocompatibility complex in Caucasians to be linked with flucloxacillin and lumiracoxib-related liver injury. The need for replication of these findings and extension of these investigations to other drug exposures and other ethnic groups will require substantial case numbers with supporting medical record documentation. With support from The Serious Adverse Event Consortium, an international consortium led by the pharmaceutical industry in conjunction with the FDA, we conducted a feasibility study to evaluate the potential for using electronic clinical and administrative data from two HMORN sites to identify provisional DILI cases. Methods Building upon previous research, we developed data specifications for electronic searches of ICD-9 codes with time proximate laboratory results indicative of liver-related disease. Electronic criteria were used to ‘rule out’ other liver diseases and other co-morbid conditions indicative of systematic liver-related effects. For feasibility testing, two methods of population identification were incorporated: the VDW and EMR reporting. All records from 1/1/00–8/1/09 that were identified as ‘potential DILI cases’ were reviewed manually, and selected data were abstracted, including suspected implicated drug(s). Results Records for 1,123,173 individuals were screened for potential case status; 29,893 records with one or more diagnoses of interest were identified. After application of the “rule out’ exclusion criteria, 584 potential DILI cases were reviewed and 99 ultimately met provisional case status. Drugs commonly associated with provisional DILI cases were sulfa-containing antibiotics

  14. Characterisation of the Candida albicans Phosphopantetheinyl Transferase Ppt2 as a Potential Antifungal Drug Target.

    Directory of Open Access Journals (Sweden)

    Katharine S Dobb

    Full Text Available Antifungal drugs acting via new mechanisms of action are urgently needed to combat the increasing numbers of severe fungal infections caused by pathogens such as Candida albicans. The phosphopantetheinyl transferase of Aspergillus fumigatus, encoded by the essential gene pptB, has previously been identified as a potential antifungal target. This study investigated the function of its orthologue in C. albicans, PPT2/C1_09480W by placing one allele under the control of the regulatable MET3 promoter, and deleting the remaining allele. The phenotypes of this conditional null mutant showed that, as in A. fumigatus, the gene PPT2 is essential for growth in C. albicans, thus fulfilling one aspect of an efficient antifungal target. The catalytic activity of Ppt2 as a phosphopantetheinyl transferase and the acyl carrier protein Acp1 as a substrate were demonstrated in a fluorescence transfer assay, using recombinant Ppt2 and Acp1 produced and purified from E.coli. A fluorescence polarisation assay amenable to high-throughput screening was also developed. Therefore we have identified Ppt2 as a broad-spectrum novel antifungal target and developed tools to identify inhibitors as potentially new antifungal compounds.

  15. Potential risk for drug resistance globalization at the Hajj.

    Science.gov (United States)

    Al-Tawfiq, J A; Memish, Z A

    2015-02-01

    Antibiotics were once considered the miracle cure for infectious diseases. The tragedy would be the loss of these miracles as we witness increased antibiotic resistance throughout the world. One of the concerns during mass gatherings is the transmission of antibiotic resistance. Hajj is one of the most common recurring mass gatherings, attracting millions of people from around the world. The transmission of drug-resistant organisms during the Hajj is not well described. In the current review, we summarize the available literature on the transmission and acquisition of antibiotic resistance during the Hajj and present possible solutions.

  16. Excitatory amino acid transporters as potential drug targets

    DEFF Research Database (Denmark)

    Bunch, Lennart; Erichsen, Mette Navy; Jensen, Anders Asbjørn

    2009-01-01

    BACKGROUND: Excitatory amino acid transporters (EAATs) are transmembrane proteins responsible for the uptake of (S)-glutamate (Glu) from the synaptic cleft, thereby terminating the glutamatergic neurotransmitter signal. Today five subtypes have been identified. Except for EAAT2, their individual...

  17. An analysis of potential costs of adverse events based on Drug Programs in Poland. Pulmonology focus

    Directory of Open Access Journals (Sweden)

    Szkultecka-Debek Monika

    2014-06-01

    Full Text Available The project was performed within the Polish Society for Pharmacoeconomics (PTFE. The objective was to estimate the potential costs of treatment of side effects, which theoretically may occur as a result of treatment of selected diseases. We analyzed the Drug Programs financed by National Health Fund in Poland in 2012 and for the first analysis we selected those Programs where the same medicinal products were used. We based the adverse events selection on the Summary of Product Characteristics of the chosen products. We extracted all the potential adverse events defined as frequent and very frequent, grouping them according to therapeutic areas. This paper is related to the results in the pulmonology area. The events described as very common had an incidence of ≥ 1/10, and the common ones ≥ 1/100, <1/10. In order to identify the resources used, we performed a survey with the engagement of clinical experts. On the basis of the collected data we allocated direct costs incurred by the public payer. We used the costs valid in December 2013. The paper presents the estimated costs of treatment of side effects related to the pulmonology disease area. Taking into account the costs incurred by the NHF and the patient separately e calculated the total spending and the percentage of each component cost in detail. The treatment of adverse drug reactions generates a significant cost incurred by both the public payer and the patient.

  18. In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Jian Li

    2016-02-01

    Full Text Available Synthetic lethality describes situations in which defects in two different genes or pathways together result in cell death. This concept has been applied to drug development for cancer treatment, as represented by Poly (ADP-ribose polymerase (PARPs inhibitors. In the current study, we performed a computational screening to discover new PARP inhibitors. Among the 11,247 compounds analyzed, one natural product, ZINC67913374, stood out by its superior performance in the simulation analyses. Compared with the FDA approved PARP1 inhibitor, olaparib, our results demonstrated that the ZINC67913374 compound achieved a better grid score (−86.8 and amber score (−51.42. Molecular dynamics simulations suggested that the PARP1-ZINC67913374 complex was more stable than olaparib. The binding free energy for ZINC67913374 was −177.28 kJ/mol while that of olaparib was −159.16 kJ/mol. These results indicated ZINC67913374 bound to PARP1 with a higher affinity, which suggest ZINC67913374 has promising potential for cancer drug development.

  19. Historical uses of saffron: Identifying potential new avenues for modern research

    Directory of Open Access Journals (Sweden)

    Seyedeh Zeinab Mousavi

    2011-09-01

    Full Text Available Objective: During the ancient times, saffron (Crocus sativus L. had many uses around the world; however, some of these uses were forgotten throughout the history. But a newly formed interest in natural active compounds brought back the attention toward historical uses of saffron. Understanding different uses of saffron in the past can help us finding the best uses at present. In this study, we reviewed different uses of saffron throughout the history among different nations.Methods: ISI web of Science and Medline, along with references of traditional Iranian medicine were searched for historical uses of saffron.Results: Saffron has been known since more than 3000 years ago by many nations. It was valued not only as a culinary condiment, but also as a dye, perfume and as a medicinal herb. Its medicinal uses ranged from treating eye problems to genitourinary and many other diseases in various cultures. It was also used as a tonic agent and antidepressant drug among many nations. Conclusion(s: Saffron has had many different uses such as a food additive and a palliative agent for many human diseases. Thus, as an important medicinal herb, it is a good candidate with many promising potentials to be considered for new drug design.

  20. Historical uses of saffron: Identifying potential new avenues for modern research

    Directory of Open Access Journals (Sweden)

    Seyedeh Zeinab Mousavi

    2011-09-01

    Full Text Available Objective: During the ancient times, saffron (Crocus sativus L. had many uses around the world; however, some of these uses were forgotten throughout the history. But a newly formed interest in natural active compounds brought back the attention toward historical uses of saffron. Understanding different uses of saffron in the past can help us finding the best uses at present.In this study, wereviewed different uses of saffron throughout the history among different nations. Methods: ISI web of Science and Medline, along with references of traditional Iranian medicine were searched for historical uses of saffron. Results: Saffron has been known since more than 3000 years ago by many nations. It was valued not only as a culinary condiment, but also as a dye, perfume and as a medicinal herb. Its medicinal uses ranged from treating eye problems to genitourinary and many other diseases in various cultures. It was also used as a tonic agent and antidepressant drug among many nations. Conclusion(s: Saffron has had many different uses such as a food additive and a palliative agent for many human diseases. Thus, as an important medicinal herb, it is a good candidate with many promising potentials to be considered for new drug design.

  1. Spontaneous swallowing frequency has potential to identify dysphagia in acute stroke.

    Science.gov (United States)

    Crary, Michael A; Carnaby, Giselle D; Sia, Isaac; Khanna, Anna; Waters, Michael F

    2013-12-01

    Spontaneous swallowing frequency has been described as an index of dysphagia in various health conditions. This study evaluated the potential of spontaneous swallow frequency analysis as a screening protocol for dysphagia in acute stroke. In a cohort of 63 acute stroke cases, swallow frequency rates (swallows per minute [SPM]) were compared with stroke and swallow severity indices, age, time from stroke to assessment, and consciousness level. Mean differences in SPM were compared between patients with versus without clinically significant dysphagia. Receiver operating characteristic curve analysis was used to identify the optimal threshold in SPM, which was compared with a validated clinical dysphagia examination for identification of dysphagia cases. Time series analysis was used to identify the minimally adequate time period to complete spontaneous swallow frequency analysis. SPM correlated significantly with stroke and swallow severity indices but not with age, time from stroke onset, or consciousness level. Patients with dysphagia demonstrated significantly lower SPM rates. SPM differed by dysphagia severity. Receiver operating characteristic curve analysis yielded a threshold of SPM≤0.40 that identified dysphagia (per the criterion referent) with 0.96 sensitivity, 0.68 specificity, and 0.96 negative predictive value. Time series analysis indicated that a 5- to 10-minute sampling window was sufficient to calculate spontaneous swallow frequency to identify dysphagia cases in acute stroke. Spontaneous swallowing frequency presents high potential to screen for dysphagia in acute stroke without the need for trained, available personnel.

  2. Spontaneous Swallowing Frequency [Has Potential to] Identify Dysphagia in Acute Stroke

    Science.gov (United States)

    Carnaby, Giselle D; Sia, Isaac; Khanna, Anna; Waters, Michael

    2014-01-01

    Background and Purpose Spontaneous swallowing frequency has been described as an index of dysphagia in various health conditions. This study evaluated the potential of spontaneous swallow frequency analysis as a screening protocol for dysphagia in acute stroke. Methods In a cohort of 63 acute stroke cases swallow frequency rates (swallows per minute: SPM) were compared to stroke and swallow severity indices, age, time from stroke to assessment, and consciousness level. Mean differences in SPM were compared between patients with vs. without clinically significant dysphagia. ROC analysis was used to identify the optimal threshold in SPM which was compared to a validated clinical dysphagia examination for identification of dysphagia cases. Time series analysis was employed to identify the minimally adequate time period to complete spontaneous swallow frequency analysis. Results SPM correlated significantly with stroke and swallow severity indices but not with age, time from stroke onset, or consciousness level. Patients with dysphagia demonstrated significantly lower SPM rates. SPM differed by dysphagia severity. ROC analysis yielded a threshold of SPM ≤ 0.40 which identified dysphagia (per the criterion referent) with 0.96 sensitivity, 0.68 specificity, and 0.96 negative predictive value. Time series analysis indicated that a 5 to 10 minute sampling window was sufficient to calculate spontaneous swallow frequency to identify dysphagia cases in acute stroke. Conclusions Spontaneous swallowing frequency presents high potential to screen for dysphagia in acute stroke without the need for trained, available personnel. PMID:24149008

  3. Characterization of potential mineralization in Afghanistan: four permissive areas identified using imaging spectroscopy data

    Science.gov (United States)

    King, Trude V.V.; Berger, Byron R.; Johnson, Michaela R.

    2014-01-01

    As part of the U.S. Geological Survey and Department of Defense Task Force for Business and Stability Operations natural resources revitalization activities in Afghanistan, four permissive areas for mineralization, Bamyan 1, Farah 1, Ghazni 1, and Ghazni 2, have been identified using imaging spectroscopy data. To support economic development, the areas of potential mineralization were selected on the occurrence of selected mineral assemblages mapped using the HyMap™ data (kaolinite, jarosite, hydrated silica, chlorite, epidote, iron-bearing carbonate, buddingtonite, dickite, and alunite) that may be indicative of past mineralization processes in areas with limited or no previous mineral resource studies. Approximately 30 sites were initially determined to be candidates for areas of potential mineralization. Additional criteria and material used to refine the selection and prioritization process included existing geologic maps, Landsat Thematic Mapper data, and published literature. The HyMapTM data were interpreted in the context of the regional geologic and tectonic setting and used the presence of alteration mineral assemblages to identify areas with the potential for undiscovered mineral resources. Further field-sampling, mapping, and supporting geochemical analyses are necessary to fully substantiate and verify the specific deposit types in the four areas of potential mineralization.

  4. Identifying Potential Areas for Future Urban Development Using Gis-Based Multi Criteria Evaluation Technique

    Directory of Open Access Journals (Sweden)

    Mohammed Khalid Sabbar

    2016-01-01

    Full Text Available Malaysia likes other Asian countries has experienced rapid urbanization due to economic development, industrialization, massive migrations as well as natural population growth. This expansion particularly the unplanned has impacted negatively on farming activities and creates huge pressure arable agriculture areas. Thus, identification of potential sites for future urban development should become important issues in ensuring sustainable development. Therefore, the aim of this paper is to use GIS based multi criteria evaluation technique to identify potential areas for urban development at Balik Pulau, Penang. The study quantified spatial and temporal dynamics of land use/cover changes and identified potential areas for future development. The results indicated that large proportions of agriculture areas had been converted to built-up areas.. Urban areas increased from 1793.2 ha in 1992 to 3235.4 ha in 2002 and became 3987.8 ha in 2010. On the other hand agricultural land decreased from 6171.3ha (53.8% in 1992 to 3883 ha (35. % in 2010. The study, then, produced map showing potential sites for future urban development. The findings also indicated built-up areas would continue to encroach into flat available agricultural land which will be diminished if no restriction imposed. Thus, the information obtained from this study is useful for planners and decision makers in controlling agriculture areas and guiding new development properly.

  5. Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development.

    Science.gov (United States)

    Brown, Kristine E; Chagoya, Gustavo; Kwatra, Shawn G; Yen, Timothy; Keir, Stephen T; Cooter, Mary; Hoadley, Katherine A; Rasheed, Ahmed; Lipp, Eric S; Mclendon, Roger; Ali-Osman, Francis; Bigner, Darell D; Sampson, John H; Kwatra, Madan M

    2015-06-01

    The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. To date, proteomic level validation of widely used patient-derived glioblastoma xenografts (PDGX) has not been performed. In the present study, we characterized 20 PDGX models according to subtype classification based on The Cancer Genome Atlas criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. The 20 PDGXs belonged to three of four The Cancer Genome Atlas subtypes: eight classical, eight mesenchymal, and four proneural; none neural. Amplification of EGFR gene was observed in 9 of 20 xenografts, and of these, 3 harbored the EGFRvIII mutation. We then performed proteomic profiling of PDGX, analyzing expression/activity of several proteins including EGFR. Levels of EGFR phosphorylated at Y1068 vary considerably between PDGX samples, and this pattern was also seen in primary GBM. Partitioning of 20 PDGX into high (n = 5) and low (n = 15) groups identified a panel of proteins associated with high EGFR activity. Thus, PDGX with high EGFR activity represent an excellent pre-clinical model to develop therapies for a subset of GBM patients whose tumors are characterized by high EGFR activity. Further, the proteins found to be associated with high EGFR activity can be monitored to assess the effectiveness of targeting EGFR. The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. We validated proteomic profiles using patient-derived glioblastoma xenografts (PDGX), characterizing 20 PDGX models according to subtype classification based on The Cancer Genome Atlas (TCGA) criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. Proteins found to be associated with high EGFR activity represent potential

  6. Platinum-RNA modifications following drug treatment in S. cerevisiae identified by click chemistry and enzymatic mapping.

    Science.gov (United States)

    Osborn, Maire F; White, Jonathan D; Haley, Michael M; DeRose, Victoria J

    2014-10-17

    With the importance of RNA-based regulatory pathways, the potential for targeting noncoding and coding RNAs by small molecule therapeutics is of great interest. Platinum(II) complexes including cisplatin (cis-diamminedichloroplatinum(II)) are widely prescribed anticancer compounds that form stable adducts on nucleic acids. In tumors, DNA damage from Pt(II) initiates apoptotic signaling, but this activity is not necessary for cytotoxicity (e.g., Yu et al., 2008), suggesting accumulation and consequences of Pt(II) lesions on non-DNA targets. We previously reported an azide-functionalized compound, picazoplatin, designed for post-treatment click labeling that enables detection of Pt complexes (White et al., 2013). Here, we report in-gel fluorescent detection of Pt-bound rRNA and tRNA extracted from picazoplatin-treated S. cerevisiae and labeled using Cu-free click chemistry. These data provide the first evidence that cellular tRNA is a platinum drug substrate. We assess Pt(II) binding sites within rRNA from cisplatin-treated S. cerevisiae, in regions where damage is linked to significant downstream consequences including the sarcin-ricin loop (SRL) Helix 95. Pt-RNA adducts occur on the nucleotide substrates of ribosome-inactivating proteins, as well as on the bulged-G motif critical for elongation factor recognition of the loop. At therapeutically relevant concentrations, Pt(II) also binds robustly within conserved cation-binding pockets in Domains V and VI rRNA at the peptidyl transferase center. Taken together, these results demonstrate a convenient click chemistry methodology that can be applied to identify other metal or covalent modification-based drug targets and suggest a ribotoxic mechanism for cisplatin cytotoxicity.

  7. Nanoporous anodic titanium dioxide layers as potential drug delivery systems: Drug release kinetics and mechanism.

    Science.gov (United States)

    Jarosz, Magdalena; Pawlik, Anna; Szuwarzyński, Michał; Jaskuła, Marian; Sulka, Grzegorz D

    2016-07-01

    Nanoporous anodic titanium dioxide (ATO) layers on Ti foil were prepared via a three step anodization process in an electrolyte based on an ethylene glycol solution with fluoride ions. Some of the ATO samples were heat-treated in order to achieve two different crystallographic structures - anatase (400°C) and a mixture of anatase and rutile (600°C). The structural and morphological characterizations of ATO layers were performed using a field emission scanning electron microscope (SEM). The hydrophilicity of ATO layers was determined with contact angle measurements using distilled water. Ibuprofen and gentamicin were loaded effectively inside the ATO nanopores. Afterwards, an in vitro drug release was conducted for 24h under a static and dynamic flow conditions in a phosphate buffer solution at 37°C. The drug concentrations were determined using UV-Vis spectrophotometry. The absorbance of ibuprofen was measured directly at 222nm, whether gentamicin was determined as a complex with silver nanoparticles (Ag NPs) at 394nm. Both compounds exhibited long term release profiles, despite the ATO structure. A new release model, based on the desorption of the drug from the ATO top surface followed by the desorption and diffusion of the drug from the nanopores, was derived. The proposed release model was fitted to the experimental drug release profiles, and kinetic parameters were calculated.

  8. Potential drug-drug interactions in pediatric wards of Gondar University Hospital, Ethiopia:A cross sectional study

    Institute of Scientific and Technical Information of China (English)

    Henok Getachew; Mohammed Assen; Feser Dula; Akshaya Srikanth Bhagavathula

    2016-01-01

    Objective: To determine the prevalence, level of severity of potential drug–drug in-teractions (PDDIs) and the associated factors for PDDIs in hospitalized pediatric patients of Gondar University Hospital. Methods: A retrospective cross-sectional study was conducted for a period of 3 months from March to May 2014 in pediatric wards of Gondar University Hospital. Systematic random sampling technique was used to select charts from all pediatric patients' charts with every 7th interval to get sample size of 384. Univariate and multivariate analysis were performed to compute crude odds ratio and adjusted odds ratio respectively. Sta-tistical significance was set at P value Results: A total of 176 (45.8%) patients had at least one PDDI. A total of 393 PDDIs, which were comprised of 283 types of interacting combinations, were identified. Of the total of 393 PDDIs, most were of moderate severity [201 (51%)] followed by minor [152 (39%)] and major severity [40 (10%)]. The most common interacting pairs of major severity were gentamicin + furosemide (6), cotrimoxazole + methotrexate (4) and phenytoin + artemether (4). The occurrence of PDDIs was significantly associated with age and polypharmacy. Conclusions: The study showed that most of the interactions had moderate severity followed by minor severity. Age and polypharmacy were found to show statistically significant association with the occurrence of PDDIs. Due to sensitive nature of pediatrics population, close monitoring is recommended for the detection and management of PDDIs to prevent its negative consequences.

  9. Pityriasis Rosea Like Drug Rash – A Need to Identify the Disease in Childhood

    OpenAIRE

    Panda, Maitreyee; Patro, Nibedita; Jena, Monalisa; Dash, Mrutunjay; Mishra, Swati

    2014-01-01

    Pityriasis rosea is a common dermatosis named by Gibert in 1860. It is an acute self limiting papulosquamous disease, probably infective in origin affecting healthy adolescents and young adults. It is characterized by distinctive skin eruptions and minimal constitutional symptoms. Drug induced pityriasis rosea tend to occur in older generation and resolution seen only after withdrawal of the offending drug. We report a case of 12-year-old boy with erythematous papules distributed over trunk a...

  10. Identifying and Addressing the Unmet Health Care Needs of Drug Court Clients.

    Science.gov (United States)

    Dugosh, Karen L; Festinger, David S; Lipkin, Jessica L

    2016-12-01

    Drug courts address issues such as employment and housing but largely miss the opportunity to address important health care issues. The current study examined the prevalence and correlates of chronic medical conditions among a sample of drug court clients who were participating in a clinical trial of an intervention to reduce HIV risk. A total of 256 clients completed a health survey at entry into the drug court program and 9 months post-entry. The baseline health survey included a comprehensive list of chronic medical conditions, and participants were asked to indicate which, if any, they had ever been diagnosed as having. They were also asked to indicate whether or not they were currently receiving treatment for each chronic condition that they endorsed. The follow-up survey was identical to the baseline survey, with the exception that it contained items reflecting (1) whether or not any member of the drug court team engaged in discussion with the client about each of the chronic conditions reported and (2) whether the client received a referral to medical care for endorsed conditions while in the drug court program. Results indicated that over 50% of clients reported at least one chronic condition and 21% reported more than one condition. Among those with chronic conditions, 71% reported having chronic conditions for which they were not currently receiving treatment. Unfortunately, drug court clients reported that the drug court team did little to address these unmet health needs. Findings from this study suggest that clients could benefit if drug court programs began to widen their focus to include addressing health-related issues.

  11. The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future.

    Science.gov (United States)

    Carhart-Harris, Robin L; Goodwin, Guy M

    2017-10-01

    Plant-based psychedelics, such as psilocybin, have an ancient history of medicinal use. After the first English language report on LSD in 1950, psychedelics enjoyed a short-lived relationship with psychology and psychiatry. Used most notably as aids to psychotherapy for the treatment of mood disorders and alcohol dependence, drugs such as LSD showed initial therapeutic promise before prohibitive legislature in the mid-1960s effectively ended all major psychedelic research programs. Since the early 1990s, there has been a steady revival of human psychedelic research: last year saw reports on the first modern brain imaging study with LSD and three separate clinical trials of psilocybin for depressive symptoms. In this circumspective piece, RLC-H and GMG share their opinions on the promises and pitfalls of renewed psychedelic research, with a focus on the development of psilocybin as a treatment for depression.

  12. Potentiation of Anticancer Drugs: Effects of Pentoxifylline on Neoplastic Cells

    Directory of Open Access Journals (Sweden)

    Miroslav Barancik

    2011-12-01

    Full Text Available The drug efflux activity of P-glycoprotein (P-gp, a product of the mdr1 gene, ABCB1 member of ABC transporter family represents a mechanism by which tumor cells escape death induced by chemotherapeutics. In this study, we investigated the mechanisms involved in the effects of pentoxifylline (PTX on P-gp-mediated multidrug resistance (MDR in mouse leukemia L1210/VCR cells. Parental sensitive mouse leukemia cells L1210, and multidrug-resistant cells, L1210/VCR, which are characterized by the overexpression of P-gp, were used as experimental models. The cells were exposed to 100 μmol/L PTX in the presence or absence of 1.2 μmol/L vincristine (VCR. Western blot analysis indicated a downregulation of P-gp protein expression when multidrug-resistant L1210/VCR cells were exposed to PTX. The effects of PTX on the sensitization of L1210/VCR cells to VCR correlate with the stimulation of apoptosis detected by Annexin V/propidium iodide apoptosis necrosis kit and proteolytic activation of both caspase-3 and caspase-9 monitored by Western blot analysis. Higher release of matrix metalloproteinases (MMPs, especially MMP-2, which could be attenuated by PTX, was found in L1210/VCR than in L1210 cells by gelatin zymography in electrophoretic gel. Exposure of resistant cells to PTX increased the content of phosphorylated Akt kinase. In contrast, the presence of VCR eliminated the effects of PTX on Akt kinase phosphorylation. Taken together, we conclude that PTX induces the sensitization of multidrug-resistant cells to VCR via downregulation of P-gp, stimulation of apoptosis and reduction of MMPs released from drug-resistant L1210/VCR cells. These facts bring new insights into the mechanisms of PTX action on cancer cells.

  13. Evaluation of quercetin as a potential drug in osteosarcoma treatment.

    Science.gov (United States)

    Berndt, Kersten; Campanile, Carmen; Muff, Roman; Strehler, Emanuel; Born, Walter; Fuchs, Bruno

    2013-04-01

    Osteosarcoma is the most common malignant bone tumor in children and young adults. Since the introduction of chemotherapy, the 5-year survival rate of patients with non-metastatic osteosarcoma is ~70%. The main problems in osteosarcoma therapy are the occurrence of metastases, severe side-effects and chemoresistance. Antiproliferative and apoptotic effects of quercetin were shown in several types of cancers, including breast cancer and lung carcinoma. The present study investigates the cytotoxic potential of quercetin, a dietary flavonoid, in a highly metastasizing human osteosarcoma cell line, 143B. We found that quercetin induces growth inhibition, G2/M phase arrest, and apoptosis in the 143B osteosarcoma cell line. We also observed impaired adhesion and migratory potential after the addition of quercetin. Since quercetin has already been shown to have low side effects in a clinical phase I trial in advanced cancer patients, this compound may have considerable potential for osteosarcoma treatment.

  14. Natural melanin: a potential pH-responsive drug release device.

    Science.gov (United States)

    Araújo, Marco; Viveiros, Raquel; Correia, Tiago R; Correia, Ilídio J; Bonifácio, Vasco D B; Casimiro, Teresa; Aguiar-Ricardo, Ana

    2014-07-20

    This work proposes melanin as a new nanocarrier for pH-responsive drug release. Melanin is an abundant natural polymer that can be easily extracted from cuttlefish as nanoparticles with a suitable size range for drug delivery. However, despite its high potentiality, the application of this biopolymer in the pharmaceutical and biomedical fields is yet to be explored. Herein, melanin nanoparticles were impregnated with metronidazole, chosen as model antibiotic drug, using supercritical carbon dioxide. The drug release profile was investigated at acidic and physiologic pH, and the dominant mechanism was found to follow a non-Fickian transport. Drug release from melanin shows a strong pH dependency, which allied to its biocompatibility and lack of cytotoxicity envisages its potential application as nanocarrier in formulations for colon and intestine targeted drug delivery.

  15. A Comparative Reverse Docking Strategy to Identify Potential Antineoplastic Targets of Tea Functional Components and Binding Mode

    Directory of Open Access Journals (Sweden)

    Rong Zheng

    2011-08-01

    Full Text Available The main functional components of green tea, such as epigallocatechin gallate (EGCG, epigallocatechin (EGC, epicatechin gallate (ECG and epicatechin (EC, are found to have a broad antineoplastic activity. The discovery of their targets plays an important role in revealing the antineoplastic mechanism. Therefore, to identify potential target proteins for tea polyphenols, we have taken a comparative virtual screening approach using two reverse docking systems, one based on Autodock software and the other on Tarfisdock. Two separate in silico workflows were implemented to derive a set of target proteins related to human diseases and ranked by the binding energy score. Several conventional clinically important proteins with anti-tumor effects are screened out from the PDTD protein database as the potential receptors by both procedures. To further analyze the validity of docking results, we study the binding mode of EGCG and the potential target protein Leukotriene A4 hydrolase in detail. We indicate that interactions mediated by electrostatic and hydrogen bond play a key role in ligand binding. EGCG binds to the enzyme with certain orientation and conformation that is suitable for nucleophilic attacks by several electrical residues inside the enzyme’s activity cavity. This study provides useful information for studying the antitumor mechanism of tea’s functional components. The comparative reverse docking strategy presented generates a tractable set of antineoplastic proteins for future experimental validation as drug targets against tumors.

  16. Hot spot analysis applied to identify ecosystem services potential in Lithuania

    Science.gov (United States)

    Pereira, Paulo; Depellegrin, Daniel; Misiune, Ieva

    2016-04-01

    Hot spot analysis are very useful to identify areas with similar characteristics. This is important for a sustainable use of the territory, since we can identify areas that need to be protected, or restored. This is a great advantage in terms of land use planning and management, since we can allocate resources, reduce the economical costs and do a better intervention in the landscape. Ecosystem services (ES) are different according land use. Since landscape is very heterogeneous, it is of major importance understand their spatial pattern and where are located the areas that provide better ES and the others that provide less services. The objective of this work is to use hot-spot analysis to identify areas with the most valuable ES in Lithuania. CORINE land-cover (CLC) of 2006 was used as the main spatial information. This classification uses a grid of 100 m resolution and extracted a total of 31 land use types. ES ranking was carried out based on expert knowledge. They were asked to evaluate the ES potential of each different CLC from 0 (no potential) to 5 (very high potential). Hot spot analysis were evaluated using the Getis-ord test, which identifies cluster analysis available in ArcGIS toolbox. This tool identifies areas with significantly high low values and significant high values at a p level of 0.05. In this work we used hot spot analysis to assess the distribution of providing, regulating cultural and total (sum of the previous 3) ES. The Z value calculated from Getis-ord was used to statistical analysis to access the clusters of providing, regulating cultural and total ES. ES with high Z value show that they have a high number of cluster areas with high potential of ES. The results showed that the Z-score was significantly different among services (Kruskal Wallis ANOVA =834. 607, pcultural (0.080±1.979) and regulating (0.076±1.961). These results suggested that providing services are more clustered than the remaining. Ecosystem Services Z score were

  17. Identifying potential recommendation domains for conservation agriculture in Ethiopia, Kenya, and Malawi.

    Science.gov (United States)

    Tesfaye, Kindie; Jaleta, Moti; Jena, Pradyot; Mutenje, Munyaradzi

    2015-02-01

    Conservation agriculture (CA) is being promoted as an option for reducing soil degradation, conserving water, enhancing crop productivity, and maintaining yield stability. However, CA is a knowledge- and technology-intensive practice, and may not be feasible or may not perform better than conventional agriculture under all conditions and farming systems. Using high resolution (≈1 km(2)) biophysical and socioeconomic geospatial data, this study identified potential recommendation domains (RDs) for CA in Ethiopia, Kenya, and Malawi. The biophysical variables used were soil texture, surface slope, and rainfall while the socioeconomic variables were market access and human and livestock population densities. Based on feasibility and comparative performance of CA over conventional agriculture, the biophysical and socioeconomic factors were first used to classify cultivated areas into three biophysical and three socioeconomic potential domains, respectively. Combinations of biophysical and socioeconomic domains were then used to develop potential RDs for CA based on adoption potential within the cultivated areas. About 39, 12, and 5% of the cultivated areas showed high biophysical and socioeconomic potential while 50, 39, and 21% of the cultivated areas showed high biophysical and medium socioeconomic potential for CA in Malawi, Kenya, and Ethiopia, respectively. The results indicate considerable acreages of land with high CA adoption potential in the mixed crop-livestock systems of the studied countries. However, there are large differences among countries depending on biophysical and socio-economic conditions. The information generated in this study could be used for targeting CA and prioritizing CA-related agricultural research and investment priorities in the three countries.

  18. Identifying Potential Recommendation Domains for Conservation Agriculture in Ethiopia, Kenya, and Malawi

    Science.gov (United States)

    Tesfaye, Kindie; Jaleta, Moti; Jena, Pradyot; Mutenje, Munyaradzi

    2015-02-01

    Conservation agriculture (CA) is being promoted as an option for reducing soil degradation, conserving water, enhancing crop productivity, and maintaining yield stability. However, CA is a knowledge- and technology-intensive practice, and may not be feasible or may not perform better than conventional agriculture under all conditions and farming systems. Using high resolution (≈1 km2) biophysical and socioeconomic geospatial data, this study identified potential recommendation domains (RDs) for CA in Ethiopia, Kenya, and Malawi. The biophysical variables used were soil texture, surface slope, and rainfall while the socioeconomic variables were market access and human and livestock population densities. Based on feasibility and comparative performance of CA over conventional agriculture, the biophysical and socioeconomic factors were first used to classify cultivated areas into three biophysical and three socioeconomic potential domains, respectively. Combinations of biophysical and socioeconomic domains were then used to develop potential RDs for CA based on adoption potential within the cultivated areas. About 39, 12, and 5 % of the cultivated areas showed high biophysical and socioeconomic potential while 50, 39, and 21 % of the cultivated areas showed high biophysical and medium socioeconomic potential for CA in Malawi, Kenya, and Ethiopia, respectively. The results indicate considerable acreages of land with high CA adoption potential in the mixed crop-livestock systems of the studied countries. However, there are large differences among countries depending on biophysical and socio-economic conditions. The information generated in this study could be used for targeting CA and prioritizing CA-related agricultural research and investment priorities in the three countries.

  19. Cancer Chemoprevention Effects of Ginger and its Active Constituents: Potential for New Drug Discovery.

    Science.gov (United States)

    Wang, Chong-Zhi; Qi, Lian-Wen; Yuan, Chun-Su

    2015-01-01

    Ginger is a commonly used spice and herbal medicine worldwide. Besides its extensive use as a condiment, ginger has been used in traditional Chinese medicine for the management of various medical conditions. In recent years, ginger has received wide attention due to its observed antiemetic and anticancer activities. This paper reviews the potential role of ginger and its active constituents in cancer chemoprevention. The phytochemistry, bioactivity, and molecular targets of ginger constituents, especially 6-shogaol, are discussed. The content of 6-shogaol is very low in fresh ginger, but significantly higher after steaming. With reported anti-cancer activities, 6-shogaol can be served as a lead compound for new drug discovery. The lead compound derivative synthesis, bioactivity evaluation, and computational docking provide a promising opportunity to identify novel anticancer compounds originating from ginger.

  20. Using high frequency consumption data to identify demand response potential for solar energy integration

    Science.gov (United States)

    Jin, L.; Borgeson, S.; Fredman, D.; Hans, L.; Spurlock, A.; Todd, A.

    2015-12-01

    California's renewable portfolio standard (2012) requires the state to get 33% of its electricity from renewable sources by 2020. Increased share of variable renewable sources such as solar and wind in the California electricity system may require more grid flexibility to insure reliable power services. Such grid flexibility can be potentially provided by changes in end use electricity consumptions in response to grid conditions (demand-response). In the solar case, residential consumption in the late afternoon can be used as reserve capacity to balance the drop in solar generation. This study presents our initial attempt to identify, from a behavior perspective, residential demand response potentials in relation to solar ramp events using a data-driven approach. Based on hourly residential energy consumption data, we derive representative daily load shapes focusing on discretionary consumption with an innovative clustering analysis technique. We aggregate the representative load shapes into behavior groups in terms of the timing and rhythm of energy use in the context of solar ramp events. Households of different behavior groups that are active during hours with high solar ramp rates are identified for capturing demand response potential. Insights into the nature and predictability of response to demand-response programs are provided.

  1. Identifying potential ground movement as a landslide mitigation approach using resistivity method

    Science.gov (United States)

    Izzati, F. N.; Laksmana, Z. S.; Marcelina, B.; Hutabarat, S. S.; Widodo

    2017-07-01

    Landslide is defined as a form of ground movement in which land mass suddenly fails downward on a slope as aresult of gravitational pull. One of the mitigative approaches into investigating landslide is to identify a potential slip zone usingresistivity method. In this study, the array chosen to acquire the resistivity data was Wenner array as it provides a robust resolution in mapping lateral resistivity variations. This method will generate a contour map portraying thedistribution of resistivity values of the subsurface. Beforehand, a 2-dimensional forward modeling was conducted to acquire anexpected ideal result of possible potential slip zone. Landslides itself are affiliated with a low resistivity zone that is locatedbetween two high resistivity zones. This study is conducted in a ground slump in Jalan Citra Green, Northern Bandung which is comprised of mostly unconsolidated soil. By applying a least-square inversion to the resistivity data obtained, resistivity values of 10-200 Ωm is attained. Based on the inversion result, a low resistivity zone of 10-20 Ωm is identified spanning from the surface to approximately 10 meters deep. In conclusion, furtherinvestigations are needed to determine whether the low resistivity zone is associated with potential slip zone as our datais limited to a single line

  2. Existing FDA pathways have potential to ensure early access to, and appropriate use of, specialty drugs.

    Science.gov (United States)

    Kesselheim, Aaron S; Tan, Yongtian Tina; Darrow, Jonathan J; Avorn, Jerry

    2014-10-01

    Specialty drugs are notable among prescription drugs in that they offer the possibility of substantial clinical improvement, come with important risks of adverse events and mortality, can be complex to manufacture or administer, and are usually extremely costly. The Food and Drug Administration (FDA) plays a critical role in ensuring that patients who could benefit from specialty drugs have access to them in a timely fashion. In this article we review the different strategies that the FDA can use to approve and influence the post-approval prescribing of specialty drugs. When specialty drugs show promise in early clinical trials, the FDA can expedite the drugs' availability to patients through expanded access programs and expedited approval pathways that speed regulatory authorization. After approval, to ensure that specialty drugs are directed to the patients who are most likely to benefit from them, the FDA can limit the scope of the drugs' indications, encourage the development of companion diagnostic tests to indicate which patients should receive the drugs, or require that manufacturers subject them to Risk Evaluation and Mitigation Strategies to ensure that their use is appropriately limited to a restricted population that is aware of the drugs' risks and benefits. Implementing these existing regulatory approaches can promote timely patient access to specialty drugs while preventing expensive and potentially inappropriate overuse.

  3. A study of potential drug-drug interactions among critically ill patients at a tertiary care hospital

    Directory of Open Access Journals (Sweden)

    Manjeeta Gupta

    2016-08-01

    Conclusions: The present study showed high concomitant administration of potentially interacting drugs. The prevalence confirmed the association of age and polypharmacy. Vigilant prescribing approach is needed to prevent hazardous outcomes of pDDI. [Int J Basic Clin Pharmacol 2016; 5(4.000: 1281-1285

  4. Potential drug–drug interactions in Alzheimer patients with behavioral symptoms

    Directory of Open Access Journals (Sweden)

    Pasqualetti G

    2015-09-01

    Full Text Available Giuseppe Pasqualetti, Sara Tognini, Valeria Calsolaro, Antonio Polini, Fabio Monzani Geriatrics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Abstract: The use of multi drug regimens among the elderly population has increased tremendously over the last decade although the benefits of medications are always accompanied by potential harm, even when prescribed at recommended doses. The elderly populations are particularly at an increased risk of adverse drug reactions considering comorbidity, poly-therapy, physiological changes affecting the pharmacokinetics and pharmacodynamics of many drugs and, in some cases, poor compliance due to cognitive impairment and/or depression. In this setting, drug–drug interaction may represent a serious and even life-threatening clinical condition. Moreover, the inability to distinguish drug-induced symptoms from a definitive medical diagnosis often results in addition of yet another drug to treat the symptoms, which in turn increases drug–drug interactions. Cognitive enhancers, including acetylcholinesterase inhibitors and memantine, are the most widely prescribed agents for Alzheimer’s disease (AD patients. Behavioral and psychological symptoms of dementia, including psychotic symptoms and behavioral disorders, represent noncognitive disturbances frequently observed in AD patients. Antipsychotic drugs are at high risk of adverse events, even at modest doses, and may interfere with the progression of cognitive impairment and interact with several drugs including anti-arrhythmics and acetylcholinesterase inhibitors. Other medications often used in AD patients are represented by anxiolytic, like benzodiazepine, or antidepressant agents. These agents also might interfere with other concomitant drugs through both pharmacokinetic and pharmacodynamic mechanisms. In this review we focus on the most frequent drug–drug interactions, potentially harmful, in AD patients with

  5. ROCK1 is a potential combinatorial drug target for BRAF mutant melanoma

    NARCIS (Netherlands)

    Smit, Marjon A; Maddalo, Gianluca; Greig, Kylie; Raaijmakers, Linsey M; Possik, Patricia A; van Breukelen, Bas; Cappadona, Salvatore; Heck, Albert Jr; Altelaar, Adrianus; Peeper, Daniel S

    2014-01-01

    Treatment of BRAF mutant melanomas with specific BRAF inhibitors leads to tumor remission. However, most patients eventually relapse due to drug resistance. Therefore, we designed an integrated strategy using (phospho)proteomic and functional genomic platforms to identify drug targets whose inhibiti

  6. Human recombinant RNASET2: A potential anti-cancer drug

    Science.gov (United States)

    Roiz, Levava; Smirnoff, Patricia; Lewin, Iris; Shoseyov, Oded; Schwartz, Betty

    2016-01-01

    The roles of cell motility and angiogenetic processes in metastatic spread and tumor aggressiveness are well established and must be simultaneously targeted to maximize antitumor drug potency. This work evaluated the antitumorigenic capacities of human recombinant RNASET2 (hrRNASET2), a homologue of the Aspergillus niger T2RNase ACTIBIND, which has been shown to display both antitumorigenic and antiangiogenic activities. hrRNASET2 disrupted intracellular actin filament and actin-rich extracellular extrusion organization in both CT29 colon cancer and A375SM melanoma cells and induced a significant dose-dependent inhibition of A375SM cell migration. hrRNASET2 also induced full arrest of angiogenin-induced tube formation and brought to a three-fold lower relative HT29 colorectal and A375SM melanoma tumor volume, when compared to Avastin-treated animals. In parallel, mean blood vessel counts were 36.9% lower in hrRNASET2-vs. Avastin-treated mice and survival rates of hrRNASET2-treated mice were 50% at 73 days post-treatment, while the median survival time for untreated animals was 22 days. Moreover, a 60-day hrRNASET2 treatment period reduced mean A375SM lung metastasis foci counts by three-fold when compared to untreated animals. Taken together, the combined antiangiogenic and antitumorigenic capacities of hrRNASET2, seemingly arising from its direct interaction with intercellular and extracellular matrices, render it an attractive anticancer therapy candidate. PMID:27014725

  7. Epigenetic Modifications, Alcoholic Brain and Potential Drug Targets

    Science.gov (United States)

    Jangra, Ashok; Sriram, Chandra Shaker; Pandey, Suryanarayan; Choubey, Priyansha; Rajput, Prabha; Saroha, Babita; Bezbaruah, Babul Kumar; Lahkar, Mangala

    2016-01-01

    Acute and chronic alcohol exposure evidently influences epigenetic changes, both transiently and permanently, and these changes in turn influence a variety of cells and organ systems throughout the body. Many of the alcohol-induced epigenetic modifications can contribute to cellular adaptations that ultimately lead to behavioral tolerance and alcohol dependence. The persistence of behavioral changes demonstrates that long-lasting changes in gene expression, within particular regions of the brain, may contribute importantly to the addiction phenotype. The research activities over the past years have demonstrated a crucial role of epigenetic mechanisms in causing long lasting and transient changes in the expression of several genes in diverse tissues, including brain. This has stimulated recent research work that is aimed at characterizing the influence of epigenetic regulatory events in mediating the long lasting and transient effects of alcohol abuse on the brain in humans and animal models of alcohol addiction. In this study, we update our current understanding of the impact of alcohol exposure on epigenetic mechanisms in the brain and refurbish the knowledge of epigenetics in the direction of new drugs development. PMID:27780992

  8. Human recombinant RNASET2: A potential anti-cancer drug.

    Science.gov (United States)

    Roiz, Levava; Smirnoff, Patricia; Lewin, Iris; Shoseyov, Oded; Schwartz, Betty

    2016-01-01

    The roles of cell motility and angiogenetic processes in metastatic spread and tumor aggressiveness are well established and must be simultaneously targeted to maximize antitumor drug potency. This work evaluated the antitumorigenic capacities of human recombinant RNASET2 (hrRNASET2), a homologue of the Aspergillus niger T2RNase ACTIBIND, which has been shown to display both antitumorigenic and antiangiogenic activities. hrRNASET2 disrupted intracellular actin filament and actin-rich extracellular extrusion organization in both CT29 colon cancer and A375SM melanoma cells and induced a significant dose-dependent inhibition of A375SM cell migration. hrRNASET2 also induced full arrest of angiogenin-induced tube formation and brought to a three-fold lower relative HT29 colorectal and A375SM melanoma tumor volume, when compared to Avastin-treated animals. In parallel, mean blood vessel counts were 36.9% lower in hrRNASET2-vs. Avastin-treated mice and survival rates of hrRNASET2-treated mice were 50% at 73 days post-treatment, while the median survival time for untreated animals was 22 days. Moreover, a 60-day hrRNASET2 treatment period reduced mean A375SM lung metastasis foci counts by three-fold when compared to untreated animals. Taken together, the combined antiangiogenic and antitumorigenic capacities of hrRNASET2, seemingly arising from its direct interaction with intercellular and extracellular matrices, render it an attractive anticancer therapy candidate.

  9. Nanoparticles of hydrophobically modified dextrans as potential drug carrier systems.

    Science.gov (United States)

    Aumelas, A; Serrero, A; Durand, A; Dellacherie, E; Leonard, M

    2007-09-01

    Nanoparticles combining a hydrophobically modified dextran core and a polysaccharide surface coverage were elaborated. Their suitability for applications like drug delivery was evaluated. The selected polysaccharide, dextran, was chemically modified by the covalent attachment of hydrocarbon groups (aliphatic or aromatic) via the formation of ether links. According to the extent of modification, either water-soluble or water-insoluble dextran derivatives were obtained. The latter exhibited solubility in organic solvents like tetrahydrofuran or dichloromethane saturated with water. Water-soluble dextran derivatives were used as polymeric surfactants for the control of nanoparticles surface characteristics. Nanoparticles were prepared either by o/w emulsion or solvent-diffusion methods. The size and surface properties of dextran nanoparticles were correlated to processing conditions. The stability of colloidal suspensions was examined as a function of ionic strength and related to the particle surface characteristics. The redispersability of freeze-dried suspensions without the addition of cryoprotectant was demonstrated. Finally, the degradability of modified dextrans was compared to that of starting dextran, after enzymatic hydrolysis in the presence of dextranase.

  10. Using Helicopter Electromagnetic Surveys to Identify Potential Hazards at Mine Waste Impoundments

    Energy Technology Data Exchange (ETDEWEB)

    Hammack, R.W.

    2008-01-01

    In July 2003, helicopter electromagnetic surveys were conducted at 14 coal waste impoundments in southern West Virginia. The purpose of the surveys was to detect conditions that could lead to impoundment failure either by structural failure of the embankment or by the flooding of adjacent or underlying mine works. Specifically, the surveys attempted to: 1) identify saturated zones within the mine waste, 2) delineate filtrate flow paths through the embankment or into adjacent strata and receiving streams, and 3) identify flooded mine workings underlying or adjacent to the waste impoundment. Data from the helicopter surveys were processed to generate conductivity/depth images. Conductivity/depth images were then spatially linked to georeferenced air photos or topographic maps for interpretation. Conductivity/depth images were found to provide a snapshot of the hydrologic conditions that exist within the impoundment. This information can be used to predict potential areas of failure within the embankment because of its ability to image the phreatic zone. Also, the electromagnetic survey can identify areas of unconsolidated slurry in the decant basin and beneath the embankment. Although shallow, flooded mineworks beneath the impoundment were identified by this survey, it cannot be assumed that electromagnetic surveys can detect all underlying mines. A preliminary evaluation of the data implies that helicopter electromagnetic surveys can provide a better understanding of the phreatic zone than the piezometer arrays that are typically used.

  11. Potential Drug Cost Saving at Five Government Hospitals in DKI Jakarta

    Directory of Open Access Journals (Sweden)

    Muhammad Syarifuddin

    2014-11-01

    Full Text Available Background: The health expenditure increases over time, while drug cost takes 30% of total health expenditure. An alternative to reduce drug cost is by using generic medicines. This research aimed to count the drug cost saving potential by the use of generic drugs. Methods: A cross sectional non intervention study has been conducted in five hospitals in DKI Jakarta province. Result: Showed the total number of prescription prescribed from all hospitals during 6 months was 72,492. From 1600 prescription analyzed there were 5,891 items of drug. Five of ten drugs which were often prescribed had no generic match. The highest price comparison of branded and generic drugs was in antibiotic groups (59 times. The price of prescription can be reduces Rp.28,733 per each and the cost saving potential from 6 months period in 5 hospitals were Rp.2,082,912,636 by using generic drugs. The Conclusionof this research was generic drug use can save drug cost approximately Rp.28,000 per prescription or equal to about 2 billion for 6 months.

  12. Microencapsulation of indocyanine green for potential applications in image-guided drug delivery.

    Science.gov (United States)

    Zhu, Zhiqiang; Si, Ting; Xu, Ronald X

    2015-02-07

    We present a novel process to encapsulate indocyanine green (ICG) in liposomal droplets at high concentration for potential applications in image-guided drug delivery. The microencapsulation process follows two consecutive steps of droplet formation by liquid-driven coaxial flow focusing (LDCFF) and solvent removal by oil phase dewetting. These biocompatible lipid vesicles may have important applications in drug delivery and fluorescence imaging.

  13. Electrochemical Oxidation by Square-Wave Potential Pulses in the Imitation of Oxidative Drug Metabolism

    NARCIS (Netherlands)

    Nouri-Nigjeh, Eslam; Permentier, Hjalmar P.; Bischoff, Rainer; Bruins, Andries P.

    2011-01-01

    Electrochemistry combined with mass spectrometry (EC-MS) is an emerging analytical technique in the imitation of oxidative drug metabolism at the early stages of new drug development. Here, we present the benefits of electrochemical oxidation by square-wave potential pulses for the oxidation of lido

  14. In Vitro and Ex Vivo Selection Procedures for Identifying Potentially Therapeutic DNA and RNA Molecules

    Directory of Open Access Journals (Sweden)

    Soledad Marton

    2010-06-01

    Full Text Available It was only relatively recently discovered that nucleic acids participate in a variety of biological functions, besides the storage and transmission of genetic information. Quite apart from the nucleotide sequence, it is now clear that the structure of a nucleic acid plays an essential role in its functionality, enabling catalysis and specific binding reactions. In vitro selection and evolution strategies have been extremely useful in the analysis of functional RNA and DNA molecules, helping to expand our knowledge of their functional repertoire and to identify and optimize DNA and RNA molecules with potential therapeutic and diagnostic applications. The great progress made in this field has prompted the development of ex vivo methods for selecting functional nucleic acids in the cellular environment. This review summarizes the most important and most recent applications of in vitro and ex vivo selection strategies aimed at exploring the therapeutic potential of nucleic acids.

  15. Identifying Pre-Service Teachers’ Beliefs About Teaching EFL and Their Potential Changes

    Directory of Open Access Journals (Sweden)

    Sergio Andrés Suárez Flórez

    2017-07-01

    Full Text Available This study aims at identifying pre-service teachers’ beliefs about teaching English as a foreign language and tracking their potential changes throughout the teaching practicum. Participants were two pre-service teachers in their fifth year of their Bachelor of Arts in Foreign Languages program in a public university in Colombia. Data were gathered through a modified version of Beliefs about Language Learning Inventory before the practicum, eight weekly journal entries administered during ten weeks, and two semi-structured interviews at the end of the teaching practicum. The findings revealed that most of the pre-service teachers’ beliefs changed once they faced the reality of the classroom.

  16. Metabolomics: a novel approach to identify potential diagnostic biomarkers and pathogenesis in Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    Xu-Hua Xu; Yue Huang; Gang Wang; Sheng-Di Chen

    2012-01-01

    Although the pathogenesis of Alzheimer's disease (AD) is still not fully understood,it is acknowledged that intervention should be made at the early stage.Therefore,identifying biomarkers for the clinical diagnosis is critical.Metabolomics,a novel "omics",uses methods based on low-molecular-weight molecules,with high-throughput evaluation of a large number of metabolites that may lead to the identification of new disease-specific biomarkers and the elucidation of pathophysiological mechanisms.This review discusses metabolomics investigations of AD and potential future developments in this field.

  17. A study of medication reviews to identify drug-related problems of polypharmacy patients in the Dutch nursing home setting

    NARCIS (Netherlands)

    Finkers, F.; Maring, J. G.; Boersma, F.; Taxis, K.

    2007-01-01

    Background: Little is known about the extent of drug-related problems of polypharmacy patients in Dutch nursing homes. Objectives: We investigated the feasibility of teams of hospital pharmacists and nursing home physicians carrying out medication reviews. We aimed to identify the number and nature

  18. Evaluation of a Community Pharmacy-Based Screening Questionnaire to Identify Patients at Risk for Drug Therapy Problems.

    Science.gov (United States)

    Pammett, Robert T; Blackburn, David; Taylor, Jeff; Mansell, Kerry; Kwan, Debbie; Papoushek, Christine; Jorgenson, Derek

    2015-09-01

    To determine if a short screening questionnaire can identify patients at risk for drug therapy problems (DTPs) in a community pharmacy setting. Self-administered questionnaire. Three community pharmacies in Saskatoon, Canada. Forty-nine adults who were picking up a refill prescription for a medication that had remained stable over the past 6 months (i.e., no changes to drug, dose, or regimen) during 4 consecutive weeks at each of the three pharmacies between November 2013 and February 2014. All patients completed a self-administered screening questionnaire and underwent a blinded comprehensive medication assessment with a clinical pharmacist. Agreement between the screening questionnaire responses and responses based on information from the medication assessment were assessed with Cohen's κ coefficient. The DTPs identified during the medication assessments were categorized in one of the eight standard DTP categories: unnecessary drug therapy, inappropriate drug, subtherapeutic dose, supratherapeutic dose, drug therapy required, adverse drug reaction, noncompliance, and other or unsure. The DTPs were also assigned a severity-mild, moderate, or severe-using adapted Schneider criteria. The number and severity of DTPs identified were compared among patients categorized as high versus low risk for DTPs as determined by the questionnaire responses. Of the 49 patients who completed the study, 18 (37%) were high risk and 31 (63%) low risk. The agreement between risk categorization based on the screening questionnaire and medication assessment was very good (κ = 0.91, pidentified as high risk on the screening questionnaire had a mean of 3.7 (prisk patients. Seventeen (94%) of the 18 high-risk patients had at least one moderate or severe DTP compared with 15 (48%) of the 31 low-risk patients. The screening questionnaire was a reliable method for identifying patients in community pharmacies who have a large number of DTPs. © 2015 Pharmacotherapy Publications, Inc.

  19. microRNAs of parasitic helminths - Identification, characterization and potential as drug targets.

    Science.gov (United States)

    Britton, Collette; Winter, Alan D; Gillan, Victoria; Devaney, Eileen

    2014-08-01

    microRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation. They were first identified in the free-living nematode Caenorhabditis elegans, where the miRNAs lin-4 and let-7 were shown to be essential for regulating correct developmental progression. The sequence of let-7 was subsequently found to be conserved in higher organisms and changes in expression of let-7, as well as other miRNAs, are associated with certain cancers, indicating important regulatory roles. Some miRNAs have been shown to have essential functions, but the roles of many are currently unknown. With the increasing availability of genome sequence data, miRNAs have now been identified from a number of parasitic helminths, by deep sequencing of small RNA libraries and bioinformatic approaches. While some miRNAs are widely conserved in a range of organisms, others are helminth-specific and many are novel to each species. Here we review the potential roles of miRNAs in regulating helminth development, in interacting with the host environment and in development of drug resistance. Use of fluorescently-labeled small RNAs demonstrates uptake by parasites, at least in vitro. Therefore delivery of miRNA inhibitors or mimics has potential to alter miRNA activity, providing a useful tool for probing the roles of miRNAs and suggesting novel routes to therapeutics for parasite control.

  20. Using structure restoration maps to comprehensively identify potential faults and fractures in compressional structures

    Institute of Scientific and Technical Information of China (English)

    OU Cheng-hua; CHEN Wei; LI Chao-chun

    2016-01-01

    Faults and fractures of multiple scales are frequently induced and generated in compressional structural system. Comprehensive identification of these potential faults and fractures that cannot be distinguished directly from seismic profile of the complex structures is still an unanswered problem. Based on the compressional structural geometry and kinematics theories as well as the structural interpretation from seismic data, a set of techniques is established for the identification of potential faults and fractures in compressional structures. Firstly, three-dimensional (3D) patterns and characteristics of the faults directly interpreted from seismic profile were illustrated by 3D structural model. Then, the unfolding index maps, the principal structural curvature maps, and tectonic stress field maps were obtained from structural restoration. Moreover, potential faults and fractures in compressional structures were quantitatively identified relying on comprehensive analysis of these three maps. Successful identification of the potential faults and fractures in Mishrif limestone formation and in Asmari dolomite formation of Buzurgan anticline in Iraq demonstrates the applicability and reliability of these techniques.

  1. Systems Pharmacology: Network Analysis to Identify Multiscale Mechanisms of Drug Action

    Science.gov (United States)

    Zhao, Shan; Iyengar, Ravi

    2013-01-01

    Systems approaches have long been used in pharmacology to understand drug action at the organ and organismal levels. The application of computational and experimental systems biology approaches to pharmacology allows us to expand the definition of systems pharmacology to include network analyses at multiple scales of biological organization and to explain both therapeutic and adverse effects of drugs. Systems pharmacology analyses rely on experimental “omics” technologies that are capable of measuring changes in large numbers of variables, often at a genome-wide level, to build networks for analyzing drug action. A major use of omics technologies is to relate the genomic status of an individual to the therapeutic efficacy of a drug of interest. Combining pathway and network analyses, pharmacokinetic and pharmacodynamic models, and a knowledge of polymorphisms in the genome will enable the development of predictive models of therapeutic efficacy. Network analyses based on publicly available databases such as the U.S. Food and Drug Administration’s Adverse Event Reporting System allow us to develop an initial understanding of the context within which molecular-level drug-target interactions can lead to distal effectors in a process that results in adverse phenotypes at the organ and organismal levels. The current state of systems pharmacology allows us to formulate a set of questions that could drive future research in the field. The long-term goal of such research is to develop polypharmacology for complex diseases and predict therapeutic efficacy and adverse event risk for individuals prior to commencement of therapy. PMID:22235860

  2. Polyisoprenylated benzophenones from Clusiaceae: potential drugs and lead compounds.

    Science.gov (United States)

    Acuña, Ulyana Muñoz; Jancovski, Nikola; Kennelly, Edward J

    2009-01-01

    Many new polyisoprenylated benzophenones with a bicyclo[3.3.1]-nonane-2,4,9-trione core structure have been isolated from plants in the Clusiaceae family, and their potent biological properties have been the subject of several studies. This review summarizes the biological activities reported for these secondary metabolites including cytotoxic, antimicrobial, antioxidant, and anti-inflammatory activities. Our efforts during the past years have foremost been directed towards isolating new polyisoprenylated benzophenones, as well as understanding the possible target and mechanism of action through which these compounds arrest cancer cells and inhibit the progression of the cell-cycle. The transcription of genes is affected in cancer cells treated with polyisoprenylated benzophenones; the oncogene c-Myb is down-regulated and endoplasmatic stress genes XBP1, ATF4, and DDIT3/CHOP are turned on. Consequently, the expression of iNOS and cell cycle regulators such as cyclin D and E are reduced. Evidence presented by independent investigators suggests that polyisoprenylated benzophenones affect the mediators in the Akt/mTOR stress pathway, although the specific target remains to be discovered. In addition, benzophenones isolated from plants display high antioxidant capacity and protect cells from oxidative stress and the formation of ROS involved during the inflammatory process. Since antiviral activity was initially reported for guttiferone A, potent synthetic analogues have been developed as effective new non-nucleoside reverse transcriptase inhibitors (NNRTI) to treat drug resistant HIV-1. In addition, benzophenones exert antimicrobial effects particularly against MRSA. The structure-activity relationships of polyisoprenylated benzophenones from natural sources and those of synthetic analogues are included in this review. Absorption, metabolism, and elimination of benzophenones are also discussed.

  3. Characterization of Different Functionalized Lipidic Nanocapsules as Potential Drug Carriers

    Directory of Open Access Journals (Sweden)

    José Manuel Peula-García

    2012-02-01

    Full Text Available Lipid nanocapsules (LNC based on a core-shell structure consisting of an oil-filled core with a surrounding polymer layer are known to be promising vehicles for the delivery of hydrophobic drugs in the new therapeutic strategies in anti-cancer treatments. The present work has been designed as basic research about different LNC systems. We have synthesized—and physico-chemically characterized—three different LNC systems in which the core was constituted by olive oil and the shell by different phospholipids (phosphatidyl-serine or lecithin and other biocompatible molecules such as Pluronic® F68 or chitosan. It is notable that the olive-oil-phosphatidyl-serine LCN is a novel formulation presented in this work and was designed to generate an enriched carboxylic surface. This carboxylic layer is meant to link specific antibodies, which could facilitate the specific nanocapsule uptake by cancer cells. This is why nanoparticles with phosphatidyl-serine in their shell have also been used in this work to form immuno-nanocapsules containing a polyclonal IgG against a model antigen (C-reactive protein covalently bounded by means of a simple and reproducible carbodiimide method. An immunological study was made to verify that these IgG-LNC complexes showed the expected specific immune response. Finally, a preliminary in vitro study was performed by culturing a breast-carcinoma cell line (MCF-7 with Nile-Red-loaded LNC. We found that these cancer cells take up the fluorescent Nile-Red molecule in a process dependent on the surface properties of the nanocarriers.

  4. Discovering Outliers of Potential Drug Toxicities Using a Large-scale Data-driven Approach.

    Science.gov (United States)

    Luo, Jake; Cisler, Ron A

    2016-01-01

    We systematically compared the adverse effects of cancer drugs to detect event outliers across different clinical trials using a data-driven approach. Because many cancer drugs are toxic to patients, better understanding of adverse events of cancer drugs is critical for developing therapies that could minimize the toxic effects. However, due to the large variabilities of adverse events across different cancer drugs, methods to efficiently compare adverse effects across different cancer drugs are lacking. To address this challenge, we present an exploration study that integrates multiple adverse event reports from clinical trials in order to systematically compare adverse events across different cancer drugs. To demonstrate our methods, we first collected data on 186,339 clinical trials from ClinicalTrials.gov and selected 30 common cancer drugs. We identified 1602 cancer trials that studied the selected cancer drugs. Our methods effectively extracted 12,922 distinct adverse events from the clinical trial reports. Using the extracted data, we ranked all 12,922 adverse events based on their prevalence in the clinical trials, such as nausea 82%, fatigue 77%, and vomiting 75.97%. To detect the significant drug outliers that could have a statistically high possibility of causing an event, we used the boxplot method to visualize adverse event outliers across different drugs and applied Grubbs' test to evaluate the significance. Analyses showed that by systematically integrating cross-trial data from multiple clinical trial reports, adverse event outliers associated with cancer drugs can be detected. The method was demonstrated by detecting the following four statistically significant adverse event cases: the association of the drug axitinib with hypertension (Grubbs' test, P < 0.001), the association of the drug imatinib with muscle spasm (P < 0.001), the association of the drug vorinostat with deep vein thrombosis (P < 0.001), and the association of the drug afatinib

  5. Cluster analysis for identifying sub-groups and selecting potential discriminatory variables in human encephalitis

    Directory of Open Access Journals (Sweden)

    Crowcroft Natasha S

    2010-12-01

    Full Text Available Abstract Background Encephalitis is an acute clinical syndrome of the central nervous system (CNS, often associated with fatal outcome or permanent damage, including cognitive and behavioural impairment, affective disorders and epileptic seizures. Infection of the central nervous system is considered to be a major cause of encephalitis and more than 100 different pathogens have been recognized as causative agents. However, a large proportion of cases have unknown disease etiology. Methods We perform hierarchical cluster analysis on a multicenter England encephalitis data set with the aim of identifying sub-groups in human encephalitis. We use the simple matching similarity measure which is appropriate for binary data sets and performed variable selection using cluster heatmaps. We also use heatmaps to visually assess underlying patterns in the data, identify the main clinical and laboratory features and identify potential risk factors associated with encephalitis. Results Our results identified fever, personality and behavioural change, headache and lethargy as the main characteristics of encephalitis. Diagnostic variables such as brain scan and measurements from cerebrospinal fluids are also identified as main indicators of encephalitis. Our analysis revealed six major clusters in the England encephalitis data set. However, marked within-cluster heterogeneity is observed in some of the big clusters indicating possible sub-groups. Overall, the results show that patients are clustered according to symptom and diagnostic variables rather than causal agents. Exposure variables such as recent infection, sick person contact and animal contact have been identified as potential risk factors. Conclusions It is in general assumed and is a common practice to group encephalitis cases according to disease etiology. However, our results indicate that patients are clustered with respect to mainly symptom and diagnostic variables rather than causal agents

  6. [Gamma-hydroxybutyric acid (GHB): more than a date rape drug, a potentially addictive drug].

    Science.gov (United States)

    Karila, Laurent; Novarin, Johanne; Megarbane, Bruno; Cottencin, Olivier; Dally, Sylvain; Lowenstein, William; Reynaud, Michel

    2009-10-01

    According to available information, GHB and its precursors--gamma-butyrolactone (GBL) and 1,4-butanediol (1,4BD)--are used especially in a nightlife scene characterized by the search for amplified sensations through the combination of electronic music, marathon dancing, and substance abuse. Evidence indicates that GHB/GHL is used particularly in some subpopulations and in places, such as in gay nightclubs. Commonly known as Gorliquid ecstasy, it was misused in the 1980s for its bodybuilding effects and in the 1990s as a recreational drug at music venues. In the same period, media coverage of the use of GHB in sexual assault (often referred to as date rape) brought the drug into the spotlight. GHB/GHL addiction is a recognized clinical entity evidenced by severe withdrawal symptoms when the drug is abruptly discontinued after regular or chronic use. There is evidence that negative health and social consequences may occur in recreational and chronic users. Nonfatal overdoses and deaths related to GHB have been reported. These undesirable effects and especially the deaths appear to have prompted campaigns to limit the use of GHB. Clinicians must also be aware of GBL, which is being sold and used as a substitute for GHB.

  7. The potential for drug supersaturation during intestinal processing of lipid-based formulations may be enhanced for basic drugs.

    Science.gov (United States)

    Yeap, Yan Yan; Trevaskis, Natalie L; Porter, Christopher J H

    2013-07-01

    Co-administration of poorly water-soluble drugs (PWSD) with dietary or formulation lipids stimulates the formation of lipid colloidal phases such as vesicular and micellar species, and significantly expands the drug solubilization capacity of the small intestine. The mechanism of drug absorption from the solubilizing phases, however, has not been fully elucidated. Recently, we observed that drug supersaturation may be triggered during endogenous processing of lipid colloidal phases containing medium-chain lipid digestion products and that this may represent a mechanism to reverse the reduction in thermodynamic activity inherent in drug solubilization and thereby enhance absorption. The current studies expand these preliminary findings and explore the supersaturation tendency of five model PWSD during endogenous processing of intestinal colloidal phases containing long-chain lipid digestion products. Bile-lipid concentration ratios progressively increase during colloid transit through the gastrointestinal tract due to biliary dispersion of lipid digestion products and lipid absorption. The supersaturation potential was therefore evaluated under conditions of increasing bile and decreasing lipid concentrations and was found to be greater for the basic drugs cinnarizine (CIN) and halofantrine (HF), than the neutral drugs fenofibrate (FF) and danazol (DAN), and acidic drug meclofenamic acid (MFA). Assessment of intestinal absorptive flux using rat jejunal perfusion experiments subsequently showed that the absorption enhancement afforded by bile dilution of lipid colloidal phases was greater for CIN than DAN. The results confirm that bile plays a significantly greater role in the absorption of CIN (a weak base) from long-chain intestinal colloids when compared to DAN (an uncharged molecule) and that the difference reflects a greater propensity for supersaturation as intestinal colloids are dispersed and diluted by bile. The data suggest that coadministered digestible

  8. Energy-optimised pharmacophore approach to identify potential hotspots during inhibition of Class II HDAC isoforms.

    Science.gov (United States)

    Ganai, Shabir Ahmad; Shanmugam, Karthi; Mahadevan, Vijayalakshmi

    2015-01-01

    Histone deacetylases (HDACs) are conjugated enzymes that modulate chromatin architecture by deacetylating lysine residues on the histone tails leading to transcriptional repression. Pharmacological interventions of these enzymes with small molecule inhibitors called Histone deacetylase inhibitors (HDACi) have shown enhanced acetylation of the genome and are hence emerging as potential targets at the clinic. Type-specific inhibition of Class II HDACs has shown enhanced therapeutic benefits against developmental and neurodegenerative disorders. However, the structural identity of class-specific isoforms limits the potential of their inhibitors in precise targeting of their enzymes. Diverse strategies have been implemented to recognise the features in HDAC enzymes which may help in identifying isoform specificity factors. This work attempts a computational approach that combines in silico docking and energy-optimised pharmacophore (E-pharmacophore) mapping of 18 known HDAC inhibitors and has identified structural variations that regulate their interactions against the six Class II HDAC enzymes considered for the study. This combined approach establishes that inhibitors possessing higher number of aromatic rings in different structural regions might function as potent inhibitors, while inhibitors with scarce ring structures might point to compromised potency. This would aid the rationale for chemical optimisation and design of isoform selective HDAC inhibitors with enhanced affinity and therapeutic efficiency.

  9. Application of human CFU-Mk assay to predict potential thrombocytotoxicity of drugs.

    Science.gov (United States)

    Pessina, A; Parent-Massin, D; Albella, B; Van Den Heuvel, R; Casati, S; Croera, C; Malerba, I; Sibiril, Y; Gomez, S; de Smedt, A; Gribaldo, L

    2009-02-01

    Megakaryocytopoiesis gives rise to platelets by proliferation and differentiation of lineage-specific progenitors, identified in vitro as Colony Forming Unit-Megakaryocytes (CFU-Mk). The aim of this study was to refine and optimize the in vitro Standard Operating Procedure (SOP) of the CFU-Mk assay for detecting drug-induced thrombocytopenia and to prevalidate a model for predicting the acute exposure levels that cause maximum tolerated decreases in the platelets count, based on the correlation with the maximal plasma concentrations (C max) in vivo. The assay was linear under the SOP conditions, and the in vitro endpoints (percentage of colonies growing) were reproducible within and across laboratories. The protocol performance phase was carried out testing 10 drugs (selected on the base of their recognised or potential in vivo haematotoxicity, according to the literature). Results showed that a relationship can be established between the maximal concentration in plasma (C max) and the in vitro concentrations that inhibited the 10-50-90 percent of colonies growth (ICs). When C max is lower than IC10, it is possible to predict that the chemicals have no direct toxicity effect on CFU-Mk and could not induce thrombocytopenia due to bone marrow damage. When the C max is higher than IC90 and/or IC50, thrombocytopenia can occur due to direct toxicity of chemicals on CFU-Mk progenitors.

  10. Identifying Potential Area and Financial Prospects of Rooftop Solar Photovoltaics (PV

    Directory of Open Access Journals (Sweden)

    Sarawut Ninsawat

    2016-10-01

    Full Text Available In an urban area, the roof is the only available surface that can be utilized for installing solar photovoltaics (PV, and the active surface area depends on the type of roof. Shadows on a solar panel can be caused by nearby tall buildings, construction materials such as water tanks, or the roof configuration itself. The azimuth angle of the sun varies, based on the season and the time of day. Therefore, the simulation of shadow for one or two days or using the rule of thumb may not be sufficient to evaluate shadow effects on solar panels throughout the year. In this paper, a methodology for estimating the solar potential of solar PV on rooftops is presented, which is particularly applicable to urban areas. The objective of this method is to assess how roof type and shadow play a role in potentiality and financial benefit. The method starts with roof type extraction from high-resolution satellite imagery, using Object Base Image Analysis (OBIA, the generation of a 3D structure from height data and roof type, the simulation of shadow throughout the year, and the identification of potential and financial prospects. Based on the results obtained, the system seems to be adequate for calculating the financial benefits of solar PV to a very fine scale. The payback period varied from 7–13 years depending on the roof type, direction, and shadow impact. Based on the potentiality, a homeowner can make a profit of up to 200%. This method could help homeowners to identify potential roof area and economic interest.

  11. An integrated structure- and system-based framework to identify new targets of metabolites and known drugs

    KAUST Repository

    Naveed, Hammad

    2015-08-18

    Motivation: The inherent promiscuity of small molecules towards protein targets impedes our understanding of healthy versus diseased metabolism. This promiscuity also poses a challenge for the pharmaceutical industry as identifying all protein targets is important to assess (side) effects and repositioning opportunities for a drug. Results: Here, we present a novel integrated structure- and system-based approach of drug-target prediction (iDTP) to enable the large-scale discovery of new targets for small molecules, such as pharmaceutical drugs, co-factors and metabolites (collectively called ‘drugs’). For a given drug, our method uses sequence order–independent structure alignment, hierarchical clustering, and probabilistic sequence similarity to construct a probabilistic pocket ensemble (PPE) that captures promiscuous structural features of different binding sites on known targets. A drug’s PPE is combined with an approximation of its delivery profile to reduce false positives. In our cross-validation study, we use iDTP to predict the known targets of eleven drugs, with 63% sensitivity and 81% specificity. We then predicted novel targets for these drugs—two that are of high pharmacological interest, the nuclear receptor PPARγ and the oncogene Bcl-2, were successfully validated through in vitro binding experiments. Our method is broadly applicable for the prediction of protein-small molecule interactions with several novel applications to biological research and drug development.

  12. A novel two-stage, transdisciplinary study identifies digoxin as a possible drug for prostate cancer treatment.

    Science.gov (United States)

    Platz, Elizabeth A; Yegnasubramanian, Srinivasan; Liu, Jun O; Chong, Curtis R; Shim, Joong Sup; Kenfield, Stacey A; Stampfer, Meir J; Willett, Walter C; Giovannucci, Edward; Nelson, William G

    2011-06-01

    Identification of novel indications for commonly prescribed drugs could accelerate translation of therapies. We investigated whether any clinically-used drugs might have utility for treating prostate cancer by coupling an efficient, high-throughput laboratory-based screen and a large, prospective cohort study. In stage 1, we conducted an in vitro prostate cancer cell cytotoxicity screen of 3,187 compounds. Digoxin emerged as the leading candidate given its potency in inhibiting proliferation in vitro (mean IC₅₀=163 nM) and common use. In stage 2, we evaluated the association between the leading candidate drug from stage 1 and prostate cancer risk in 47,884 men followed 1986-2006. Regular digoxin users (versus nonusers: RR=0.76, 95% CI 0.61-0.95), especially users for ≥ 10 years (RR=0.54, 95% CI 0.37-0.79, P-trendtransdisciplinary approach for drug repositioning provides compelling justification for further mechanistic and possibly clinical testing of the leading nonchemotherapy candidate, digoxin, a cardiac glycoside, as a drug for prostate cancer treatment. Perhaps of equal importance, our study illustrates the power of the transdisciplinary approach in translational cancer research. By coupling laboratory and epidemiologic methods and thinking, we reduced the probability of identifying false-positive candidate drugs for the next steps in testing.

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

    Directory of Open Access Journals (Sweden)

    Taylor David J

    2011-11-01

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

  14. Proteomic Analysis of Saliva Identifies Potential Biomarkers for Orthodontic Tooth Movement

    Directory of Open Access Journals (Sweden)

    Mohd Faiz Ellias

    2012-01-01

    Full Text Available Orthodontic treatment has been shown to induce inflammation, followed by bone remodelling in the periodontium. These processes trigger the secretion of various proteins and enzymes into the saliva. This study aims to identify salivary proteins that change in expression during orthodontic tooth movement. These differentially expressed proteins can potentially serve as protein biomarkers for the monitoring of orthodontic treatment and tooth movement. Whole saliva from three healthy female subjects were collected before force application using fixed appliance and at 14 days after 0.014′′ Niti wire was applied. Salivary proteins were resolved using two-dimensional gel electrophoresis (2DE over a pH range of 3–10, and the resulting proteome profiles were compared. Differentially expressed protein spots were then identified by MALDI-TOF/TOF tandem mass spectrometry. Nine proteins were found to be differentially expressed; however, only eight were identified by MALDI-TOF/TOF. Four of these proteins—Protein S100-A9, immunoglobulin J chain, Ig alpha-1 chain C region, and CRISP-3—have known roles in inflammation and bone resorption.

  15. Potential of microemulsified entacapone drug delivery systems in the management of acute Parkinson's disease

    Institute of Scientific and Technical Information of China (English)

    Harini Chowdary Vadlamudi; Prasanna Raju Yalavarthi; Jyotsna Thanniru; Vandana KR; Sundaresan CR

    2016-01-01

    Objective: To design solid self-microemulsifying drug delivery system (S-SMEDDS) of entacapone and evaluate for its anti-Parkinson's potentials. Methods: Solubility studies were performed in various vehicles i.e., oils, surfactants and co-surfactants and pseudo-ternary phase diagrams were plotted to understand the microemulsion formation region. Liquid self-microemulsifying drug delivery systems (SMEDDS) were developed using gingelly and rice bran oil as lipid vehicles, Tween 80 and Span 20 as surfactants and glycerin, propylene glycol as co-surfactants. They were characterized by Fourier transform infrared spectroscopy, pH, viscosity, zeta potential, polydispersibility index and droplet size analysis and evaluated for drug content, in-vitro release, in-vitro diffusion and ex-vivo permeation. Optimized liquid SMEDDS were converted into S-SMEDDS by adsorption and melt granulation procedures. Character-ization by differential scanning calorimetry, SEM, micrometrics, reconstitution property, moisture content and evaluation by drug content, drug release kinetics and shelf-life were performed for S-SMEDDS. Parkinsonism was induced and pharmacodynamic potentials of S-SMEDDS were evaluated. Results: S-SMEDDS formulation AG8 had shown the highest drug release of 90.92%within 60 min. Pharmacodynamic studies also proved the efficiency of entacapone S-SMEDDS against Parkinsonism. Conclusions: Entacapone S-SMEDDS is an effective drug delivery system that offers more predictable and extensive drug release with enhanced shelf-life in the treatment of acute Parkinsonism.

  16. Serine Proteases of Malaria Parasite Plasmodium falciparum: Potential as Antimalarial Drug Targets

    Directory of Open Access Journals (Sweden)

    Asrar Alam

    2014-01-01

    Full Text Available Malaria is a major global parasitic disease and a cause of enormous mortality and morbidity. Widespread drug resistance against currently available antimalarials warrants the identification of novel drug targets and development of new drugs. Malarial proteases are a group of molecules that serve as potential drug targets because of their essentiality for parasite life cycle stages and feasibility of designing specific inhibitors against them. Proteases belonging to various mechanistic classes are found in P. falciparum, of which serine proteases are of particular interest due to their involvement in parasite-specific processes of egress and invasion. In P. falciparum, a number of serine proteases belonging to chymotrypsin, subtilisin, and rhomboid clans are found. This review focuses on the potential of P. falciparum serine proteases as antimalarial drug targets.

  17. Identifying Potential Areas for Siting Interim Nuclear Waste Facilities Using Map Algebra and Optimization Approaches

    Energy Technology Data Exchange (ETDEWEB)

    Omitaomu, Olufemi A [ORNL; Liu, Cheng [ORNL; Cetiner, Sacit M [ORNL; Belles, Randy [ORNL; Mays, Gary T [ORNL; Tuttle, Mark A [ORNL

    2013-01-01

    The renewed interest in siting new nuclear power plants in the United States has brought to the center stage, the need to site interim facilities for long-term management of spent nuclear fuel (SNF). In this paper, a two-stage approach for identifying potential areas for siting interim SNF facilities is presented. In the first stage, the land area is discretized into grids of uniform size (e.g., 100m x 100m grids). For the continental United States, this process resulted in a data matrix of about 700 million cells. Each cell of the matrix is then characterized as a binary decision variable to indicate whether an exclusion criterion is satisfied or not. A binary data matrix is created for each of the 25 siting criteria considered in this study. Using map algebra approach, cells that satisfy all criteria are clustered and regarded as potential siting areas. In the second stage, an optimization problem is formulated as a p-median problem on a rail network such that the sum of the shortest distance between nuclear power plants with SNF and the potential storage sites from the first stage is minimized. The implications of obtained results for energy policies are presented and discussed.

  18. Zirconium Phosphate Nanoplatelet Potential for Anticancer Drug Delivery Applications.

    Science.gov (United States)

    González, Millie L; Ortiz, Mayra; Hernández, Carmen; Cabán, Jennifer; Rodríguez, Axel; Colón, Jorge L; Báez, Adriana

    2016-01-01

    Zirconium phosphate (ZrP) nanoplatelets can intercalate anticancer agents via an ion exchange reaction creating an inorganic delivery system with potential for cancer treatment. ZrP delivery of anticancer agents inside tumor cells was explored in vitro. Internalization and cytotoxicity of ZrP nanoplatelets were studied in MCF-7 and MCF-10A cells. DOX-loaded ZrP nanoplatelets (DOX@ZrP) uptake was assessed by confocal (CLSM) and transmission electron microscopy (TEM). Cytotoxicity to MCF-7 and MCF-10A cells was determined by the MTT assay. Reactive Oxy- gen Species (ROS) production was analyzed by fluorometric assay, and cell cycle alterations and induction of apoptosis were analyzed by flow cytometry. ZrP nanoplatelets were localized in the endosomes of MCF-7 cells. DOX and ZrP nanoplatelets were co-internalized into MCF-7 cells as detected by CLSM. While ZrP showed limited toxicity to MCF-7 cells, DOX@ZrP was cytotoxic at an IC₅₀ similar to that of free DOX. Meanwhile, DOX lC₅₀ was significantly lower than the equivalent concentration of DOX@ZrP in MCF-10A cells. ZrP did not induce apoptosis in both cell lines. DOX and DOX@ZrP induced significant oxidative stress in both cell models. Results suggest that ZrP nanoplatelets are promising as carriers of anticancer agents into cancer cells.

  19. Potential chemotherapeutic targets for Japanese encephalitis: current status of antiviral drug development and future challenges.

    Science.gov (United States)

    Ishikawa, Tomohiro; Konishi, Eiji

    2015-01-01

    Japanese encephalitis (JE) remains a public health threat in Asia. Although several vaccines have been licensed, ∼ 67,900 cases of the disease are estimated to occur annually, probably because the vaccine coverage is low. Therefore, effective antiviral drugs are required to control JE. However, no licensed anti-JE drugs are available, despite extensive efforts to develop them. We provide a general overview of JE and JE virus, including its transmission cycle, distribution, structure, replication machinery, immune evasion mechanisms and vaccines. The current situation in antiviral drug development is then reviewed and future perspectives are discussed. Although the development of effective anti-JE drugs is an urgent issue, only supportive care is currently available. Recent progress in our understanding of the viral replication machinery and immune evasion strategies has identified new targets for anti-JE drug development. To date, most candidate drugs have only been evaluated in single-drug formulations, and efficient drug delivery to the CNS has virtually not been considered. However, an effective anti-JE treatment is expected to be achieved with multiple-drug formulations and a targeted drug delivery system in the near future.

  20. Identifying potential virulence determinants in viral haemorrhagic septicaemia virus (VHSV) for rainbow trout.

    Science.gov (United States)

    Campbell, S; Collet, B; Einer-Jensen, K; Secombes, C J; Snow, M

    2009-11-09

    We identified viral haemorrhagic septicaemia virus (VHSV) isolates classified within Genotype Ib which are genetically similar (>99.4% glycoprotein amino acid identity) yet, based on their isolation history, were suspected to differ in virulence in juvenile rainbow trout. The virulence of an isolate recovered in 2000 from a viral haemorrhagic septicaemia disease episode in a marine rainbow trout farm in Sweden (SE-SVA-1033) was evaluated in juvenile rainbow trout via intraperitoneal injection and immersion challenge alongside 3 isolates recovered from wild-caught marine fish (DK-4p37, DK-5e59 and UKMLA98/6HE1) suspected of being of low pathogenicity to trout. Mortality data revealed that isolate SE-SVA-1033 caused VHSV-specific mortality in both intraperitoneal and immersion challenges (75.0 and 15.4%, respectively). The remaining Genotype Ib isolates caused significantly lower mortalities using the same experimental infection routes (<35.0 and <2.0%, respectively). Having identified VHSV isolates with clear differences in their pathogenicity, coding and inter-genic non-coding regions of 2 isolates (SE-SVA-1033 and DK-4p37) were determined and compared in order to identify potential markers responsible for the observed differences in virulence. Only 4 predicted amino acid substitutions were identified across the genome sequenced; these occurred in the N (R46G), G (S113G), NV (L12F) and L (S56A) proteins. These findings form the basis for further studies aimed at determining the biological significance of these mutations and suggest that small changes at the molecular level can cause significant changes in the virulence properties of VHSV isolates.

  1. Utilizing Chemical Genomics to Identify Cytochrome b as a Novel Drug Target for Chagas Disease.

    Directory of Open Access Journals (Sweden)

    Shilpi Khare

    2015-07-01

    Full Text Available Unbiased phenotypic screens enable identification of small molecules that inhibit pathogen growth by unanticipated mechanisms. These small molecules can be used as starting points for drug discovery programs that target such mechanisms. A major challenge of the approach is the identification of the cellular targets. Here we report GNF7686, a small molecule inhibitor of Trypanosoma cruzi, the causative agent of Chagas disease, and identification of cytochrome b as its target. Following discovery of GNF7686 in a parasite growth inhibition high throughput screen, we were able to evolve a GNF7686-resistant culture of T. cruzi epimastigotes. Clones from this culture bore a mutation coding for a substitution of leucine by phenylalanine at amino acid position 197 in cytochrome b. Cytochrome b is a component of complex III (cytochrome bc1 in the mitochondrial electron transport chain and catalyzes the transfer of electrons from ubiquinol to cytochrome c by a mechanism that utilizes two distinct catalytic sites, QN and QP. The L197F mutation is located in the QN site and confers resistance to GNF7686 in both parasite cell growth and biochemical cytochrome b assays. Additionally, the mutant cytochrome b confers resistance to antimycin A, another QN site inhibitor, but not to strobilurin or myxothiazol, which target the QP site. GNF7686 represents a promising starting point for Chagas disease drug discovery as it potently inhibits growth of intracellular T. cruzi amastigotes with a half maximal effective concentration (EC50 of 0.15 µM, and is highly specific for T. cruzi cytochrome b. No effect on the mammalian respiratory chain or mammalian cell proliferation was observed with up to 25 µM of GNF7686. Our approach, which combines T. cruzi chemical genetics with biochemical target validation, can be broadly applied to the discovery of additional novel drug targets and drug leads for Chagas disease.

  2. Tankyrase 1 Inhibitors with Drug-like Properties Identified by Screening a DNA-Encoded Chemical Library.

    Science.gov (United States)

    Samain, Florent; Ekblad, Torun; Mikutis, Gediminas; Zhong, Nan; Zimmermann, Mauro; Nauer, Angela; Bajic, Davor; Decurtins, Willy; Scheuermann, Jörg; Brown, Peter J; Hall, Jonathan; Gräslund, Susanne; Schüler, Herwig; Neri, Dario; Franzini, Raphael M

    2015-06-25

    We describe the synthesis and screening of a DNA-encoded chemical library containing 76230 compounds. In this library, sets of amines and carboxylic acids are directly linked producing encoded compounds with compact structures and drug-like properties. Affinity screening of this library yielded inhibitors of the potential pharmaceutical target tankyrase 1, a poly(ADP-ribose) polymerase. These compounds have drug-like characteristics, and the most potent hit compound (X066/Y469) inhibited tankyrase 1 with an IC50 value of 250 nM.

  3. Mining the topography and dynamics of the 4D Nucleome to identify novel CNS drug pathways.

    Science.gov (United States)

    Higgins, Gerald A; Allyn-Feuer, Ari; Georgoff, Patrick; Nikolian, Vahagn; Alam, Hasan; Athey, Brian D

    2017-04-03

    The pharmacoepigenome can be defined as the active, noncoding province of the genome including canonical spatial and temporal regulatory mechanisms of gene regulation that respond to xenobiotic stimuli. Many psychotropic drugs that have been in clinical use for decades have ill-defined mechanisms of action that are beginning to be resolved as we understand the transcriptional hierarchy and dynamics of the nucleus. In this review, we describe spatial, temporal and biomechanical mechanisms mediated by psychotropic medications. Focus is placed on a bioinformatics pipeline that can be used both for detection of pharmacoepigenomic variants that discretize drug response and adverse events to improve pharmacogenomic testing, and for the discovery of novel CNS therapeutics. This approach integrates the functional topology and dynamics of the transcriptional hierarchy of the pharmacoepigenome, gene variant-driven identification of pharmacogenomic regulatory domains, and mesoscale mapping for the discovery of novel CNS pharmacodynamic pathways in human brain. Examples of the application of this pipeline are provided, including the discovery of valproic acid (VPA) mediated transcriptional reprogramming of neuronal cell fate following injury, and mapping of a CNS pathway glutamatergic pathway for the mood stabilizer lithium. These examples in regulatory pharmacoepigenomics illustrate how ongoing research using the 4D nucleome provides a foundation to further insight into previously unrecognized psychotropic drug pharmacodynamic pathways in the human CNS.

  4. A RETROSPECTIVE STUDY ON THE POTENTIAL DRUG INTERACTION BETWEEN ANGIOTENSIN CONVERTING ENZYME INHIBITOR OR ANGIOTENSIN RECEPTOR ANTAGONIST AND OTHER DRUGS IN END-STAGE CHRONIC RENAL FAILURE PATIENTS

    Directory of Open Access Journals (Sweden)

    Honey Iskandar

    2012-10-01

    Full Text Available Increasing number of chronic renal failure (CRF patients had reflected an increase in the number of patients with diabetes and hypertension. Therefore, health practitioners would be faced with management of complicated medical problems for the patients of chronic renal disease. In this way, various complications of chronic renal failure would lead to polypharmacy, where the patients receive three to five drugs in a dose. Development of polypharmacy had made the potential of drug interaction greater. The objective was to determine whether CRF patients admitted to hospital with specific adverse drug reactions were likely to have been prescribed with interacting drugs. Retrospective study was designed. The study was conducted at the General Practice Rooms Floor 1 – Floor VI of Central Army Hospital Gatot Soebroto Jakarta. The study was conducted from December 2011 – February 2012. The data were collected in a retrospective way for a year (January – December 2011. End-stage CRF patients who were having hemodialysis therapy and receiving ACE Inhibitor drugs or Angiotensin II Receptor Antagonist (AIIRA and receiving treatment at the General Practice Rooms at Central Army Hospital Gatot Soebroto Jakarta. During the period of January – December 2011, 84 patients were treated with end-stage CRF at the Central Army Hospital and having routine hemodialysis and 44 patients were receiving therapy with ACE Inhibitor and AIIRA. Other drugs simultaneously given with ACE Inhibitor and AIIRA were captopril-spironolactone, captopril-aspirin, captopril-allopurinol, captopril-KSR, captopril-furosemide, lisinopril-furosemide and valsartan-mefenemic acid. An increase in adverse effects of the drugs was found based on the clinical evaluation and laboratory examination. The adverse effects included hyperkalemia (9,09%, decrease in anti-hypertension effect (6,8%, acute hypotension (40%, and declining renal function (11,36%. The study identifies drug interaction

  5. Potential Coastal Pumped Hydroelectric Energy Storage Locations Identified using GIS-based Topographic Analysis

    Science.gov (United States)

    Parsons, R.; Barnhart, C. J.; Benson, S. M.

    2013-12-01

    Large-scale electrical energy storage could accommodate variable, weather dependent energy resources such as wind and solar. Pumped hydroelectric energy storage (PHS) and compressed energy storage area (CAES) have life cycle energy and financial costs that are an order of magnitude lower than conventional electrochemical storage technologies. However PHS and CAES storage technologies require specific geologic conditions. Conventional PHS requires an upper and lower reservoir separated by at least 100 m of head, but no more than 10 km in horizontal distance. Conventional PHS also impacts fresh water supplies, riparian ecosystems, and hydrologic environments. A PHS facility that uses the ocean as the lower reservoir benefits from a smaller footprint, minimal freshwater impact, and the potential to be located near off shore wind resources and population centers. Although technologically nascent, today one coastal PHS facility exists. The storage potential for coastal PHS is unknown. Can coastal PHS play a significant role in augmenting future power grids with a high faction of renewable energy supply? In this study we employ GIS-based topographic analysis to quantify the coastal PHS potential of several geographic locations, including California, Chile and Peru. We developed automated techniques that seek local topographic minima in 90 m spatial resolution shuttle radar topography mission (SRTM) digital elevation models (DEM) that satisfy the following criteria conducive to PHS: within 10 km from the sea; minimum elevation 150 m; maximum elevation 1000 m. Preliminary results suggest the global potential for coastal PHS could be very significant. For example, in northern Chile we have identified over 60 locations that satisfy the above criteria. Two of these locations could store over 10 million cubic meters of water or several GWh of energy. We plan to report a global database of candidate coastal PHS locations and to estimate their energy storage capacity.

  6. Characterization and validation of an in silico toxicology model to predict the mutagenic potential of drug impurities*

    Energy Technology Data Exchange (ETDEWEB)

    Valerio, Luis G., E-mail: luis.valerio@fda.hhs.gov [Science and Research Staff, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993–0002 (United States); Cross, Kevin P. [Leadscope, Inc., 1393 Dublin Road, Columbus, OH, 43215–1084 (United States)

    2012-05-01

    Control and minimization of human exposure to potential genotoxic impurities found in drug substances and products is an important part of preclinical safety assessments of new drug products. The FDA's 2008 draft guidance on genotoxic and carcinogenic impurities in drug substances and products allows use of computational quantitative structure–activity relationships (QSAR) to identify structural alerts for known and expected impurities present at levels below qualified thresholds. This study provides the information necessary to establish the practical use of a new in silico toxicology model for predicting Salmonella t. mutagenicity (Ames assay outcome) of drug impurities and other chemicals. We describe the model's chemical content and toxicity fingerprint in terms of compound space, molecular and structural toxicophores, and have rigorously tested its predictive power using both cross-validation and external validation experiments, as well as case studies. Consistent with desired regulatory use, the model performs with high sensitivity (81%) and high negative predictivity (81%) based on external validation with 2368 compounds foreign to the model and having known mutagenicity. A database of drug impurities was created from proprietary FDA submissions and the public literature which found significant overlap between the structural features of drug impurities and training set chemicals in the QSAR model. Overall, the model's predictive performance was found to be acceptable for screening drug impurities for Salmonella mutagenicity. -- Highlights: ► We characterize a new in silico model to predict mutagenicity of drug impurities. ► The model predicts Salmonella mutagenicity and will be useful for safety assessment. ► We examine toxicity fingerprints and toxicophores of this Ames assay model. ► We compare these attributes to those found in drug impurities known to FDA/CDER. ► We validate the model and find it has a desired predictive

  7. Assessment of Pseudomonas aeruginosa N5,N10-methylenetetrahydrofolate dehydrogenase-cyclohydrolase as a potential antibacterial drug target.

    Directory of Open Access Journals (Sweden)

    Thomas C Eadsforth

    Full Text Available The bifunctional enzyme methylenetetrahydrofolate dehydrogenase - cyclohydrolase (FolD is identified as a potential drug target in Gram-negative bacteria, in particular the troublesome Pseudomonas aeruginosa. In order to provide a comprehensive and realistic assessment of the potential of this target for drug discovery we generated a highly efficient recombinant protein production system and purification protocol, characterized the enzyme, carried out screening of two commercial compound libraries by differential scanning fluorimetry, developed a high-throughput enzyme assay and prosecuted a screening campaign against almost 80,000 compounds. The crystal structure of P. aeruginosa FolD was determined at 2.2 Å resolution and provided a template for an assessment of druggability and for modelling of ligand complexes as well as for comparisons with the human enzyme. New FolD inhibitors were identified and characterized but the weak levels of enzyme inhibition suggest that these compounds are not optimal starting points for future development. Furthermore, the close similarity of the bacterial and human enzyme structures suggest that selective inhibition might be difficult to attain. In conclusion, although the preliminary biological data indicates that FolD represents a valuable target for the development of new antibacterial drugs, indeed spurred us to investigate it, our screening results and structural data suggest that this would be a difficult enzyme to target with respect to developing the appropriate lead molecules required to underpin a serious drug discovery effort.

  8. Computational drugs repositioning identifies inhibitors of oncogenic PI3K/AKT/P70S6K-dependent pathways among FDA-approved compounds

    Science.gov (United States)

    Carrella, Diego; Manni, Isabella; Tumaini, Barbara; Dattilo, Rosanna; Papaccio, Federica; Mutarelli, Margherita; Sirci, Francesco; Amoreo, Carla A.; Mottolese, Marcella; Iezzi, Manuela; Ciolli, Laura; Aria, Valentina; Bosotti, Roberta; Isacchi, Antonella; Loreni, Fabrizio; Bardelli, Alberto; Avvedimento, Vittorio E.; di Bernardo, Diego; Cardone, Luca

    2016-01-01

    The discovery of inhibitors for oncogenic signalling pathways remains a key focus in modern oncology, based on personalized and targeted therapeutics. Computational drug repurposing via the analysis of FDA-approved drug network is becoming a very effective approach to identify therapeutic opportunities in cancer and other human diseases. Given that gene expression signatures can be associated with specific oncogenic mutations, we tested whether a “reverse” oncogene-specific signature might assist in the computational repositioning of inhibitors of oncogenic pathways. As a proof of principle, we focused on oncogenic PI3K-dependent signalling, a molecular pathway frequently driving cancer progression as well as raising resistance to anticancer-targeted therapies. We show that implementation of “reverse” oncogenic PI3K-dependent transcriptional signatures combined with interrogation of drug networks identified inhibitors of PI3K-dependent signalling among FDA-approved compounds. This led to repositioning of Niclosamide (Niclo) and Pyrvinium Pamoate (PP), two anthelmintic drugs, as inhibitors of oncogenic PI3K-dependent signalling. Niclo inhibited phosphorylation of P70S6K, while PP inhibited phosphorylation of AKT and P70S6K, which are downstream targets of PI3K. Anthelmintics inhibited oncogenic PI3K-dependent gene expression and showed a cytostatic effect in vitro and in mouse mammary gland. Lastly, PP inhibited the growth of breast cancer cells harbouring PI3K mutations. Our data indicate that drug repositioning by network analysis of oncogene-specific transcriptional signatures is an efficient strategy for identifying oncogenic pathway inhibitors among FDA-approved compounds. We propose that PP and Niclo should be further investigated as potential therapeutics for the treatment of tumors or diseases carrying the constitutive activation of the PI3K/P70S6K signalling axis. PMID:27542212

  9. Analysis of Potential Drug-Drug Interactions and Its Clinical Manifestation of Pediatric Prescription on 2 Pharmacies in Bandung

    Directory of Open Access Journals (Sweden)

    Melisa I. Barliana

    2013-09-01

    Full Text Available The potential of Drug-Drug Interactions (DDI in prescription have high incidence around the world, including Indonesia. However, scientific evidence regarding DDI in Indonesia is not available. Therefore, in this study we have conducted survey in 2 pharmacies in Bandung against pediatric prescription given by pediatrician. These prescriptions then analyzed the potential for DDI contained in the prescription and clinical manifestation. The analysis showed that in pharmacy A, there are 33 prescriptions (from a total of 155 prescriptions that have potential DDI, or approximately 21.19% (2 prescriptions have the potential DDI major categories, 23 prescriptions categorized as moderate, and 8 prescriptions as minor. In Pharmacy B, there are 6 prescriptions (from a total of 40 prescriptions or 15% of potential DDI (4 prescriptions categorized as moderate and 2 prescriptions as minor. This result showed that potential DDI happened less than 50% in pediatric prescription from both pharmacies. However, this should get attention because DDI should not happen in a prescription considering its clinical manifestations caused by DDI. Moreover, current pharmaceutical care refers to patient oriented than product oriented. In addition, further study for the pediatric prescription on DDI incidence in large scale need to be investigated.

  10. Identifying potentially induced seismicity and assessing statistical significance in Oklahoma and California

    CERN Document Server

    McClure, Mark; Chiu, Kitkwan; Ranganath, Rajesh

    2016-01-01

    In this study, we develop a statistical method for identifying induced seismicity from large datasets and apply the method to decades of wastewater disposal and seismicity data in California and Oklahoma. The method is robust against a variety of potential pitfalls. The study regions are divided into gridblocks. We use a longitudinal study design, seeking associations between seismicity and wastewater injection along time-series within each gridblock. The longitudinal design helps control for non-random application of wastewater injection. We define a statistical model that is flexible enough to describe the seismicity observations, which have temporal correlation and high kurtosis. In each gridblock, we find the maximum likelihood estimate for a model parameter that relates induced seismicity hazard to total volume of wastewater injected each year. To assess significance, we compute likelihood ratio test statistics in each gridblock and each state, California and Oklahoma. Resampling is used to empirically d...

  11. Identifying Multiple Potential Metabolic Cycles in Time-Series from Biolog Experiments.

    Science.gov (United States)

    Shubin, Mikhail; Schaufler, Katharina; Tedin, Karsten; Vehkala, Minna; Corander, Jukka

    Biolog Phenotype Microarray (PM) is a technology allowing simultaneous screening of the metabolic behaviour of bacteria under a large number of different conditions. Bacteria may often undergo several cycles of metabolic activity during a Biolog experiment. We introduce a novel algorithm to identify these metabolic cycles in PM experimental data, thus increasing the potential of PM technology in microbiology. Our method is based on a statistical decomposition of the time-series measurements into a set of growth models. We show that the method is robust to measurement noise and captures accurately the biologically relevant signals from the data. Our implementation is made freely available as a part of an R package for PM data analysis and can be found at www.helsinki.fi/bsg/software/Biolog_Decomposition.

  12. Transcript and protein profiling identify candidate gene sets of potential adaptive significance in New Zealand Pachycladon

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    Schmidt Silvia

    2010-05-01

    Full Text Available Abstract Background Transcript profiling of closely related species provides a means for identifying genes potentially important in species diversification. However, the predictive value of transcript profiling for inferring downstream-physiological processes has been unclear. In the present study we use shotgun proteomics to validate inferences from microarray studies regarding physiological differences in three Pachycladon species. We compare transcript and protein profiling and evaluate their predictive value for inferring glucosinolate chemotypes characteristic of these species. Results Evidence from heterologous microarrays and shotgun proteomics revealed differential expression of genes involved in glucosinolate hydrolysis (myrosinase-associated proteins and biosynthesis (methylthioalkylmalate isomerase and dehydrogenase, the interconversion of carbon dioxide and bicarbonate (carbonic anhydrases, water use efficiency (ascorbate peroxidase, 2 cys peroxiredoxin, 20 kDa chloroplastic chaperonin, mitochondrial succinyl CoA ligase and others (glutathione-S-transferase, serine racemase, vegetative storage proteins, genes related to translation and photosynthesis. Differences in glucosinolate hydrolysis products were directly confirmed. Overall, prediction of protein abundances from transcript profiles was stronger than prediction of transcript abundance from protein profiles. Protein profiles also proved to be more accurate predictors of glucosinolate profiles than transcript profiles. The similarity of species profiles for both transcripts and proteins reflected previously inferred phylogenetic relationships while glucosinolate chemotypes did not. Conclusions We have used transcript and protein profiling to predict physiological processes that evolved differently during diversification of three Pachycladon species. This approach has also identified candidate genes potentially important in adaptation, which are now the focus of ongoing study

  13. The potential of metatranscriptomics for identifying screening targets for bacterial vaginosis.

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    Jimmy Twin

    Full Text Available BACKGROUND: The ribosomal RNA content of a sample collected from a woman with bacterial vaginosis (BV was analysed to determine the active microbial community, and to identify potential targets for further screening. METHODOLOGY/PRINCIPAL FINDINGS: The sample from the BV patient underwent total RNA extraction, followed by physical subtraction of human rRNA and whole transcriptome amplification. The metatranscriptome was sequenced using Roche 454 titanium chemistry. The bioinformatics pipeline MG-RAST and desktop DNA analysis platforms were utilised to analyse results. Bacteria of the genus Prevotella (predominately P. amnii constituted 36% of the 16S rRNA reads, followed by Megasphaera (19%, Leptotrichia/Sneathia (8% and Fusobacterium (8%. Comparison of the abundances of several bacteria to quantitative PCR (qPCR screening of extracted DNA revealed comparable relative abundances. This suggests a correlation between what was present and transcriptionally active in this sample: however distinct differences were seen when compared to the microbiome determined by 16S rRNA gene amplicon sequencing. To assess the presence of P. amnii in a larger pool of samples, 90 sexually active women were screened using qPCR. This bacterium was found to be strongly associated with BV (P<0.001, OR 23.3 (95%CI:2.9-190.7 among the 90 women. CONCLUSIONS/SIGNIFICANCE: This study highlighted the potential of metatranscriptomics as a tool for characterising metabolically active microbiota and identifying targets for further screening. Prevotella amnii was chosen as an example target, being the most metabolically active species present in the single patient with BV, and was found to be detected at a high concentration by qPCR in 31% of cohort with BV, with an association with both oral and penile-vaginal sex.

  14. Gut Bacteria Missing in Severe Acute Malnutrition, Can We Identify Potential Probiotics by Culturomics?

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    Maryam Tidjani Alou

    2017-05-01

    Full Text Available Severe acute malnutrition is the world-leading cause of children under-five's death. Recent metagenomics studies have established a link between gut microbiota and severe acute malnutrition, describing an immaturity with a striking depletion in oxygen-sensitive prokaryotes. Amoxicillin and therapeutic diet cure most of the children with severe acute malnutrition but an irreversible disruption of the gut microbiota is suspected in the refractory and most severe cases. In these cases, therapeutic diet may be unable to reverse the microbiota alteration leading to persistent impaired development or death. In addition, as enteric sepsis is a major cause of death in this context, identification of missing gut microbes to be tested as probiotics (live bacteria that confer a benefit to the host to restore rapidly the healthy gut microbiota and prevent the gut pathogenic invasion is of foremost importance. In this study, stool samples of malnourished patients with kwashiorkor and healthy children were collected from Niger and Senegal and analyzed by culturomics and metagenomics. We found a globally decreased diversity, a decrease in the hitherto unknown diversity (new species isolation, a depletion in oxygen-sensitive prokaryotes including Methanobrevibacter smithii and an enrichment in potentially pathogenic Proteobacteria, Fusobacteria and Streptococcus gallolyticus. A complex of 12 species identified only in healthy children using culturomics and metagenomics were identified as probiotics candidates, providing a possible, defined, reproducible, safe, and convenient alternative to fecal transplantation to restore a healthy gut microbiota in malnourished children. Microbiotherapy based on selected strains has the potential to improve the current treatment of severe acute malnutrition and prevent relapse and death by reestablishing a healthy gut microbiota.

  15. Identifying potentially cost effective chronic care programs for people with COPD

    Directory of Open Access Journals (Sweden)

    L M G Steuten

    2008-12-01

    Full Text Available L M G Steuten1, K M M Lemmens2, A P Nieboer2, H JM Vrijhoef31Maastricht University Medical Centre, School for Care and Public Health Research, Department of Health, Organisation, Policy and Economics, Maastricht, The Netherlands; 2Erasmus University Medical Centre, Institute of Health Policy and Management, Rotterdam, The Netherlands; 3Maastricht University Medical Centre, School for Care and Public Health Research, Department of Integrated Care, Maastricht, The NetherlandsObjective: To review published evidence regarding the cost effectiveness of multi-component COPD programs and to illustrate how potentially cost effective programs can be identified.Methods: Systematic search of Medline and Cochrane databases for evaluations of multi-component disease management or chronic care programs for adults with COPD, describing process, intermediate, and end results of care. Data were independently extracted by two reviewers and descriptively summarized.Results: Twenty articles describing 17 unique COPD programs were included. There is little evidence for significant improvements in process and intermediate outcomes, except for increased provision of patient self-management education and improved disease-specific knowledge. Overall, the COPD programs generate end results equivalent to usual care, but programs containing ≥3 components show lower relative risks for hospitalization. There is limited scope for programs to break-even or save money.Conclusion: Identifying cost effective multi-component COPD programs remains a challenge due to scarce methodologically sound studies that demonstrate significant improvements on process, intermediate and end results of care. Estimations of potential cost effectiveness of specific programs illustrated in this paper can, in the absence of ‘perfect data’, support timely decision-making regarding these programs. Nevertheless, well-designed health economic studies are needed to decrease the current decision

  16. Evolutionary analysis of vision genes identifies potential drivers of visual differences between giraffe and okapi

    Directory of Open Access Journals (Sweden)

    Edson Ishengoma

    2017-04-01

    Full Text Available Background The capacity of visually oriented species to perceive and respond to visual signal is integral to their evolutionary success. Giraffes are closely related to okapi, but the two species have broad range of phenotypic differences including their visual capacities. Vision studies rank giraffe’s visual acuity higher than all other artiodactyls despite sharing similar vision ecological determinants with many of them. The extent to which the giraffe’s unique visual capacity and its difference with okapi is reflected by changes in their vision genes is not understood. Methods The recent availability of giraffe and okapi genomes provided opportunity to identify giraffe and okapi vision genes. Multiple strategies were employed to identify thirty-six candidate mammalian vision genes in giraffe and okapi genomes. Quantification of selection pressure was performed by a combination of branch-site tests of positive selection and clade models of selection divergence through comparing giraffe and okapi vision genes and orthologous sequences from other mammals. Results Signatures of selection were identified in key genes that could potentially underlie giraffe and okapi visual adaptations. Importantly, some genes that contribute to optical transparency of the eye and those that are critical in light signaling pathway were found to show signatures of adaptive evolution or selection divergence. Comparison between giraffe and other ruminants identifies significant selection divergence in CRYAA and OPN1LW. Significant selection divergence was identified in SAG while positive selection was detected in LUM when okapi is compared with ruminants and other mammals. Sequence analysis of OPN1LW showed that at least one of the sites known to affect spectral sensitivity of the red pigment is uniquely divergent between giraffe and other ruminants. Discussion By taking a systemic approach to gene function in vision, the results provide the first molecular clues

  17. Evolutionary analysis of vision genes identifies potential drivers of visual differences between giraffe and okapi

    Science.gov (United States)

    Agaba, Morris; Cavener, Douglas R.

    2017-01-01

    Background The capacity of visually oriented species to perceive and respond to visual signal is integral to their evolutionary success. Giraffes are closely related to okapi, but the two species have broad range of phenotypic differences including their visual capacities. Vision studies rank giraffe’s visual acuity higher than all other artiodactyls despite sharing similar vision ecological determinants with many of them. The extent to which the giraffe’s unique visual capacity and its difference with okapi is reflected by changes in their vision genes is not understood. Methods The recent availability of giraffe and okapi genomes provided opportunity to identify giraffe and okapi vision genes. Multiple strategies were employed to identify thirty-six candidate mammalian vision genes in giraffe and okapi genomes. Quantification of selection pressure was performed by a combination of branch-site tests of positive selection and clade models of selection divergence through comparing giraffe and okapi vision genes and orthologous sequences from other mammals. Results Signatures of selection were identified in key genes that could potentially underlie giraffe and okapi visual adaptations. Importantly, some genes that contribute to optical transparency of the eye and those that are critical in light signaling pathway were found to show signatures of adaptive evolution or selection divergence. Comparison between giraffe and other ruminants identifies significant selection divergence in CRYAA and OPN1LW. Significant selection divergence was identified in SAG while positive selection was detected in LUM when okapi is compared with ruminants and other mammals. Sequence analysis of OPN1LW showed that at least one of the sites known to affect spectral sensitivity of the red pigment is uniquely divergent between giraffe and other ruminants. Discussion By taking a systemic approach to gene function in vision, the results provide the first molecular clues associated with

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

    Science.gov (United States)

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

    2015-11-01

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

  19. Chitosan/sulfobutylether-β-cyclodextrin nanoparticles as a potential approach for ocular drug delivery.

    Science.gov (United States)

    Mahmoud, Azza A; El-Feky, Gina S; Kamel, Rabab; Awad, Ghada E A

    2011-07-15

    Development of efficient ocular delivery nanosystems remains a major challenge to achieve sustained therapeutic effect. The purpose of this work was to develop chitosan nanoparticles using sulfobutylether-β-cyclodextrin (SBE-β-CD) as polyanionic crosslinker and to investigate the potential of using those nanostructures as ocular drug delivery systems. Econazole nitrate (ECO) was chosen as model drug molecule. The influence of different process variables (chitosan molecular weight and the concentration of the two ionic agents) on particle size, polydispersity index, zeta potential, drug content, in vitro release and mucoadhesive properties was investigated. The results showed that the prepared nanoparticles were predominant spherical in shape having average particle diameter from 90 to 673 nm with positive zeta potential values from 22 to 33 mV and drug content values ranging from 13 to 45%. Drug release from optimized nanoparticles was controlled with approximately 50% of the original amount released over a 8h period. The release profile of nanoparticles followed a zero-order release kinetics. The optimized nanoparticles were tested for their use as ocular drug delivery systems on albino rabbits. The in vivo studies revealed that the prepared mucoadhesive nanoparticles had better ability in sustaining the antifungal effect of ECO than the ECO solution. Therefore, chitosan/SBE-β-CD nanoparticles developed showed a promising carrier for controlled delivery of drug to the eye.

  20. The potential utility of animal poisoning data to identify human exposure to environmental toxins.

    Science.gov (United States)

    Hungerford, L L; Trammel, H L; Clark, J M

    1995-04-01

    The database of the National Animal Poison Control Center (NAPCC) was evaluated as a source for animal poison data indicating human health hazards in indoor and outdoor environments. From 14,150 calls in the 1985 database, 259 cases were identified with histories suggesting human exposure. A subgroup of 25 cases with known human exposure was found. Dogs were the most common sentinel animal, but bird cases represented the highest proportional selection from the total 1985 call list. Indoor exposures represented 43.2% of cases; the most common toxicants were insecticides, lead and toxic fumes. Exposures associated with lawns were mainly due to insecticides and herbicides and constituted 25.5% of cases. Other outdoor exposures composed the remaining 31.7% of cases, with insecticides, herbicides and unidentified toxins the leading categories. Many of the specific agents identified, such as organophosphate insecticides, lead, gas and fume toxins, and phenoxy herbicides are also risk factors in human diseases. This study indicates that databases such as NAPCC could serve as sources of sentinel animal intoxications for followup studies to evaluate known and potential human health hazards.

  1. Enterococcus phages as potential tool for identifying sewage inputs in the Great Lakes region

    Science.gov (United States)

    ,; K.Vijayavel,; Byappanahalli, Muruleedhara N.; J. Ebdon,; ,; H. Taylor,; ,; Whitman, Richard L.; ,; D.R. Kashian,

    2014-01-01

    Bacteriophages are viruses living in bacteria that can be used as a tool to detect fecal contamination in surface waters around the world. However, the lack of a universal host strain makes them unsuitable for tracking fecal sources. We evaluated the suitability of two newly isolated Enterococcus host strains (ENT-49 and ENT-55) capable for identifying sewage contamination in impacted waters by targeting phages specific to these hosts. Both host strains were isolated from wastewater samples and identified as E. faecium by 16S rRNA gene sequencing. Occurrence of Enterococcus phages was evaluated in sewage samples (n = 15) from five wastewater treatment plants and in fecal samples from twenty-two species of wild and domesticated animals (individual samples; n = 22). Levels of Enterococcus phages, F + coliphages, Escherichia coli and enterococci were examined from four rivers, four beaches, and three harbors. Enterococcus phages enumeration was at similar levels (Mean = 6.72 Log PFU/100 mL) to F + coliphages in all wastewater samples, but were absent from all non-human fecal sources tested. The phages infecting Enterococcus spp. and F + coliphages were not detected in the river samples (detection threshold bacteriophages associated with these particular Enterococcus host strains offer potentially sensitive and human-source specific indicators of enteric pathogen risk.

  2. BCIP: a gene-centered platform for identifying potential regulatory genes in breast cancer

    Science.gov (United States)

    Wu, Jiaqi; Hu, Shuofeng; Chen, Yaowen; Li, Zongcheng; Zhang, Jian; Yuan, Hanyu; Shi, Qiang; Shao, Ningsheng; Ying, Xiaomin

    2017-01-01

    Breast cancer is a disease with high heterogeneity. Many issues on tumorigenesis and progression are still elusive. It is critical to identify genes that play important roles in the progression of tumors, especially for tumors with poor prognosis such as basal-like breast cancer and tumors in very young women. To facilitate the identification of potential regulatory or driver genes, we present the Breast Cancer Integrative Platform (BCIP, http://omics.bmi.ac.cn/bcancer/). BCIP maintains multi-omics data selected with strict quality control and processed with uniform normalization methods, including gene expression profiles from 9,005 tumor and 376 normal tissue samples, copy number variation information from 3,035 tumor samples, microRNA-target interactions, co-expressed genes, KEGG pathways, and mammary tissue-specific gene functional networks. This platform provides a user-friendly interface integrating comprehensive and flexible analysis tools on differential gene expression, copy number variation, and survival analysis. The prominent characteristic of BCIP is that users can perform analysis by customizing subgroups with single or combined clinical features, including subtypes, histological grades, pathologic stages, metastasis status, lymph node status, ER/PR/HER2 status, TP53 mutation status, menopause status, age, tumor size, therapy responses, and prognosis. BCIP will help to identify regulatory or driver genes and candidate biomarkers for further research in breast cancer. PMID:28327601

  3. Practical In-Depth Analysis of IDS Alerts for Tracing and Identifying Potential Attackers on Darknet

    Directory of Open Access Journals (Sweden)

    Jungsuk Song

    2017-02-01

    Full Text Available The darknet (i.e., a set of unused IP addresses is a very useful solution for observing the global trends of cyber threats and analyzing attack activities on the Internet. Since the darknet is not connected with real systems, in most cases, the incoming packets on the darknet (‘the darknet traffic’ do not contain a payload. This means that we are unable to get real malware from the darknet traffic. This situation makes it difficult for security experts (e.g., academic researchers, engineers, operators, etc. to identify whether the source hosts of the darknet traffic are infected by real malware or not. In this paper, we present the overall procedure of the in-depth analysis between the darknet traffic and IDS alerts using real data collected at the Science and Technology Cyber Security Center (S&T CSC in Korea and provide the detailed in-depth analysis results. The ultimate goal of this paper is to provide practical experience, insight and know-how to security experts so that they are able to identify and trace the root cause of the darknet traffic. The experimental results show that correlation analysis between the darknet traffic and IDS alerts is very useful to discover potential attack hosts, especially internal hosts, and to find out what kinds of malware infected them.

  4. Exome sequencing identifies potential risk variants for Mendelian disorders at high prevalence in Qatar.

    Science.gov (United States)

    Rodriguez-Flores, Juan L; Fakhro, Khalid; Hackett, Neil R; Salit, Jacqueline; Fuller, Jennifer; Agosto-Perez, Francisco; Gharbiah, Maey; Malek, Joel A; Zirie, Mahmoud; Jayyousi, Amin; Badii, Ramin; Al-Nabet Al-Marri, Ajayeb; Chouchane, Lotfi; Stadler, Dora J; Mezey, Jason G; Crystal, Ronald G

    2014-01-01

    Exome sequencing of families of related individuals has been highly successful in identifying genetic polymorphisms responsible for Mendelian disorders. Here, we demonstrate the value of the reverse approach, where we use exome sequencing of a sample of unrelated individuals to analyze allele frequencies of known causal mutations for Mendelian diseases. We sequenced the exomes of 100 individuals representing the three major genetic subgroups of the Qatari population (Q1 Bedouin, Q2 Persian-South Asian, Q3 African) and identified 37 variants in 33 genes with effects on 36 clinically significant Mendelian diseases. These include variants not present in 1000 Genomes and variants at high frequency when compared with 1000 Genomes populations. Several of these Mendelian variants were only segregating in one Qatari subpopulation, where the observed subpopulation specificity trends were confirmed in an independent population of 386 Qataris. Premarital genetic screening in Qatar tests for only four out of the 37, such that this study provides a set of Mendelian disease variants with potential impact on the epidemiological profile of the population that could be incorporated into the testing program if further experimental and clinical characterization confirms high penetrance. © 2013 WILEY PERIODICALS, INC.

  5. SWATH-based proteomics identified carbonic anhydrase 2 as a potential diagnosis biomarker for nasopharyngeal carcinoma

    Science.gov (United States)

    Luo, Yanzhang; Mok, Tin Seak; Lin, Xiuxian; Zhang, Wanling; Cui, Yizhi; Guo, Jiahui; Chen, Xing; Zhang, Tao; Wang, Tong

    2017-01-01

    Nasopharyngeal carcinoma (NPC) is a serious threat to public health, and the biomarker discovery is of urgent needs. The data-independent mode (DIA) based sequential window acquisition of all theoretical fragment-ion spectra (SWATH) mass spectrometry (MS) has been proved to be precise in protein quantitation and efficient for cancer biomarker researches. In this study, we performed the first SWATH-MS analysis comparing the NPC and normal tissues. Spike-in stable isotope labeling by amino acids in cell culture (super-SILAC) MS was used as a shotgun reference. We identified and quantified 1414 proteins across all SWATH-MS analyses. We found that SWATH-MS had a unique feature to preferentially detect proteins with smaller molecular weights than either super-SILAC MS or human proteome background. With SWATH-MS, 29 significant differentially express proteins (DEPs) were identified. Among them, carbonic anhydrase 2 (CA2) was selected for further validation per novelty, MS quality and other supporting rationale. With the tissue microarray analysis, we found that CA2 had an AUC of 0.94 in differentiating NPC from normal tissue samples. In conclusion, SWATH-MS has unique features in proteome analysis, and it leads to the identification of CA2 as a potentially new diagnostic biomarker for NPC. PMID:28117408

  6. Identifying potential misfit items in cognitive process of learning engineering mathematics based on Rasch model

    Science.gov (United States)

    Ataei, Sh; Mahmud, Z.; Khalid, M. N.

    2014-04-01

    The students learning outcomes clarify what students should know and be able to demonstrate after completing their course. So, one of the issues on the process of teaching and learning is how to assess students' learning. This paper describes an application of the dichotomous Rasch measurement model in measuring the cognitive process of engineering students' learning of mathematics. This study provides insights into the perspective of 54 engineering students' cognitive ability in learning Calculus III based on Bloom's Taxonomy on 31 items. The results denote that some of the examination questions are either too difficult or too easy for the majority of the students. This analysis yields FIT statistics which are able to identify if there is data departure from the Rasch theoretical model. The study has identified some potential misfit items based on the measurement of ZSTD where the removal misfit item was accomplished based on the MNSQ outfit of above 1.3 or less than 0.7 logit. Therefore, it is recommended that these items be reviewed or revised to better match the range of students' ability in the respective course.

  7. LC-MS based Metabolomics Analysis to Identify Potential Allelochemicals in Wedelia trilobata

    Directory of Open Access Journals (Sweden)

    Kamalrul Azlan Azizan

    2016-05-01

    Full Text Available Wedelia trilobata is a noxious invasive weed that has been widely cultivated as a decorative and groundcover plant. The plant has been reported to contain diverse bioactive compounds with a broad spectrum of biological activities including allelochemicals. Allelochemicals contribute to allelopathy interactions that suppress the growth and development of nearby plants. Several studies have reported the allelopathic potential of W. trilobata and its negative effects to crop plants. However, relatively little is known about the allelochemicals’ composition and how allelochemicals contribute to the allelopathic behavior of this plant. In order to prove allelopathy, the identification of the causative allelochemicals is required. The identification of potential allelochemicals that serve as biomarkers could be useful for assessing allelopathy interactions. In this study, a liquid chromatography (LC based metabolomics approach was applied to find biomarkers with allelopathic effects from W. trilobata. Ethanol and water were used to extract metabolites from the leaves of W. trilobata and analyzed using liquid chromatography coupled with quadrupole high-resolution time of flight mass spectrometry (LC-QTOF-MS. Using multivariate statistical analysis (MVA, we identified eight Rt-m/z pairs as candidate marker compounds for assessing allelopathy interactions of W. trilobata. The results highlight the application of metabolomics for understanding of the role of allelochemicals in allelopathy interactions of W. trilobata .

  8. Omen: identifying potential spear-phishing targets before the email is sent.

    Energy Technology Data Exchange (ETDEWEB)

    Wendt, Jeremy Daniel.

    2013-07-01

    We present the results of a two year project focused on a common social engineering attack method called "spear phishing". In a spear phishing attack, the user receives an email with information specifically focused on the user. This email contains either a malware-laced attachment or a link to download the malware that has been disguised as a useful program. Spear phishing attacks have been one of the most effective avenues for attackers to gain initial entry into a target network. This project focused on a proactive approach to spear phishing. To create an effective, user-specific spear phishing email, the attacker must research the intended recipient. We believe that much of the information used by the attacker is provided by the target organization's own external website. Thus when researching potential targets, the attacker leaves signs of his research in the webserver's logs. We created tools and visualizations to improve cybersecurity analysts' abilities to quickly understand a visitor's visit patterns and interests. Given these suspicious visitors and log-parsing tools, analysts can more quickly identify truly suspicious visitors, search for potential spear-phishing targeted users, and improve security around those users before the spear phishing email is sent.

  9. Structured methods for identifying and correcting potential human errors in space operations.

    Science.gov (United States)

    Nelson, W R; Haney, L N; Ostrom, L T; Richards, R E

    1998-01-01

    Human performance plays a significant role in the development and operation of any complex system, and human errors are significant contributors to degraded performance, incidents, and accidents for technologies as diverse as medical systems, commercial aircraft, offshore oil platforms, nuclear power plants, and space systems. To date, serious accidents attributed to human error have fortunately been rare in space operations. However, as flight rates go up and the duration of space missions increases, the accident rate could increase unless proactive action is taken to identity and correct potential human errors in space operations. The Idaho National Engineering and Environmental Laboratory (INEEL) has developed and applied structured methods of human error analysis to identify potential human errors, assess their effects on system performance, and develop strategies to prevent the errors or mitigate their consequences. These methods are being applied in NASA-sponsored programs to the domain of commercial aviation, focusing on airplane maintenance and air traffic management. The application of human error analysis to space operations could contribute to minimize the risks associated with human error in the design and operation of future space systems.

  10. Airborne Quercus pollen in SW Spain: Identifying favourable conditions for atmospheric transport and potential source areas.

    Science.gov (United States)

    Maya-Manzano, José María; Fernández-Rodríguez, Santiago; Smith, Matt; Tormo-Molina, Rafael; Reynolds, Andrew M; Silva-Palacios, Inmaculada; Gonzalo-Garijo, Ángela; Sadyś, Magdalena

    2016-11-15

    The pollen grains of Quercus spp. (oak trees) are allergenic. This study investigates airborne Quercus pollen in SW Spain with the aim identifying favourable conditions for atmospheric transport and potential sources areas. Two types of Quercus distribution maps were produced. Airborne Quercus pollen concentrations were measured at three sites located in the Extremadura region (SW Spain) for 3 consecutive years. The seasonal occurrence of Quercus pollen in the air was investigated, as well as days with pollen concentrations ≥80Pm(-3). The distance that Quercus pollen can be transported in appreciable numbers was calculated using clusters of back trajectories representing the air mass movement above the source areas (oak woodlands), and by using a state-of-the-art dispersion model. The two main potential sources of Quercus airborne pollen captured in SW Spain are Q. ilex subsp. ballota and Q. suber. The minimum distances between aerobiological stations and Quercus woodlands have been estimated as: 40km (Plasencia), 66km (Don Benito), 62km (Zafra) from the context of this study. Daily mean Quercus pollen concentration can exceed 1,700Pm(-3), levels reached not less than 24 days in a single year. High Quercus pollen concentration were mostly associated with moderate wind speed events (6-10ms(-1)), whereas that a high wind speed (16-20ms(-1)) seems to be associated with low concentrations.

  11. Predicting Fish Growth Potential and Identifying Water Quality Constraints: A Spatially-Explicit Bioenergetics Approach

    Science.gov (United States)

    Budy, Phaedra; Baker, Matthew; Dahle, Samuel K.

    2011-10-01

    Anthropogenic impairment of water bodies represents a global environmental concern, yet few attempts have successfully linked fish performance to thermal habitat suitability and fewer have distinguished co-varying water quality constraints. We interfaced fish bioenergetics, field measurements, and Thermal Remote Imaging to generate a spatially-explicit, high-resolution surface of fish growth potential, and next employed a structured hypothesis to detect relationships among measures of fish performance and co-varying water quality constraints. Our thermal surface of fish performance captured the amount and spatial-temporal arrangement of thermally-suitable habitat for three focal species in an extremely heterogeneous reservoir, but interpretation of this pattern was initially confounded by seasonal covariation of water residence time and water quality. Subsequent path analysis revealed that in terms of seasonal patterns in growth potential, catfish and walleye responded to temperature, positively and negatively, respectively; crappie and walleye responded to eutrophy (negatively). At the high eutrophy levels observed in this system, some desired fishes appear to suffer from excessive cultural eutrophication within the context of elevated temperatures whereas others appear to be largely unaffected or even enhanced. Our overall findings do not lead to the conclusion that this system is degraded by pollution; however, they do highlight the need to use a sensitive focal species in the process of determining allowable nutrient loading and as integrators of habitat suitability across multiple spatial and temporal scales. We provide an integrated approach useful for quantifying fish growth potential and identifying water quality constraints on fish performance at spatial scales appropriate for whole-system management.

  12. The in vitro real-time oscillation monitoring system identifies potential entrainment factors for circadian clocks

    Directory of Open Access Journals (Sweden)

    Yasuda Akio

    2006-02-01

    Full Text Available Abstract Background Circadian rhythms are endogenous, self-sustained oscillations with approximately 24-hr rhythmicity that are manifested in various physiological and metabolic processes. The circadian organization of these processes in mammals is governed by the master oscillator within the suprachiasmatic nuclei (SCN of the hypothalamus. Recent findings revealed that circadian oscillators exist in most organs, tissues, and even in immortalized cells, and that the oscillators in peripheral tissues are likely to be coordinated by SCN, the master oscillator. Some candidates for endogenous entrainment factors have sporadically been reported, however, their details remain mainly obscure. Results We developed the in vitro real-time oscillation monitoring system (IV-ROMS by measuring the activity of luciferase coupled to the oscillatory gene promoter using photomultiplier tubes and applied this system to screen and identify factors able to influence circadian rhythmicity. Using this IV-ROMS as the primary screening of entrainment factors for circadian clocks, we identified 12 candidates as the potential entrainment factor in a total of 299 peptides and bioactive lipids. Among them, four candidates (endothelin-1, all-trans retinoic acid, 9-cis retinoic acid, and 13-cis retinoic acid have already been reported as the entrainment factors in vivo and in vitro. We demonstrated that one of the novel candidates, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2, a natural ligand of the peroxisome proliferator-activated receptor-γ (PPAR-γ, triggers the rhythmic expression of endogenous clock genes in NIH3T3 cells. Furthermore, we showed that 15d-PGJ2 transiently induces Cry1, Cry2, and Rorα mRNA expressions and that 15d-PGJ2-induced entrainment signaling pathway is PPAR-γ – and MAPKs (ERK, JNK, p38MAPK-independent. Conclusion Here, we identified 15d-PGJ2 as an entrainment factor in vitro. Using our developed IV-ROMS to screen 299 compounds, we found eight

  13. Potential Impact of Diet on Treatment Effect from Anti-TNF Drugs in Inflammatory Bowel Disease.

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    Andersen, Vibeke; Hansen, Axel Kornerup; Heitmann, Berit Lilienthal

    2017-03-15

    We wanted to investigate the current knowledge on the impact of diet on anti-TNF response in inflammatory bowel diseases (IBD), to identify dietary factors that warrant further investigations in relation to anti-TNF treatment response, and, finally, to discuss potential strategies for such investigations. PubMed was searched using specified search terms. One small prospective study on diet and anti-TNF treatment in 56 patients with CD found similar remission rates after 56 weeks among 32 patients with good compliance that received concomitant enteral nutrition and 24 with poor compliance that had no dietary restrictions (78% versus 67%, p = 0.51). A meta-analysis of 295 patients found higher odds of achieving clinical remission and remaining in clinical remission among patients on combination therapy with specialised enteral nutrition and Infliximab (IFX) compared with IFX monotherapy (OR 2.73; 95% CI: 1.73-4.31, p TNF treatment response for clinical use is scarce. Here we propose a mechanism by which Western style diet high in meat and low in fibre may promote colonic inflammation and potentially impact treatment response to anti-TNF drugs. Further studies using hypothesis-driven and data-driven strategies in prospective observational, animal and interventional studies are warranted.

  14. Novel Phenotypic Outcomes Identified for a Public Collection of Approved Drugs from a Publicly Accessible Panel of Assays.

    Directory of Open Access Journals (Sweden)

    Jonathan A Lee

    Full Text Available Phenotypic assays have a proven track record for generating leads that become first-in-class therapies. Whole cell assays that inform on a phenotype or mechanism also possess great potential in drug repositioning studies by illuminating new activities for the existing pharmacopeia. The National Center for Advancing Translational Sciences (NCATS pharmaceutical collection (NPC is the largest reported collection of approved small molecule therapeutics that is available for screening in a high-throughput setting. Via a wide-ranging collaborative effort, this library was analyzed in the Open Innovation Drug Discovery (OIDD phenotypic assay modules publicly offered by Lilly. The results of these tests are publically available online at www.ncats.nih.gov/expertise/preclinical/pd2 and via the PubChem Database (https://pubchem.ncbi.nlm.nih.gov/ (AID 1117321. Phenotypic outcomes for numerous drugs were confirmed, including sulfonylureas as insulin secretagogues and the anti-angiogenesis actions of multikinase inhibitors sorafenib, axitinib and pazopanib. Several novel outcomes were also noted including the Wnt potentiating activities of rotenone and the antifolate class of drugs, and the anti-angiogenic activity of cetaben.

  15. Potential of surface-eroding poly(ethylene carbonate) for drug delivery to macrophages.

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    Bohr, Adam; Water, Jorrit J; Wang, Yingya; Arnfast, Lærke; Beck-Broichsitter, Moritz

    2016-09-25

    Films composed of poly(ethylene carbonate) (PEC), a biodegradable polymer, were compared with poly(lactide-co-glycolide) (PLGA) films loaded with and without the tuberculosis drug rifampicin to study the characteristics and performance of PEC as a potential carrier for controlled drug delivery to macrophages. All drug-loaded PLGA and PEC films were amorphous indicating good miscibility of the drug in the polymers, even at high drug loading (up to 50wt.%). Polymer degradation studies showed that PLGA degraded slowly via bulk erosion while PEC degraded more rapidly and near-linearly via enzyme mediated surface erosion (by cholesterol esterase). Drug release studies performed with polymer films indicated a diffusion/erosion dependent delivery behavior for PLGA while an almost zero-order drug release profile was observed from PEC due to the controlled polymer degradation process. When exposed to polymer degradation products the murine macrophage cell line J774A.1 showed less susceptibility to PEC than to PLGA. However, when seeding the macrophages on PLGA and PEC films no relevant difference in cell proliferation/growth kinetics was observed. Overall, this study emphasizes that PEC is an attractive polymer for controlled drug release and could provide superior performance to PLGA for some drug delivery applications including the treatment of macrophage infections.

  16. Interaction Potential of the Multitargeted Receptor Tyrosine Kinase Inhibitor Dovitinib with Drug Transporters and Drug Metabolising Enzymes Assessed in Vitro

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    Johanna Weiss

    2014-12-01

    Full Text Available Dovitinib (TKI-258 is under development for the treatment of diverse cancer entities. No published information on its pharmacokinetic drug interaction potential is available. Thus, we assessed its interaction with important drug metabolising enzymes and drug transporters and its efficacy in multidrug resistant cells in vitro. P-glycoprotein (P-gp, MDR1, ABCB1 inhibition was evaluated by calcein assay, inhibition of breast cancer resistance protein (BCRP, ABCG2 by pheophorbide A efflux, and inhibition of organic anion transporting polypeptides (OATPs by 8-fluorescein-cAMP uptake. Inhibition of cytochrome P450 3A4, 2C19, and 2D6 was assessed by using commercial kits. Induction of transporters and enzymes was quantified by real-time RT-PCR. Possible aryl hydrocarbon receptor (AhR activating properties were assessed by a reporter gene assay. Substrate characteristics were evaluated by growth inhibition assays in cells over-expressing P-gp or BCRP. Dovitinib weakly inhibited CYP2C19, CYP3A4, P-gp and OATPs. The strongest inhibition was observed for BCRP (IC50 = 10.3 ± 4.5 μM. Among the genes investigated, dovitinib only induced mRNA expression of CYP1A1, CYP1A2, ABCC3 (coding for multidrug resistance-associated protein 3, and ABCG2 and suppressed mRNA expression of some transporters and drug metabolising enzymes. AhR reporter gene assay demonstrated that dovitinib is an activator of this nuclear receptor. Dovitinib retained its efficacy in cell lines over-expressing P-gp or BCRP. Our analysis indicates that dovitinib will most likely retain its efficacy in tumours over-expressing P-gp or BCRP and gives first evidence that dovitinib might act as a perpetrator drug in pharmacokinetic drug–drug interactions.

  17. In silico and microarray-based genomic approaches to identifying potential vaccine candidates against Leptospira interrogans

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    Jiang Xu-Cheng

    2006-11-01

    Full Text Available Abstract Background Currently available vaccines against leptospirosis are of low efficacy, have an unacceptable side-effect profile, do not induce long-term protection, and provide no cross-protection against the different serovars of pathogenic leptospira. The current major focus in leptospirosis research is to discover conserved protective antigens that may elicit longer-term protection against a broad range of Leptospira. There is a need to screen vaccine candidate genes in the genome of Leptospira interrogans. Results Bioinformatics, comparative genomic hybridization (CGH analysis and transcriptional analysis were used to identify vaccine candidates in the genome of L. interrogans serovar Lai strain #56601. Of a total of 4727 open reading frames (ORFs, 616 genes were predicted to encode surface-exposed proteins by P-CLASSIFIER combined with signal peptide prediction, α-helix transmembrane topology prediction, integral β-barrel outer membrane protein and lipoprotein prediction, as well as by retaining the genes shared by the two sequenced L. interrogans genomes and by subtracting genes with human homologues. A DNA microarray of L. interrogans strain #56601 was constructed for CGH analysis and transcriptome analysis in vitro. Three hundred and seven differential genes were identified in ten pathogenic serovars by CGH; 1427 genes had high transcriptional levels (Cy3 signal ≥ 342 and Cy5 signal ≥ 363.5, respectively. There were 565 genes in the intersection between the set encoding surface-exposed proteins and the set of 307 differential genes. The number of genes in the intersection between this set of 565 and the set of 1427 highly transcriptionally active genes was 226. These 226 genes were thus identified as putative vaccine candidates. The proteins encoded by these genes are not only potentially surface-exposed in the bacterium, but also conserved in two sequenced L. interrogans. Moreover, these genes are conserved among ten epidemic

  18. Developing tools to identify marginal lands and assess their potential for bioenergy production

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    Galatsidas, Spyridon; Gounaris, Nikolaos; Dimitriadis, Elias; Rettenmaier, Nils; Schmidt, Tobias; Vlachaki, Despoina

    2017-04-01

    The term "marginal land" is currently intertwined in discussions about bioenergy although its definition is neither specific nor firm. The uncertainty arising from marginal land classification and quantification is one of the major constraining factors for its potential use. The clarification of political aims, i.e. "what should be supported?" is also an important constraining factor. Many approaches have been developed to identify marginal lands, based on various definitions according to the management goals. Concerns have been frequently raised regarding the impacts of marginal land use on environment, ecosystem services and sustainability. Current tools of soil quality and land potentials assessment fail to meet the needs of marginal land identification and exploitation for biomass production, due to the lack of comprehensive analysis of interrelated land functions and their quantitative evaluation. Land marginality is determined by dynamic characteristics in many cases and may therefore constitute a transitional state, which requires reassessment in due time. Also, marginal land should not be considered simply a dormant natural resource waiting to be used, since it may already provide multiple benefits and services to society relating to wildlife, biodiversity, carbon sequestration, etc. The consequences of cultivating such lands need to be fully addressed to present a balanced view of their sustainable potential for bioenergy. This framework is the basis for the development of the SEEMLA tools, which aim at supporting the identification, assessment, management of marginal lands in Europe and the decision-making for sustainable biomass production of them using appropriate bioenergy crops. The tools comprise two applications, a web-based one (independent of spatial data) and a GIS-based application (land regionalization on the basis of spatial data), which both incorporate: - Land resource characteristics, restricting the cultivation of agricultural crops but

  19. MEDICI: Mining Essentiality Data to Identify Critical Interactions for Cancer Drug Target Discovery and Development | Office of Cancer Genomics

    Science.gov (United States)

    Protein-protein interactions (PPIs) mediate the transmission and regulation of oncogenic signals that are essential to cellular proliferation and survival, and thus represent potential targets for anti-cancer therapeutic discovery. Despite their significance, there is no method to experimentally disrupt and interrogate the essentiality of individual endogenous PPIs. The ability to computationally predict or infer PPI essentiality would help prioritize PPIs for drug discovery and help advance understanding of cancer biology.

  20. Cancer incidence and adverse pregnancy outcome in registered nurses potentially exposed to antineoplastic drugs

    Directory of Open Access Journals (Sweden)

    Le Nhu D

    2010-09-01

    Full Text Available Abstract Background To determine the relationships of potential occupational exposure to antineoplastic drugs with cancer incidence and adverse pregnancy outcomes in a historical prospective cohort study of female registered nurses (RNs from British Columbia, Canada (BC. Methods Female RNs registered with a professional regulatory body for at least one year between 1974 and 2000 formed the cohort (n = 56,213. The identifier file was linked to Canadian cancer registries. An RN offspring cohort from 1986 was created by linkages with the BC Birth and Health Status Registries. Exposure was assessed by work history in oncology or cancer agencies (method 1 and by estimating weighted duration of exposure developed from a survey of pharmacists and nursing unit administrators of all provincial hospitals and treatment centers and the work history of the nurses (method 2. Relative risks (RR were calculated using Poisson regression for cancer incidence and odds ratios (OR were calculated for congenital anomaly, stillbirth, low birth weight, and prematurity incidence, with 95% confidence intervals. Results In comparison with other female RNs, method 1 revealed that RNs who ever worked in a cancer center or in an oncology nursing unit had an increased risk of breast cancer (RR = 1.83; 95% CI = 1.03 - 3.23, 12 cases and their offspring were at risk for congenital anomalies of the eye (OR = 3.46, 95% CI = 1.08 - 11.14, 3 cases. Method 2 revealed that RNs classified as having the highest weighted durations of exposure to antineoplastic drugs had an excess risk of cancer of the rectum (RR = 1.87, 95% CI = 1.07 - 3.29, 14 cases. No statistically significant increased risks of leukemia, other cancers, stillbirth, low birth weight, prematurity, or other congenital anomalies in the RNs' offspring were noted. Conclusions Female RNs having had potential exposure to antineoplastic drugs were not found to have an excess risk of leukemia, stillbirth, or congenital

  1. Studies on pectins as potential hydrogel matrices for controlled-release drug delivery.

    Science.gov (United States)

    Sungthongjeen, S; Pitaksuteepong, T; Somsiri, A; Sriamornsak, P

    1999-12-01

    Polymeric hydrogels are widely used as controlled-release matrix tablets. In the present study, we investigated high-methoxy pectins for their potential value in controlled-release matrix formulations. The effects of compression force, ratio of drug to pectin, and type of pectin on drug release from matrix tablets were also investigated. The results of the in vitro release studies show that the drug release from compressed matrix tablets prepared from pectin can be modified by changing the amount and the type of pectin in the matrix tablets. However, compression force did not significantly affect the drug release. The mechanisms controlling release rate were discussed with respect to drug diffusion through the polymer matrices, but may be more complex.

  2. Population genomics studies identify signatures of global dispersal and drug resistance in Plasmodium vivax

    Science.gov (United States)

    Hupalo, Daniel N; Luo, Zunping; Melnikov, Alexandre; Sutton, Patrick L; Rogov, Peter; Escalante, Ananias; Vallejo, Andrés F; Herrera, Sócrates; Arévalo-Herrera, Myriam; Fan, Qi; Wang, Ying; Cui, Liwang; Lucas, Carmen M; Durand, Salomon; Sanchez, Juan F; Baldeviano, G Christian; Lescano, Andres G; Laman, Moses; Barnadas, Celine; Barry, Alyssa; Mueller, Ivo; Kazura, James W; Eapen, Alex; Kanagaraj, Deena; Valecha, Neena; Ferreira, Marcelo U; Roobsoong, Wanlapa; Nguitragool, Wang; Sattabonkot, Jetsumon; Gamboa, Dionicia; Kosek, Margaret; Vinetz, Joseph M; González-Cerón, Lilia; Birren, Bruce W; Neafsey, Daniel E; Carlton, Jane M

    2017-01-01

    Plasmodium vivax is a major public health burden, responsible for the majority of malaria infections outside Africa. We explored the impact of demographic history and selective pressures on the P. vivax genome by sequencing 182 clinical isolates sampled from 11 countries across the globe, using hybrid selection to overcome human DNA contamination. We confirmed previous reports of high genomic diversity in P. vivax relative to the more virulent Plasmodium falciparum species; regional populations of P. vivax exhibited greater diversity than the global P. falciparum population, indicating a large and/or stable population. Signals of natural selection suggest that P. vivax is evolving in response to antimalarial drugs and is adapting to regional differences in the human host and the mosquito vector. These findings underline the variable epidemiology of this parasite species and highlight the breadth of approaches that may be required to eliminate P. vivax globally. PMID:27348298

  3. How the Probability and Potential Clinical Significance of Pharmacokinetically Mediated Drug-Drug Interactions Are Assessed in Drug Development: Desvenlafaxine as an Example

    Science.gov (United States)

    Nichols, Alice I.; Preskorn, Sheldon H.

    2015-01-01

    Objective: The avoidance of adverse drug-drug interactions (DDIs) is a high priority in terms of both the US Food and Drug Administration (FDA) and the individual prescriber. With this perspective in mind, this article illustrates the process for assessing the risk of a drug (example here being desvenlafaxine) causing or being the victim of DDIs, in accordance with FDA guidance. Data Sources/Study Selection: DDI studies for the serotonin-norepinephrine reuptake inhibitor desvenlafaxine conducted by the sponsor and published since 2009 are used as examples of the systematic way that the FDA requires drug developers to assess whether their new drug is either capable of causing clinically meaningful DDIs or being the victim of such DDIs. In total, 8 open-label studies tested the effects of steady-state treatment with desvenlafaxine (50–400 mg/d) on the pharmacokinetics of cytochrome (CYP) 2D6 and/or CYP 3A4 substrate drugs, or the effect of CYP 3A4 inhibition on desvenlafaxine pharmacokinetics. The potential for DDIs mediated by the P-glycoprotein (P-gp) transporter was assessed in in vitro studies using Caco-2 monolayers. Data Extraction: Changes in area under the plasma concentration-time curve (AUC; CYP studies) and efflux (P-gp studies) were reviewed for potential DDIs in accordance with FDA criteria. Results: Desvenlafaxine coadministration had minimal effect on CYP 2D6 and/or 3A4 substrates per FDA criteria. Changes in AUC indicated either no interaction (90% confidence intervals for the ratio of AUC geometric least-squares means [GM] within 80%–125%) or weak inhibition (AUC GM ratio 125% to desvenlafaxine (AUC GM ratio of 143%). Desvenlafaxine was not a substrate (efflux ratio 250 μM) of P-gp. Conclusions: A 2-step process based on FDA guidance can be used first to determine whether a pharmacokinetically mediated interaction occurs and then to assess the potential clinical significance of the DDI. In the case of the drug tested in this series of studies

  4. The maximum potential market for dengue drugs V 1.0.

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    Dow, Geoffrey; Mora, Eric

    2012-11-01

    Drugs offer a complementary approach to vaccines for preventing the progression of symptoms and onset of the severe manifestations of dengue. Despite the rapid maturation of the research and development infrastructure for dengue drugs and the increasing frequency of dengue inhibitors reported in the scientific literature, the potential size of the market for dengue drugs has not been articulated. In the present work, extrapolating from publicly available information, we explored the economic burden attributable to dengue, the impact of dengue vaccines on clinical case loads, a possible alternative to tiered pricing for products for neglected diseases, and defined the maximum potential market for a dengue drug. Our projections suggest that in 2006, the annual global burden of dengue was US $1.7billion. Our proposed alternative to existing tiered pricing structures is that during a temporary period of market exclusivity, individual countries would pay 50% of the per-case equivalent of economic costs saved through the use of a dengue drug. This would yield prices per case of US $13-$239 depending on drug effectiveness and cost of medical and indirect costs and lost productivity in different countries. Assuming that such a pricing scheme was embraced, the maximum potential market for a dengue drug or drugs that on average reduced 40% of economic costs might be as high as US $338million annually. Our simulations suggest that dengue vaccines will begin to reduce the clinical case load of dengue in 2022, but that the number of cases will not decrease below 2006 levels and the proportion vaccinated will remain well below that required for the onset of herd immunity during the period of market exclusivity after the licensure of the first wave of dengue drugs.

  5. Clementine juice has the potential for drug interactions - In vitro comparison with grapefruit and mandarin juice.

    Science.gov (United States)

    Theile, Dirk; Hohmann, Nicolas; Kiemel, Dominik; Gattuso, Giuseppe; Barreca, Davide; Mikus, Gerd; Haefeli, Walter Emil; Schwenger, Vedat; Weiss, Johanna

    2017-01-15

    Adverse drug interactions due to grapefruit juice are well known prompting warnings even in drug labels. Similar issues have not been reported for clementines and available data is scarce, despite of genetic descent. We observed substantially increased tacrolimus trough concentrations in a renal transplant patient consuming high clementine amounts and, thus, scrutinised the effects of clementine juice on drug metabolism and drug transporters in vitro and compared it to the effects of mandarin and grapefruit juice. All citrus juices profoundly induced several drug transporters and drug metabolising enzymes, whereas the effects of grapefruit juice were most pronounced (e.g. 156-fold and 34-fold induction of cytochrome P450 (CYP) 3A4 mRNA by grapefruit juice and clementine juice, respectively). However, the juices also inhibited e.g. CYP3A4, raising the question which effect prevails in vivo. Using an enzymatic activity assay, we demonstrated that at least in vitro CYP3A4 inhibition prevails for both grapefruit and clementine juice, whereas for CYP1A2 induction appears to predominate. Thus, inhibition of CYP3A4 is presumably the underlying reason for the observed increase in the concentrations of the CYP3A4 substrate tacrolimus in the patient. Taken together, our data indicate that clementine juice as well as grapefruit juice and to a lesser extent also mandarin juice can induce several important drug metabolising enzymes and drug transporters, but also inhibit some of these proteins. Our data indicate that clementine juice similar to grapefruit juice bears the potential for profound interactions with drugs potentially leading to adverse drug effects e.g. through over-exposure to CYP3A4 substrates. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Surface Modifications of Titanium Implants by Multilayer Bioactive Coatings with Drug Delivery Potential: Antimicrobial, Biological, and Drug Release Studies

    Science.gov (United States)

    Ordikhani, Farideh; Zustiak, Silviya Petrova; Simchi, Abdolreza

    2016-04-01

    Recent strategies to locally deliver antimicrobial agents to combat implant-associated infections—one of the most common complications in orthopedic surgery—are gaining interest. However, achieving a controlled release profile over a desired time frame remains a challenge. In this study, we present an innovative multifactorial approach to combat infections which comprises a multilayer chitosan/bioactive glass/vancomycin nanocomposite coating with an osteoblastic potential and a drug delivery capacity. The bioactive drug-eluting coating was prepared on the surface of titanium foils by a multistep electrophoretic deposition technique. The adopted deposition strategy allowed for a high antibiotic loading of 1038.4 ± 40.2 µg/cm2. The nanocomposite coating exhibited a suppressed burst release with a prolonged sustained vancomycin release for up to 6 weeks. Importantly, the drug release profile was linear with respect to time, indicating a zero-order release kinetics. An in vitro bactericidal assay against Staphylococcus aureus confirmed that releasing the drug reduced the risk of bacterial infection. Excellent biocompatibility of the developed coating was also demonstrated by in vitro cell studies with a model MG-63 osteoblast cell line.

  7. Potential drug-drug interactions in medical intensive care unit of a tertiary care hospital in Pakistan.

    Science.gov (United States)

    Ismail, Mohammad; Khan, Farmanullah; Noor, Sidra; Haider, Iqbal; Haq, Inam-Ul; Ali, Zahid; Shah, Zahir; Hassam, Mohsin

    2016-10-01

    Background Patients admitted to intensive care unit (ICU) present with severe and life-threatening illnesses. Most of them suffer from various comorbidities. They usually receive complex pharmacotherapy with large number of medicines which increase the risk of drug-drug interactions (DDIs). Objective The present report aimed to investigate prevalence and levels of potential DDIs (pDDIs) in medical ICU. Methods Medications profiles of 416 patients were checked for pDDIs using Micromedex Drug-Reax(®). Prevalence, levels of severity and levels of documentation were reported. Results Of total 416 patients, 310 were exposed to pDDIs (overall prevalence = 74.5 %). Likewise, a prevalence rate of 13.9 % was recorded for contraindicated pDDIs, 52.2 % for major pDDI and 58.4 % for moderate pDDI. This study reported 740 interacting drug pairs that were presented in total 1686 pDDIs. Of 1686 pDDIs, 4.3 % were of contraindicated severity, 33.8 % of major severity and 49.6 % of moderate severity, whereas 45.5 % were of fair scientific evidence and 41.4 % of good scientific evidence. Conclusion In this study, pDDIs were found highly prevalent in ICU patients at a rate of 74.5 %. Most of the pDDIs had moderate severity; however, substantial number of interactions (38.1 %) had major and contraindicated severity.

  8. Potential of phage-displayed peptide library technology to identify functional targeting peptides

    Science.gov (United States)

    Krumpe, Lauren RH; Mori, Toshiyuki

    2010-01-01

    Combinatorial peptide library technology is a valuable resource for drug discovery and development. Several peptide drugs developed through phage-displayed peptide library technology are presently in clinical trials and the authors envision that phage-displayed peptide library technology will assist in the discovery and development of many more. This review attempts to compile and summarize recent literature on targeting peptides developed through peptide library technology, with special emphasis on novel peptides with targeting capacity evaluated in vivo. PMID:20150977

  9. Health Systems Science Curricula in Undergraduate Medical Education: Identifying and Defining a Potential Curricular Framework.

    Science.gov (United States)

    Gonzalo, Jed D; Dekhtyar, Michael; Starr, Stephanie R; Borkan, Jeffrey; Brunett, Patrick; Fancher, Tonya; Green, Jennifer; Grethlein, Sara Jo; Lai, Cindy; Lawson, Luan; Monrad, Seetha; O'Sullivan, Patricia; Schwartz, Mark D; Skochelak, Susan

    2017-01-01

    The authors performed a review of 30 Accelerating Change in Medical Education full grant submissions and an analysis of the health systems science (HSS)-related curricula at the 11 grant recipient schools to develop a potential comprehensive HSS curricular framework with domains and subcategories. In phase 1, to identify domains, grant submissions were analyzed and coded using constant comparative analysis. In phase 2, a detailed review of all existing and planned syllabi and curriculum documents at the grantee schools was performed, and content in the core curricular domains was coded into subcategories. The lead investigators reviewed and discussed drafts of the categorization scheme, collapsed and combined domains and subcategories, and resolved disagreements via group discussion. Analysis yielded three types of domains: core, cross-cutting, and linking. Core domains included health care structures and processes; health care policy, economics, and management; clinical informatics and health information technology; population and public health; value-based care; and health system improvement. Cross-cutting domains included leadership and change agency; teamwork and interprofessional education; evidence-based medicine and practice; professionalism and ethics; and scholarship. One linking domain was identified: systems thinking. This broad framework aims to build on the traditional definition of systems-based practice and highlight the need for medical and other health professions schools to better align education programs with the anticipated needs of the systems in which students will practice. HSS will require a critical investigation into existing curricula to determine the most efficient methods for integration with the basic and clinical sciences.

  10. Identifying preperimetric functional loss in glaucoma: a blue-on-yellow multifocal visual evoked potentials study.

    Science.gov (United States)

    Arvind, Hemamalini; Graham, Stuart; Leaney, John; Grigg, John; Goldberg, Ivan; Billson, Frank; Klistorner, Alexander

    2009-06-01

    To determine the ability of blue-on-yellow multifocal visual evoked potentials (BonY mfVEP) to identify functional loss in preperimetric glaucoma. Prospective case series. Thirty patients with glaucomatous optic discs and normal standard visual fields. All patients underwent BonY mfVEP, dilated optic disc stereophotography, and optical coherence tomography (Fast RNFL protocol). Optic disc photographs were assessed by 2 independent examiners in a masked fashion. The mfVEP amplitude asymmetry and latency values were analyzed and compared topographically with findings of disc assessment. Average retinal nerve fiber layer (RNFL) thickness, RNFL asymmetry, and sectors with RNFL thinning were compared between patients with and without mfVEP defects. Fourteen (46.7%) patients demonstrated significant abnormality on amplitude asymmetry deviation plots of BonY mfVEP. In all 14 cases, the defect was monocular and corresponded to the eye with the worse disc. In 13 of 14 patients, the defect also corresponded to the location of the worst affected rim. Average RNFL thickness of eyes with mfVEP defects was 81.2+/-9.9 microm, significantly lower than that of patients without defects (90+/-10.5 microm; P = 0.035). Mean asymmetry of RNFL (better minus worse eye) also was significantly higher for patients with mfVEP defects compared with those without such defects (9.0+/-6.4 microm vs. 3.0+/-7 microm; P = 0.03). Average latency of both eyes of glaucomatous patients was delayed compared with that of controls, with no difference in latency between worse and better eyes of glaucoma patients. There was no association of latency delay with either the location of disc changes or mfVEP amplitude defects. Amplitude asymmetry of the BonY mfVEP seems to be a promising tool to identify functional loss in preperimetric glaucoma. Proprietary or commercial disclosure may be found after the references.

  11. Clinical incidents involving students on placement: an analysis of incident reports to identify potential risk factors.

    Science.gov (United States)

    Gaida, J E; Maloney, S; Lo, K; Morgan, P

    2015-06-01

    Students are sometimes involved in incidents during clinical training. To the authors' knowledge, no quantitative studies of incidents specifically involving physiotherapy students on clinical placement are available in the literature. A retrospective audit (2008 to 2011) of incident reports involving physiotherapy students was conducted to identify the nature and features of incidents. The study aimed to determine if injuries to a student or patient were more or less likely when the supervisor was in close proximity, and whether students with lower academic performance in their preclinical semester were more likely to be involved in an incident. There were 19 care-delivery-related and three equipment-related incidents. There were no incidents of violent, aggressive or demeaning behaviour towards students. The incident rate was 9.0/100,000 student-hours for third-year students and 6.8/100,000 student-hours for fourth-year students. The majority of incidents (55%) occurred from 11 am to 12-noon and from 3 pm to 3.30 pm. Incidents more often resulted in patient or student injury when the supervisor was not in close proximity (approximately 50% vs approximately 20%), although the difference was not significant (P=0.336). The academic results of students involved in incidents were equivalent to the whole cohort in their preclinical semester {mean 75 [standard deviation (SD) 6] vs 76 (SD 7); P=0.488}. The unexpected temporal clustering of incidents warrants further investigation. Student fatigue may warrant attention as a potential contributor; however, contextual factors, such as staff workload, along with organisational systems, structures and procedures may be more relevant. The potential relationship between supervisor proximity and injury also warrants further exploration. The findings of the present study should be integrated into clinical education curricula and communicated to clinical educators. Copyright © 2014 Chartered Society of Physiotherapy. Published by

  12. Germline DNA copy number aberrations identified as potential prognostic factors for breast cancer recurrence.

    Directory of Open Access Journals (Sweden)

    Yadav Sapkota

    Full Text Available Breast cancer recurrence (BCR is a common treatment outcome despite curative-intent primary treatment of non-metastatic breast cancer. Currently used prognostic and predictive factors utilize tumor-based markers, and are not optimal determinants of risk of BCR. Germline-based copy number aberrations (CNAs have not been evaluated as determinants of predisposition to experience BCR. In this study, we accessed germline DNA from 369 female breast cancer subjects who received curative-intent primary treatment following diagnosis. Of these, 155 experienced BCR and 214 did not, after a median duration of follow up after breast cancer diagnosis of 6.35 years (range = 0.60-21.78 and 8.60 years (range = 3.08-13.57, respectively. Whole genome CNA genotyping was performed on the Affymetrix SNP array 6.0 platform. CNAs were identified using the SNP-Fast Adaptive States Segmentation Technique 2 algorithm implemented in Nexus Copy Number 6.0. Six samples were removed due to poor quality scores, leaving 363 samples for further analysis. We identified 18,561 CNAs with ≥1 kb as a predefined cut-off for observed aberrations. Univariate survival analyses (log-rank tests identified seven CNAs (two copy number gains and five copy neutral-loss of heterozygosities, CN-LOHs showing significant differences (P<2.01×10(-5 in recurrence-free survival (RFS probabilities with and without CNAs.We also observed three additional but distinct CN-LOHs showing significant differences in RFS probabilities (P<2.86×10(-5 when analyses were restricted to stratified cases (luminal A, n = 208 only. After adjusting for tumor stage and grade in multivariate analyses (Cox proportional hazards models, all the CNAs remained strongly associated with the phenotype of BCR. Of these, we confirmed three CNAs at 17q11.2, 11q13.1 and 6q24.1 in representative samples using independent genotyping platforms. Our results suggest further investigations on the potential use of germline DNA

  13. Identifying potentially preventable emergency department visits by nursing home residents in the United States

    Science.gov (United States)

    Burke, Robert E.; Rooks, Sean P.; Levy, Cari; Schwartz, Robert; Ginde, Adit A.

    2015-01-01

    Objectives To identify and describe potentially preventable emergency department (ED) visits by nursing home (NH) residents in the United States. These visits are important because they are common, frequently lead to hospitalization, and can be associated with significant cost to the patient and the health care system. Design Retrospective analysis of the 2005-2010 National Hospital Ambulatory Care Survey (NHAMCS), comparing ED visits by nursing home residents that did not lead to hospital admission (potentially preventable) to those that led to admission (less likely preventable). Setting Nationally representative sample of United States EDs; Federal hospitals and hospitals with less than six beds were excluded. Participants Older (age ≥65 years) nursing home residents with an ED visit during this time period. Measurements Patient demographics, ED visit information including testing performed, interventions (both procedures and medications) provided, and diagnoses treated. Results Older NH residents accounted for 3,857 of 208,956 ED visits during the time period of interest (1.8%). When weighted to be nationally representative, these represent 13.97 million ED visits, equivalent to 1.8 ED visits annually per NH resident in the United States. More than half of visits (53.5%) did not lead to hospital admission; of those discharged from the ED, 62.8% had normal vital signs on presentation and 18.9% did not have any diagnostic testing prior to ED discharge. Injuries were 1.78 times more likely to be discharged than admitted (44.8% versus 25.3%, respectively, p<0.001), while infections were 2.06 times as likely to be admitted as discharged (22.9% versus 11.1%, respectively). CT scans were performed in 25.4% and 30.1% of older NH residents who were discharged from the ED and admitted to the hospital, respectively, and more than 70% of these were CTs of the head. NH residents received centrally acting, sedating medications prior to ED discharge in 9.4% of visits

  14. Double layered hydroxides as potential anti-cancer drug delivery agents.

    Science.gov (United States)

    Riaz, Ufana; Ashraf, S M

    2013-04-01

    The emergence of nanotechnology has changed the scenario of the medical world by revolutionizing the diagnosis, monitoring and treatment of cancer. This nanotechnology has been proved miraculous in detecting cancer cells, delivering chemotherapeutic agents and monitoring treatment from non-specific to highly targeted killing of tumor cells. In the past few decades, a number of inorganic materials have been investigated such as calcium phosphate, gold, carbon materials, silicon oxide, iron oxide, and layered double hydroxide (LDH) for examining their efficacy in targeting drug delivery. The reason behind the selection of these inorganic materials was their versatile and unique features efficient in drug delivery, such as wide availability, rich surface functionality, good biocompatibility, potential for target delivery, and controlled release of the drug from these inorganic nanomaterials. Although, the drug-LDH hybrids are found to be quite instrumental because of their application as advanced anti-cancer drug delivery systems, there has not been much research on them. This mini review is set to highlight the advancement made in the use of layered double hydroxides (LDHs) as anti-cancer drug delivery agents. Along with the advantages of LDHs as anti-cancer drug delivery agents, the process of interaction of some of the common anti-cancer drugs with LDH has also been discussed.

  15. Laboratory tests in the clinical risk management of potential drug-drug interactions: a cross-sectional study using drug-dispensing data from 100 Dutch community pharmacies.

    Science.gov (United States)

    Geerts, Arjen F J; De Koning, Fred H P; De Smet, Peter A G M; Van Solinge, Wouter W; Egberts, Toine C G

    2009-01-01

    Patient safety and the life cycle of a drug are negatively influenced by the still increasing occurrence of potential drug-drug interactions (DDIs). Clinical risk management of potential DDIs is required in patients using drugs to influence the benefit-risk profile positively. Information about laboratory test results, in particular, may be useful in the assessment of potential DDIs for the individual patient. The objective of this study was to examine the frequency and nature of laboratory tests required for the assessment of the clinical relevance of potential DDIs in Dutch community pharmacies. In addition, the nature and clinical relevance of these potential DDIs is analysed. All patients from 100 Dutch community pharmacies using, according to dispensing information, two or more drugs concomitantly on a specified date (Wednesday, 4 April 2007), were included (n = 223,019). The anonymous dispensing data of the included patients were analysed against a list of DDIs requiring laboratory tests for the assessment of their clinical relevance. The number of patients at risk for these potential DDIs with severe adverse reactions was calculated. The frequency of potential DDIs requiring laboratory tests were stratified by age, sex and degree of polypharmacy. Of the included patients, 24.4% had one or more potential DDIs (n = 54,427). In 9.0% of the included patients, one or more laboratory tests for the assessment of clinical relevance of the potential DDI were required (n = 19,968). The frequency of DDIs requiring laboratory tests increased with increasing age and number of drugs, but was not related to sex. The most commonly required laboratory tests were for renal function (42.2%), electrolytes (20.1%) and coagulation (13.1%). The percentage of patients at risk for potential DDIs requiring laboratory tests with adverse reaction category F (serious, irrecoverable disablement or death) was 2.5%; category E (increased risk of failure of life-saving therapy) was 0

  16. Potential High-Temperature Shape-Memory Alloys Identified in the Ti(Ni,Pt) System

    Science.gov (United States)

    Noebe, Ronald D.; Biles, Tiffany A.; Garg, Anita; Nathal, Michael V.

    2004-01-01

    "Shape memory" is a unique property of certain alloys that, when deformed (within certain strain limits) at low temperatures, will remember and recover to their original predeformed shape upon heating. It occurs when an alloy is deformed in the low-temperature martensitic phase and is then heated above its transformation temperature back to an austenitic state. As the material passes through this solid-state phase transformation on heating, it also recovers its original shape. This behavior is widely exploited, near room temperature, in commercially available NiTi alloys for connectors, couplings, valves, actuators, stents, and other medical and dental devices. In addition, there are limitless applications in the aerospace, automotive, chemical processing, and many other industries for materials that exhibit this type of shape-memory behavior at higher temperatures. But for high temperatures, there are currently no commercial shape-memory alloys. Although there are significant challenges to the development of high-temperature shape-memory alloys, at the NASA Glenn Research Center we have identified a series of alloy compositions in the Ti-Ni-Pt system that show great promise as potential high-temperature shape-memory materials.

  17. Multiplatform molecular profiling identifies potentially targetable biomarkers in malignant phyllodes tumors of the breast.

    Science.gov (United States)

    Gatalica, Zoran; Vranic, Semir; Ghazalpour, Anatole; Xiu, Joanne; Ocal, Idris Tolgay; McGill, John; Bender, Ryan P; Discianno, Erin; Schlum, Aaron; Sanati, Souzan; Palazzo, Juan; Reddy, Sandeep; Pockaj, Barbara

    2016-01-12

    Malignant phyllodes tumor is a rare breast malignancy with sarcomatous overgrowth and with limited effective treatment options for recurrent and metastatic cases. Recent clinical trials indicated a potential for anti-angiogenic, anti-EGFR and immunotherapeutic approaches for patients with sarcomas, which led us to investigate these and other targetable pathways in malignant phyllodes tumor of the breast. Thirty-six malignant phyllodes tumors (including 8 metastatic tumors with two cases having matched primary and metastatic tumors) were profiled using gene sequencing, gene copy number analysis, whole genome expression, and protein expression. Whole genome expression analysis demonstrated consistent over-expression of genes involved in angiogenesis including VEGFA, Angiopoietin-2, VCAM1, PDGFRA, and PTTG1. EGFR protein overexpression was observed in 26/27 (96%) of cases with amplification of the EGFR gene in 8/24 (33%) cases. Two EGFR mutations were identified including EGFRvIII and a presumed pathogenic V774M mutation, respectively. The most common pathogenic mutations included TP53 (50%) and PIK3CA (15%). Cases with matched primary and metastatic tumors harbored identical mutations in both sites (PIK3CA/KRAS and RB1 gene mutations, respectively). Tumor expression of PD-L1 immunoregulatory protein was observed in 3/22 (14%) of cases. Overexpression of molecular biomarkers of increased angiogenesis, EGFR and immune checkpoints provides novel targeted therapy options in malignant phyllodes tumors of the breast.

  18. A multicenter photoprovocation study to identify potential biomarkers by global peptide profiling in cutaneous lupus erythematosus.

    Science.gov (United States)

    Calderon, C; Zucht, H D; Kuhn, A; Wozniacka, A; Szepietowski, J C; Nyberg, F; Weichenthal, M; Piantone, A; Budde, P

    2015-11-01

    Cutaneous lupus erythematosus (CLE) is an inflammatory autoimmune skin disease in which abnormal photosensitivity is an important pathogenetic factor but is difficult to predict, creating a challenge in determining treatment efficacy. Although photosensitivity in CLE patients may change over time, photoprovocation testing with ultraviolet (UV) A and UVB irradiation can be a helpful tool to explore differences between responders and nonresponders during photoprovocation. To identify biomarkers that could substitute for the clinical endpoint lesion development, we performed a global peptidomics profiling analysis of CLE subjects in a controlled photoprovocation study. Plasma and skin biopsy samples were collected before and after UV-irradiation from 13 healthy volunteers and 47 CLE subjects. Twenty-two of the 47 CLE subjects developed skin lesions. The samples were analyzed using a label-free quantitative peptidomics workflow combined with univariate and multivariate statistical analyses. The primary finding was identification of a specific plasma peptide signature separating responders versus nonresponders at baseline. The peptide signature consisted of beta 2-microglobulin (B2MG), human beta-defensin-1, and peptides derived from CD99, polymeric immunoglobulin receptor, and immunoglobulin kappa light chains. In skin, elevated B2MG levels correlated with lesion formation. Our results show that the peptidome is a rich source of potential biomarkers for predicting photosensitivity in CLE.

  19. Analytical approaches to identify potential migrants in polyester-polyurethane can coatings.

    Science.gov (United States)

    Louise Bradley, Emma; Driffield, Malcolm; Guthrie, James; Harmer, Nick; Thomas Oldring, Peter Kenneth; Castle, Laurence

    2009-12-01

    The safety of a polyester-polyurethane can coating has been assessed using a suite of complementary analytical methods to identify and estimate the concentrations of potential chemical migrants. The polyester was based on phthalic acids and aliphatic diols. The polyisocyanate cross-linking agent was 1-isocyanato-3-isocyanatomethyl-3,5,5-trimethyl cyclohexane homopolymer (IPDI) blocked with methylethylketone oxime (MEKO) to make a one-part formulation. The overall migrate, obtained using solvent extraction of cured films, comprised almost completely of 12 cyclic and one linear polyester oligomer up to molecular weight 800 and containing up to six monomer units. These 13 oligomers covered a total of 28 isomeric forms. Other minor components detected were plasticisers and surfactants as well as impurities present in the starting materials. There was no detectable residue of either the blocked isocyanate (<0.01 microg/dm(2)) used as the starting substance or the unblocked isocyanate (<0.02 microg/dm(2)). The level of extractable IPDI was used as an indicator of the completeness of cure in experimental coatings. These studies revealed that there was an influence of time, temperature and catalyst content. Polymerisation was also influenced by the additives used and by the ageing of the wet coating formulation over several months. These studies allow parameters to be specified to ensure that commercial production coatings receive a full cure giving low migration characteristics.

  20. Use of a latency-based demand assessment to identify potential demands for functional analyses.

    Science.gov (United States)

    Call, Nathan A; Miller, Sarah J; Mintz, Joslyn Cynkus; Mevers, Joanna Lomas; Scheithauer, Mindy C; Eshelman, Julie E; Beavers, Gracie A

    2016-12-01

    Unlike potential tangible positive reinforcers, which are typically identified for inclusion in functional analyses empirically using preference assessments, demands are most often selected arbitrarily or based on caregiver report. The present study evaluated the use of a demand assessment with 12 participants who exhibited escape-maintained problem behavior. Participants were exposed to 10 demands, with aversiveness measured by average latency to the first instance of problem behavior. In subsequent functional analyses, results of a demand condition that included the demand with the shortest latency to problem behavior resulted in identification of an escape function for 11 of the participants. In contrast, a demand condition that included the demand with the longest latency resulted in identification of an escape function for only 5 participants. The implication of these findings is that for the remaining 7 participants, selection of the demand for the functional analysis without using the results of the demand assessment could have produced a false-negative finding. © 2016 Society for the Experimental Analysis of Behavior.

  1. Recursive Random Lasso (RRLasso) for Identifying Anti-Cancer Drug Targets.

    Science.gov (United States)

    Park, Heewon; Imoto, Seiya; Miyano, Satoru

    2015-01-01

    Uncovering driver genes is crucial for understanding heterogeneity in cancer. L1-type regularization approaches have been widely used for uncovering cancer driver genes based on genome-scale data. Although the existing methods have been widely applied in the field of bioinformatics, they possess several drawbacks: subset size limitations, erroneous estimation results, multicollinearity, and heavy time consumption. We introduce a novel statistical strategy, called a Recursive Random Lasso (RRLasso), for high dimensional genomic data analysis and investigation of driver genes. For time-effective analysis, we consider a recursive bootstrap procedure in line with the random lasso. Furthermore, we introduce a parametric statistical test for driver gene selection based on bootstrap regression modeling results. The proposed RRLasso is not only rapid but performs well for high dimensional genomic data analysis. Monte Carlo simulations and analysis of the "Sanger Genomics of Drug Sensitivity in Cancer dataset from the Cancer Genome Project" show that the proposed RRLasso is an effective tool for high dimensional genomic data analysis. The proposed methods provide reliable and biologically relevant results for cancer driver gene selection.

  2. Recursive Random Lasso (RRLasso for Identifying Anti-Cancer Drug Targets.

    Directory of Open Access Journals (Sweden)

    Heewon Park

    Full Text Available Uncovering driver genes is crucial for understanding heterogeneity in cancer. L1-type regularization approaches have been widely used for uncovering cancer driver genes based on genome-scale data. Although the existing methods have been widely applied in the field of bioinformatics, they possess several drawbacks: subset size limitations, erroneous estimation results, multicollinearity, and heavy time consumption. We introduce a novel statistical strategy, called a Recursive Random Lasso (RRLasso, for high dimensional genomic data analysis and investigation of driver genes. For time-effective analysis, we consider a recursive bootstrap procedure in line with the random lasso. Furthermore, we introduce a parametric statistical test for driver gene selection based on bootstrap regression modeling results. The proposed RRLasso is not only rapid but performs well for high dimensional genomic data analysis. Monte Carlo simulations and analysis of the "Sanger Genomics of Drug Sensitivity in Cancer dataset from the Cancer Genome Project" show that the proposed RRLasso is an effective tool for high dimensional genomic data analysis. The proposed methods provide reliable and biologically relevant results for cancer driver gene selection.

  3. Understanding how data triangulation identifies acute toxicity of novel psychoactive drugs.

    Science.gov (United States)

    Wood, D M; Dargan, P I

    2012-09-01

    Over the last decade, there has been an increase in the availability and use of novel psychoactive substances (also known as "legal highs"). There is limited information available on the potential acute toxicity (harms) associated with the use of these novel psychoactive substances. Gold standard evidence, such as animal studies or human clinical trials, is rarely available to users or healthcare professionals. However, it is possible to use triangulation of data on the acute toxicity from multiple sources to describe the overall pattern of toxicity associated with a novel psychoactive substance. In this review, we will describe these potential data sources, which include self-reported toxicity on internet discussion fora, data from sub-population user surveys, data from regional and national poisons information services and published case reports and case series. We will then describe how pattern of acute toxicity associated with the use of the cathinone mephedrone (4-methylmethcathinone) was established using triangulation of these different data sources.

  4. Identification of clinically significant drug-drug interactions in cardiac ...

    African Journals Online (AJOL)

    Purpose: To identify clinically significant potential drug-drug interactions in cardiac intensive care units of two tertiary care ... Keywords: Pharmacy service, Drug interactions, Critical/intensive care, Adverse outcomes. Tropical .... Standard error.

  5. Application of a drug-induced apoptosis assay to identify treatment strategies in recurrent or metastatic breast cancer.

    Directory of Open Access Journals (Sweden)

    Linda Bosserman

    Full Text Available A drug-induced apoptosis assay has been developed to determine which chemotherapy drugs or regimens can produce higher cell killing in vitro. This study was done to determine if this assay could be performed in patients with recurrent or metastatic breast cancer patients, to characterize the patterns of drug-induced apoptosis, and to evaluate the clinical utility of the assay. A secondary goal was to correlate assay use with clinical outcomes.In a prospective, non-blinded, multi institutional controlled trial, 30 evaluable patients with recurrent or metastatic breast cancer who were treated with chemotherapy had tumor samples submitted for the MiCK drug-induced apoptosis assay. After receiving results within 72 hours after biopsy, physicians could use the test to determine therapy (users, or elect to not use the test (non-users.The assay was able to characterize drug-induced apoptosis in tumor specimens from breast cancer patients and identified which drugs or combinations gave highest levels of apoptosis. Patterns of drug activity were also analyzed in triple negative breast cancer. Different drugs from a single class of agents often produced significantly different amounts of apoptosis. Physician frequently (73% used the assay to help select chemotherapy treatments in patients, Patients whose physicians were users had a higher response (CR+PR rate compared to non-users (38.1% vs 0%, p = 0.04 and a higher disease control (CR+PR+Stable rate (81% vs 25%, p<0.01. Time to relapse was longer in users 7.4 mo compared to non-users 2.2 mo (p<0.01.The MiCK assay can be performed in breast cancer specimens, and results are often used by physicians in breast cancer patients with recurrent or metastatic disease. These results from a good laboratory phase II study can be the basis for a future larger prospective multicenter study to more definitively establish the value of the assay.Clinicaltrials.gov NCT00901264.

  6. Application of a Drug-Induced Apoptosis Assay to Identify Treatment Strategies in Recurrent or Metastatic Breast Cancer

    Science.gov (United States)

    Bosserman, Linda; Rogers, Karl; Willis, Carl; Davidson, Dirk; Whitworth, Pat; Karimi, Misagh; Upadhyaya, Gargi; Rutledge, James; Hallquist, Allan; Perree, Mathieu; Presant, Cary A.

    2015-01-01

    Background A drug-induced apoptosis assay has been developed to determine which chemotherapy drugs or regimens can produce higher cell killing in vitro. This study was done to determine if this assay could be performed in patients with recurrent or metastatic breast cancer patients, to characterize the patterns of drug-induced apoptosis, and to evaluate the clinical utility of the assay. A secondary goal was to correlate assay use with clinical outcomes. Methods In a prospective, non-blinded, multi institutional controlled trial, 30 evaluable patients with recurrent or metastatic breast cancer who were treated with chemotherapy had tumor samples submitted for the MiCK drug-induced apoptosis assay. After receiving results within 72 hours after biopsy, physicians could use the test to determine therapy (users), or elect to not use the test (non-users). Results The assay was able to characterize drug-induced apoptosis in tumor specimens from breast cancer patients and identified which drugs or combinations gave highest levels of apoptosis. Patterns of drug activity were also analyzed in triple negative breast cancer. Different drugs from a single class of agents often produced significantly different amounts of apoptosis. Physician frequently (73%) used the assay to help select chemotherapy treatments in patients, Patients whose physicians were users had a higher response (CR+PR) rate compared to non-users (38.1% vs 0%, p = 0.04) and a higher disease control (CR+PR+Stable) rate (81% vs 25%, p<0.01). Time to relapse was longer in users 7.4 mo compared to non-users 2.2 mo (p<0.01). Conclusions The MiCK assay can be performed in breast cancer specimens, and results are often used by physicians in breast cancer patients with recurrent or metastatic disease. These results from a good laboratory phase II study can be the basis for a future larger prospective multicenter study to more definitively establish the value of the assay. Trial Registration Clinicaltrials.gov NCT

  7. Oral administration of drugs with hypersensitivity potential induces germinal center hyperplasia in secondary lymphoid organ/tissue in Brown Norway rats, and this histological lesion is a promising candidate as a predictive biomarker for drug hypersensitivity occurrence in humans.

    Science.gov (United States)

    Tamura, Akitoshi; Miyawaki, Izuru; Yamada, Toru; Kimura, Juki; Funabashi, Hitoshi

    2013-08-15

    It is important to evaluate the potential of drug hypersensitivity as well as other adverse effects during the preclinical stage of the drug development process, but validated methods are not available yet. In the present study we examined whether it would be possible to develop a new predictive model of drug hypersensitivity using Brown Norway (BN) rats. As representative drugs with hypersensitivity potential in humans, phenytoin (PHT), carbamazepine (CBZ), amoxicillin (AMX), and sulfamethoxazole (SMX) were orally administered to BN rats for 28days to investigate their effects on these animals by examinations including observation of clinical signs, hematology, determination of serum IgE levels, histology, and flow cytometric analysis. Skin rashes were not observed in any animals treated with these drugs. Increases in the number of circulating inflammatory cells and serum IgE level did not necessarily occur in the animals treated with these drugs. However, histological examination revealed that germinal center hyperplasia was commonly induced in secondary lymphoid organs/tissues in the animals treated with these drugs. In cytometric analysis, changes in proportions of lymphocyte subsets were noted in the spleen of the animals treated with PHT or CBZ during the early period of administration. The results indicated that the potential of drug hypersensitivity was identified in BN rat by performing histological examination of secondary lymphoid organs/tissues. Data obtained herein suggested that drugs with hypersensitivity potential in humans gained immune reactivity in BN rat, and the germinal center hyperplasia induced by administration of these drugs may serve as a predictive biomarker for drug hypersensitivity occurrence.

  8. A genome-wide association study identifies potential susceptibility loci for Hirschsprung disease.

    Directory of Open Access Journals (Sweden)

    Jeong-Hyun Kim

    Full Text Available Hirschsprung disease (HSCR is a congenital and heterogeneous disorder characterized by the absence of intramural nervous plexuses along variable lengths of the hindgut. Although RET is a well-established risk factor, a recent genome-wide association study (GWAS of HSCR has identified NRG1 as an additional susceptibility locus. To discover additional risk loci, we performed a GWAS of 123 sporadic HSCR patients and 432 unaffected controls using a large-scale platform with coverage of over 1 million polymorphic markers. The result was that our study replicated the findings of RET-CSGALNACT2-RASGEF1A genomic region (rawP = 5.69×10(-19 before a Bonferroni correction; corrP = 4.31×10(-13 after a Bonferroni correction and NRG1 as susceptibility loci. In addition, this study identified SLC6A20 (adjP = 2.71×10(-6, RORA (adjP = 1.26×10(-5, and ABCC9 (adjP = 1.86×10(-5 as new potential susceptibility loci under adjusting the already known loci on the RET-CSGALNACT2-RASGEF1A and NRG1 regions, although none of the SNPs in these genes passed the Bonferroni correction. In further subgroup analysis, the RET-CSGALNACT2-RASGEF1A genomic region was observed to have different significance levels among subgroups: short-segment (S-HSCR, corrP = 1.71×10(-5, long-segment (L-HSCR, corrP = 6.66×10(-4, and total colonic aganglionosis (TCA, corrP>0.05. This differential pattern in the significance level suggests that other genomic loci or mechanisms may affect the length of aganglionosis in HSCR subgroups during enteric nervous system (ENS development. Although functional evaluations are needed, our findings might facilitate improved understanding of the mechanisms of HSCR pathogenesis.

  9. Efficient Data Mining Algorithms for Screening Potential Proteins of Drug Target

    Directory of Open Access Journals (Sweden)

    Qi Wang

    2017-01-01

    Full Text Available The past few decades have witnessed the boom in pharmacology as well as the dilemma of drug development. Playing a crucial role in drug design, the screening of potential human proteins of drug targets from open access database with well-measured physical and chemical properties is a task of challenge but significance. In this paper, the screening of potential drug target proteins (DTPs from a fine collected dataset containing 5376 unlabeled proteins and 517 known DTPs was researched. Our objective is to screen potential DTPs from the 5376 proteins. Here we proposed two strategies assisting the construction of dataset of reliable nondrug target proteins (NDTPs and then bagging of decision trees method was employed in the final prediction. Such two-stage algorithms have shown their effectiveness and superior performance on the testing set. Both of the algorithms maintained higher recall ratios of DTPs, respectively, 93.5% and 97.4%. In one turn of experiments, strategy1-based bagging of decision trees algorithm screened about 558 possible DTPs while 1782 potential DTPs were predicted in the second algorithm. Besides, two strategy-based algorithms showed the consensus of the predictions in the results, with approximately 442 potential DTPs in common. These selected DTPs provide reliable choices for further verification based on biomedical experiments.

  10. Profound activity of the anti-cancer drug bortezomib against Echinococcus multilocularis metacestodes identifies the proteasome as a novel drug target for cestodes.

    Directory of Open Access Journals (Sweden)

    Britta Stadelmann

    2014-12-01

    Full Text Available A library of 426 FDA-approved drugs was screened for in vitro activity against E. multilocularis metacestodes employing the phosphoglucose isomerase (PGI assay. Initial screening at 20 µM revealed that 7 drugs induced considerable metacestode damage, and further dose-response studies revealed that bortezomib (BTZ, a proteasome inhibitor developed for the chemotherapy of myeloma, displayed high anti-metacestodal activity with an EC50 of 0.6 µM. BTZ treatment of E. multilocularis metacestodes led to an accumulation of ubiquinated proteins and unequivocally parasite death. In-gel zymography assays using E. multilocularis extracts demonstrated BTZ-mediated inhibition of protease activity in a band of approximately 23 kDa, the same size at which the proteasome subunit beta 5 of E. multilocularis could be detected by Western blot. Balb/c mice experimentally infected with E. multilocularis metacestodes were used to assess BTZ treatment, starting at 6 weeks post-infection by intraperitoneal injection of BTZ. This treatment led to reduced parasite weight, but to a degree that was not statistically significant, and it induced adverse effects such as diarrhea and neurological symptoms. In conclusion, the proteasome was identified as a drug target in E. multilocularis metacestodes that can be efficiently inhibited by BTZ in vitro. However, translation of these findings into in vivo efficacy requires further adjustments of treatment regimens using BTZ, or possibly other proteasome inhibitors.

  11. Profound activity of the anti-cancer drug bortezomib against Echinococcus multilocularis metacestodes identifies the proteasome as a novel drug target for cestodes.

    Science.gov (United States)

    Stadelmann, Britta; Aeschbacher, Denise; Huber, Cristina; Spiliotis, Markus; Müller, Joachim; Hemphill, Andrew

    2014-12-01

    A library of 426 FDA-approved drugs was screened for in vitro activity against E. multilocularis metacestodes employing the phosphoglucose isomerase (PGI) assay. Initial screening at 20 µM revealed that 7 drugs induced considerable metacestode damage, and further dose-response studies revealed that bortezomib (BTZ), a proteasome inhibitor developed for the chemotherapy of myeloma, displayed high anti-metacestodal activity with an EC50 of 0.6 µM. BTZ treatment of E. multilocularis metacestodes led to an accumulation of ubiquinated proteins and unequivocally parasite death. In-gel zymography assays using E. multilocularis extracts demonstrated BTZ-mediated inhibition of protease activity in a band of approximately 23 kDa, the same size at which the proteasome subunit beta 5 of E. multilocularis could be detected by Western blot. Balb/c mice experimentally infected with E. multilocularis metacestodes were used to assess BTZ treatment, starting at 6 weeks post-infection by intraperitoneal injection of BTZ. This treatment led to reduced parasite weight, but to a degree that was not statistically significant, and it induced adverse effects such as diarrhea and neurological symptoms. In conclusion, the proteasome was identified as a drug target in E. multilocularis metacestodes that can be efficiently inhibited by BTZ in vitro. However, translation of these findings into in vivo efficacy requires further adjustments of treatment regimens using BTZ, or possibly other proteasome inhibitors.

  12. Crystal Structure of an Integron Gene Cassette-Associated Protein from Vibrio cholerae Identifies a Cationic Drug-Binding Module

    Energy Technology Data Exchange (ETDEWEB)

    Deshpande, Chandrika N.; Harrop, Stephen J.; Boucher, Yan; Hassan, Karl A.; Di Leo, Rosa; Xu, Xiaohui; Cui, Hong; Savchenko, Alexei; Chang, Changsoo; Labbate, Maurizio; Paulsen, Ian T.; Stokes, H.W.; Curmi, Paul M.G.; Mabbutt, Bridget C. (MIT); (UT-Australia); (Macquarie); (Toronto); (New South)

    2012-02-15

    The direct isolation of integron gene cassettes from cultivated and environmental microbial sources allows an assessment of the impact of the integron/gene cassette system on the emergence of new phenotypes, such as drug resistance or virulence. A structural approach is being exploited to investigate the modularity and function of novel integron gene cassettes. We report the 1.8 {angstrom} crystal structure of Cass2, an integron-associated protein derived from an environmental V. cholerae. The structure defines a monomeric beta-barrel protein with a fold related to the effector-binding portion of AraC/XylS transcription activators. The closest homologs of Cass2 are multi-drug binding proteins, such as BmrR. Consistent with this, a binding pocket made up of hydrophobic residues and a single glutamate side chain is evident in Cass2, occupied in the crystal form by polyethylene glycol. Fluorescence assays demonstrate that Cass2 is capable of binding cationic drug compounds with submicromolar affinity. The Cass2 module possesses a protein interaction surface proximal to its drug-binding cavity with features homologous to those seen in multi-domain transcriptional regulators. Genetic analysis identifies Cass2 to be representative of a larger family of independent effector-binding proteins associated with lateral gene transfer within Vibrio and closely-related species. We propose that the Cass2 family not only has capacity to form functional transcription regulator complexes, but represents possible evolutionary precursors to multi-domain regulators associated with cationic drug compounds.

  13. Crystal structure of an integron gene cassette-associated protein from Vibrio cholerae identifies a cationic drug-binding module.

    Directory of Open Access Journals (Sweden)

    Chandrika N Deshpande

    Full Text Available The direct isolation of integron gene cassettes from cultivated and environmental microbial sources allows an assessment of the impact of the integron/gene cassette system on the emergence of new phenotypes, such as drug resistance or virulence. A structural approach is being exploited to investigate the modularity and function of novel integron gene cassettes.We report the 1.8 Å crystal structure of Cass2, an integron-associated protein derived from an environmental V. cholerae. The structure defines a monomeric beta-barrel protein with a fold related to the effector-binding portion of AraC/XylS transcription activators. The closest homologs of Cass2 are multi-drug binding proteins, such as BmrR. Consistent with this, a binding pocket made up of hydrophobic residues and a single glutamate side chain is evident in Cass2, occupied in the crystal form by polyethylene glycol. Fluorescence assays demonstrate that Cass2 is capable of binding cationic drug compounds with submicromolar affinity. The Cass2 module possesses a protein interaction surface proximal to its drug-binding cavity with features homologous to those seen in multi-domain transcriptional regulators.Genetic analysis identifies Cass2 to be representative of a larger family of independent effector-binding proteins associated with lateral gene transfer within Vibrio and closely-related species. We propose that the Cass2 family not only has capacity to form functional transcription regulator complexes, but represents possible evolutionary precursors to multi-domain regulators associated with cationic drug compounds.

  14. Potential Broad Spectrum Inhibitors of the Coronavirus 3CLpro: A Virtual Screening and Structure-Based Drug Design Study.

    Science.gov (United States)

    Berry, Michael; Fielding, Burtram C; Gamieldien, Junaid

    2015-12-15

    Human coronaviruses represent a significant disease burden; however, there is currently no antiviral strategy to combat infection. The outbreak of severe acute respiratory syndrome (SARS) in 2003 and Middle East respiratory syndrome (MERS) less than 10 years later demonstrates the potential of coronaviruses to cross species boundaries and further highlights the importance of identifying novel lead compounds with broad spectrum activity. The coronavirus 3CL(pro) provides a highly validated drug target and as there is a high degree of sequence homology and conservation in main chain architecture the design of broad spectrum inhibitors is viable. The ZINC drugs-now library was screened in a consensus high-throughput pharmacophore modeling and molecular docking approach by Vina, Glide, GOLD and MM-GBSA. Molecular dynamics further confirmed results obtained from structure-based techniques. A highly defined hit-list of 19 compounds was identified by the structure-based drug design methodologies. As these compounds were extensively validated by a consensus approach and by molecular dynamics, the likelihood that at least one of these compounds is bioactive is excellent. Additionally, the compounds segregate into 15 significantly dissimilar (p < 0.05) clusters based on shape and features, which represent valuable scaffolds that can be used as a basis for future anti-coronaviral inhibitor discovery experiments. Importantly though, the enriched subset of 19 compounds identified from the larger library has to be validated experimentally.

  15. Potential biomarkers of fatigue identified by plasma metabolome analysis in rats.

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    Satoshi Kume

    Full Text Available In the present study, prior to the establishment of a method for the clinical diagnosis of chronic fatigue in humans, we validated the utility of plasma metabolomic analysis in a rat model of fatigue using capillary electrophoresis-mass spectrometry (CE-MS. In order to obtain a fatigued animal group, rats were placed in a cage filled with water to a height of 2.2 cm for 5 days. A food-restricted group, in which rats were limited to 10 g/d of food (around 50% of the control group, was also assessed. The food-restricted group exhibited weight reduction similar to that of the fatigued group. CE-MS measurements were performed to evaluate the profile of food intake-dependent metabolic changes, as well as the profile in fatigue loading, resulting in the identification of 48 metabolites in plasma. Multivariate analyses using hierarchical clustering and principal component analysis revealed that the plasma metabolome in the fatigued group showed clear differences from those in the control and food-restricted groups. In the fatigued group, we found distinctive changes in metabolites related to branched-chain amino acid metabolism, urea cycle, and proline metabolism. Specifically, the fatigued group exhibited significant increases in valine, leucine, isoleucine, and 2-oxoisopentanoate, and significant decreases in citrulline and hydroxyproline compared with the control and food-restricted groups. Plasma levels of total nitric oxide were increased in the fatigued group, indicating systemic oxidative stress. Further, plasma metabolites involved in the citrate cycle, such as cis-aconitate and isocitrate, were reduced in the fatigued group. The levels of ATP were significantly decreased in the liver and skeletal muscle, indicative of a deterioration in energy metabolism in these organs. Thus, this comprehensive metabolic analysis furthered our understanding of the pathophysiology of fatigue, and identified potential diagnostic biomarkers based on fatigue

  16. Potential biomarkers of fatigue identified by plasma metabolome analysis in rats.

    Science.gov (United States)

    Kume, Satoshi; Yamato, Masanori; Tamura, Yasuhisa; Jin, Guanghua; Nakano, Masayuki; Miyashige, Yukiharu; Eguchi, Asami; Ogata, Yoshiyuki; Goda, Nobuhito; Iwai, Kazuhiro; Yamano, Emi; Watanabe, Yasuyoshi; Soga, Tomoyoshi; Kataoka, Yosky

    2015-01-01

    In the present study, prior to the establishment of a method for the clinical diagnosis of chronic fatigue in humans, we validated the utility of plasma metabolomic analysis in a rat model of fatigue using capillary electrophoresis-mass spectrometry (CE-MS). In order to obtain a fatigued animal group, rats were placed in a cage filled with water to a height of 2.2 cm for 5 days. A food-restricted group, in which rats were limited to 10 g/d of food (around 50% of the control group), was also assessed. The food-restricted group exhibited weight reduction similar to that of the fatigued group. CE-MS measurements were performed to evaluate the profile of food intake-dependent metabolic changes, as well as the profile in fatigue loading, resulting in the identification of 48 metabolites in plasma. Multivariate analyses using hierarchical clustering and principal component analysis revealed that the plasma metabolome in the fatigued group showed clear differences from those in the control and food-restricted groups. In the fatigued group, we found distinctive changes in metabolites related to branched-chain amino acid metabolism, urea cycle, and proline metabolism. Specifically, the fatigued group exhibited significant increases in valine, leucine, isoleucine, and 2-oxoisopentanoate, and significant decreases in citrulline and hydroxyproline compared with the control and food-restricted groups. Plasma levels of total nitric oxide were increased in the fatigued group, indicating systemic oxidative stress. Further, plasma metabolites involved in the citrate cycle, such as cis-aconitate and isocitrate, were reduced in the fatigued group. The levels of ATP were significantly decreased in the liver and skeletal muscle, indicative of a deterioration in energy metabolism in these organs. Thus, this comprehensive metabolic analysis furthered our understanding of the pathophysiology of fatigue, and identified potential diagnostic biomarkers based on fatigue pathophysiology.

  17. Identifying and reducing potentially wrong immunoassay results even when plausible and "not-unreasonable".

    Science.gov (United States)

    Ismail, Adel A A

    2014-01-01

    The primary role of the clinical laboratory is to report accurate results for diagnosis of disease and management of illnesses. This goal has, to a large extent been achieved for routine biochemical tests, but not for immunoassays which remained susceptible to interference from endogenous immunoglobulin antibodies, causing false, and clinically misleading results. Clinicians regard all abnormal results including false ones as "pathological" necessitating further investigations, or concluding iniquitous diagnosis. Even more seriously, "false-negative" results may wrongly exclude pathology, thus denying patients' necessary treatment. Analytical error rate in immunoassays is relatively high, ranging from 0.4% to 4.0%. Because analytical interference from endogenous antibodies is confined to individuals' sera, it can be inconspicuous, pernicious, sporadic, and insidious because it cannot be detected by internal or external quality assessment procedures. An approach based on Bayesian reasoning can enhance the robustness of clinical validation in highlighting potentially erroneous immunoassay results. When this rational clinical/statistical approach is followed by analytical affirmative follow-up tests, it can help identifying inaccurate and clinically misleading immunoassay data even when they appear plausible and "not-unreasonable." This chapter is largely based on peer reviewed articles associated with and related to this approach. The first section underlines (without mathematical equations) the dominance and misuse of conventional statistics and the underuse of Bayesian paradigm and shows that laboratorians are intuitively (albeit unwittingly) practicing Bayesians. Secondly, because interference from endogenous antibodies is method's dependent (with numerous formats and different reagents), it is almost impossible to accurately assess its incidence in all differently formulated immunoassays and for each analytes/biomarkers. However, reiterating the basic concepts

  18. Clinical relevancy and risks of potential drug–drug interactions in intensive therapy

    Science.gov (United States)

    Rodrigues, Aline Teotonio; Stahlschmidt, Rebeca; Granja, Silvia; Falcão, Antonio Luis Eiras; Moriel, Patricia; Mazzola, Priscila Gava

    2014-01-01

    Purpose Evaluate the potential Drug–Drug Interactions (pDDI) found in prescription orders of adult Intensive Care Unit (ICU) of a Brazilian public health system hospital; quantify and qualify the pDDI regarding their severity and risks to the critical patient, using the database from Micromedex®. Methods Prospective study (January–December of 2011) collecting and evaluating 369 prescription orders (convenient sampling), one per patient. Results During the study 1844 pDDIs were identified and distributed in 405 pairs (medication A × medication B combination). There was an average of 5.00 ± 5.06 pDDIs per prescription order, the most prevalent being moderate and important interactions, present in 74% and 67% of prescription orders, respectively. In total, there were 9 contraindicated, 129 important and 204 moderate pDDIs. Among them 52 had as management recommendation to “avoid concomitant use” or “suspension of medication”, while 306 had as recommendation “continuous and adequate monitoring”. Conclusion The high number of pDDIs found in the study combined with the evaluation of the clinical relevancy of the most frequent pDDIs in the ICU shows that moderate and important interactions are highly incident. As the majority of them demand monitoring and adequate management, being aware of these interactions is major information for the safe and individualized risk management. PMID:27134536

  19. Drug design with Cdc7 kinase: a potential novel cancer therapy target

    Directory of Open Access Journals (Sweden)

    Masaaki Sawa

    2008-11-01

    Full Text Available Masaaki Sawa1, Hisao Masai21Carna Biosciences, Inc., Kobe, Japan; 2Genome Dynamics Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, JapanAbstract: Identification of novel molecular targets is critical in development of new and efficient cancer therapies. Kinases are one of the most common drug targets with a potential for cancer therapy. Cell cycle progression is regulated by a number of kinases, some of which are being developed to treat cancer. Cdc7 is a serine-threonine kinase originally discovered in budding yeast, which has been shown to be necessary to initiate the S phase. Inhibition of Cdc7 in cancer cells retards the progression of the S phase, accumulates DNA damage, and induces p53-independent cell death, but the same treatment in normal cells does not significantly affect viability. Low-molecular-weight compounds that inhibit Cdc7 kinase with an IC50 of less than 10 nM have been identified, and shown to be effective in the inhibition of tumor growth in animal models. Thus Cdc7 kinase can be recognized as a novel molecular target for cancer therapy.Keywords: Cdc7 kinase, cell cycle, replication fork, genome stability, DNA damages, ATP-binding pocket, kinase inhibitor

  20. Inorganically modified diatomite as a potential prolonged-release drug carrier.

    Science.gov (United States)

    Janićijević, Jelena; Krajišnik, Danina; Calija, Bojan; Dobričić, Vladimir; Daković, Aleksandra; Krstić, Jugoslav; Marković, Marija; Milić, Jela

    2014-09-01

    Inorganic modification of diatomite was performed with the precipitation product of partially neutralized aluminum sulfate solution at three different mass ratios. The starting and the modified diatomites were characterized by SEM-EDS, FTIR, thermal analysis and zeta potential measurements and evaluated for drug loading capacity in adsorption batch experiments using diclofenac sodium (DS) as a model drug. In vitro drug release studies were performed in phosphate buffer pH6.8 from comprimates containing: the drug adsorbed onto the selected modified diatomite sample (DAMD), physical mixture of the drug with the selected modified diatomite sample (PMDMD) and physical mixture of the drug with the starting diatomite (PMDD). In vivo acute toxicity testing of the modified diatomite samples was performed on mice. High adsorbent loading of the selected modified diatomite sample (~250mg/g in 2h) enabled the preparation of comprimates containing adsorbed DS in the amount near to its therapeutic dose. Drug release studies demonstrated prolonged release of DS over a period of 8h from both DAMD comprimates (18% after 8h) and PMDMD comprimates (45% after 8h). The release kinetics for DAMD and PMDMD comprimates fitted well with Korsmeyer-Peppas and Bhaskar models, indicating that the release mechanism was a combination of non-Fickian diffusion and ion exchange process. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Medicinal plant reported with adverse reactions in Cuba: potential interactions with conventional drugs

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    Ioanna Martínez

    2015-04-01

    Full Text Available Context: Herbal drugs are a mixture of active compounds and the chemical complexity of each formulation increase with the possibility of interactions between them and conventional drugs. Many mechanisms are implicated in the interactions; scientific community has dedicated the attentions to enzymes as P-gp and CYP450. Aims: To investigate in the literature the principal plants with suspicions of adverse reactions in Cuba and their potential interactions with conventional drugs. Methods: PubMed was the database used as source of information until February 2014. Key words: Herb-Drug, Drug-Plant, Herbal–Drug, Interactions with scientific names of plants was used. Information was structured and analysed with EndNote X4. Analysis and integration of the information: Allium sativum L. (garlic was the plant with the high number of studies related with CYP450 and P-gp. Plants with great demand as Morinda citrifolia L. (noni, Psidium guajava L. (guayaba, Zingiber officinale Roscoe (ginger and Eucalyptus spp. (eucalyptus have a very small number of studies. The professionals of the health should keep in mind the possibility of interactions between herbal products and conventional drugs to increase the effectiveness of phytotherapy. Conclusions: It is necessary enhance reports and investigations and to put to disposition of the system of health information on the interactions of plants and to stimulate the investigation that offers information for the rational use of our medicinal plants.

  2. Caulerpin as a potential antiviral drug against herpes simplex virus type 1

    Directory of Open Access Journals (Sweden)

    Nathália Regina Porto Vieira Macedo

    2012-08-01

    Full Text Available About 80% of the human adult population is infected with HSV-1. Although there are many anti-HSV-1 drugs available (acyclovir, ganciclovir, valaciclovir, foscarnet, their continuous use promotes the selection of resistant strains, mainly in ACV patients. In addition to resistance, the drugs also have toxicity, particularly when administration is prolonged. The study of new molecules isolated from green algae with potential antiviral activity represents a good opportunity for the development of antiviral drugs. Caulerpin, the major product from the marine algae Caulerpa Lamouroux (Caulerpales, is known for its biological activities such as antioxidant, antifungal, acetylcholinesterase inhibitor (AChE and antibacterial activity. In this work, we show that caulerpin could be an alternative to acyclovir as an anti-HSV-1 drug that inhibits the alpha and beta phases of the replication cycle.

  3. Antiepileptic drugs: are women aware of interactions with oral contraceptives and potential teratogenicity?

    Science.gov (United States)

    Pack, Alison M; Davis, Anne R; Kritzer, Jordana; Yoon, Ava; Camus, Adela

    2009-04-01

    Women with epilepsy (WWE)'s knowledge of the interaction between antiepileptic drugs (AEDs) and oral contraceptives (OCs) and the potential teratogenicity of AEDs has received limited study. We conducted a cross-sectional questionnaire study (English or Spanish) among young WWE (18-44 years) to assess demographic characteristics, current AED use, and knowledge of AED interactions with OCs and teratogenicity. We used the Food and Drug Administration's classification system to categorize each AED's teratogenic potential. Participants (n=148) had a mean age of 32 years (SD 8); 32% spoke Spanish and described themselves as Hispanic. Among women prescribed a cytochrome p450-inducing AED, 65% were unaware of decreased OC efficacy. Forty percent of those prescribed Category D AEDs were unaware of potential teratogenic effects. WWE have limited knowledge of the potential interaction between AEDs and OCs and the teratogenic effects of AEDs. Educational efforts should highlight the reproductive health effects of AEDs in WWE.

  4. Potential of marine natural products against drug-resistant fungal, viral, and parasitic infections.

    Science.gov (United States)

    Abdelmohsen, Usama Ramadan; Balasubramanian, Srikkanth; Oelschlaeger, Tobias A; Grkovic, Tanja; Pham, Ngoc B; Quinn, Ronald J; Hentschel, Ute

    2017-02-01

    Antibiotics have revolutionised medicine in many aspects, and their discovery is considered a turning point in human history. However, the most serious consequence of the use of antibiotics is the concomitant development of resistance against them. The marine environment has proven to be a very rich source of diverse natural products with significant antibacterial, antifungal, antiviral, antiparasitic, antitumour, anti-inflammatory, antioxidant, and immunomodulatory activities. Many marine natural products (MNPs)-for example, neoechinulin B-have been found to be promising drug candidates to alleviate the mortality and morbidity rates caused by drug-resistant infections, and several MNP-based anti-infectives have already entered phase 1, 2, and 3 clinical trials, with six approved for usage by the US Food and Drug Administration and one by the EU. In this Review, we discuss the diversity of marine natural products that have shown in-vivo efficacy or in-vitro potential against drug-resistant infections of fungal, viral, and parasitic origin, and describe their mechanism of action. We highlight the drug-like physicochemical properties of the reported natural products that have bioactivity against drug-resistant pathogens in order to assess their drug potential. Difficulty in isolation and purification procedures, toxicity associated with the active compound, ecological impacts on natural environment, and insufficient investments by pharmaceutical companies are some of the clear reasons behind market failures and a poor pipeline of MNPs available to date. However, the diverse abundance of natural products in the marine environment could serve as a ray of light for the therapy of drug-resistant infections. Development of resistance-resistant antibiotics could be achieved via the coordinated networking of clinicians, microbiologists, natural product chemists, and pharmacologists together with pharmaceutical venture capitalist companies. Copyright © 2017 Elsevier Ltd

  5. Structure-Guided Lead Optimization of Triazolopyrimidine-Ring Substituents Identifies Potent Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors with Clinical Candidate Potential

    Energy Technology Data Exchange (ETDEWEB)

    Coteron, Jose M.; Marco, Maria; Esquivias, Jorge; Deng, Xiaoyi; White, Karen L.; White, John; Koltun, Maria; El Mazouni, Farah; Kokkonda, Sreekanth; Katneni, Kasiram; Bhamidipati, Ravi; Shackleford, David M.; Angulo-Barturen, Inigo; Ferrer, Santiago B.; Jimenez-Diaz, Maria Belen; Gamo, Francisco-Javier; Goldsmith, Elizabeth J.; Charman, William N.; Bathurst, Ian; Floyd, David; Matthews, David; Burrows, Jeremy N.; Rathod, Pradipsinh K.; Charman, Susan A.; Phillips, Margaret A. (UWASH); (MMV, Switzerland); (GSK); (Monash); (UW); (UTSMC)

    2012-02-27

    Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure of PfDHODH was used to inform the medicinal chemistry program allowing the identification of a potent and selective inhibitor (DSM265) that acts through DHODH inhibition to kill both sensitive and drug resistant strains of the parasite. This compound has similar potency to chloroquine in the humanized SCID mouse P. falciparum model, can be synthesized by a simple route, and rodent pharmacokinetic studies demonstrated it has excellent oral bioavailability, a long half-life and low clearance. These studies have identified the first candidate in the triazolopyrimidine series to meet previously established progression criteria for efficacy and ADME properties, justifying further development of this compound toward clinical candidate status.

  6. Herbal medicines in Brazil: pharmacokinetic profile and potential herb-drug interactions.

    Science.gov (United States)

    Mazzari, Andre L D A; Prieto, Jose M

    2014-01-01

    A plethora of active compounds found in herbal medicines can serve as substrate for enzymes involved in the metabolism of xenobiotics. When a medicinal plant is co-administered with a conventional drug and little or no information is known about the pharmacokinetics of the plant metabolites, there is an increased risk of potential herb-drug interactions. Moreover, genetic polymorphisms in a population may act to predispose individuals to adverse reactions. The use of herbal medicines is rapidly increasing in many countries, particularly Brazil where the vast biodiversity is a potential source of new and more affordable treatments for numerous conditions. Accordingly, the Brazilian Unified Public Health System (SUS) produced a list of 71 plant species of interest, which could be made available to the population in the near future. Physicians at SUS prescribe a number of essential drugs and should herbal medicines be added to this system the chance of herb-drug interactions further increases. A review of the effects of these medicinal plants on Phase 1 and Phase 2 metabolic mechanisms and the transporter P-glycoprotein was conducted. The results have shown that approximately half of these medicinal plants lack any pharmacokinetic data. Moreover, most of the studies carried out are in vitro. Only a few reports on herb-drug interactions with essential drugs prescribed by SUS were found, suggesting that very little attention is being given to the safety of herbal medicines. Here we have taken this information to discuss the potential interactions between herbal medicines and essential drugs prescribed to Brazilian patients whilst taking into account the most common polymorphisms present in the Brazilian population. A number of theoretical interactions are pinpointed but more pharmacokinetic studies and pharmacovigilance data are needed to ascertain their clinical significance.

  7. Transient receptor potential (TRP) channels as drug targets for diseases of the digestive system.

    Science.gov (United States)

    Holzer, Peter

    2011-07-01

    Approximately 20 of the 30 mammalian transient receptor potential (TRP) channel subunits are expressed by specific neurons and cells within the alimentary canal. They subserve important roles in taste, chemesthesis, mechanosensation, pain and hyperalgesia and contribute to the regulation of gastrointestinal motility, absorptive and secretory processes, blood flow, and mucosal homeostasis. In a cellular perspective, TRP channels operate either as primary detectors of chemical and physical stimuli, as secondary transducers of ionotropic or metabotropic receptors, or as ion transport channels. The polymodal sensory function of TRPA1, TRPM5, TRPM8, TRPP2, TRPV1, TRPV3 and TRPV4 enables the digestive system to survey its physical and chemical environment, which is relevant to all processes of digestion. TRPV5 and TRPV6 as well as TRPM6 and TRPM7 contribute to the absorption of Ca²⁺ and Mg²⁺, respectively. TRPM7 participates in intestinal pacemaker activity, and TRPC4 transduces muscarinic acetylcholine receptor activation to smooth muscle contraction. Changes in TRP channel expression or function are associated with a variety of diseases/disorders of the digestive system, notably gastro-esophageal reflux disease, inflammatory bowel disease, pain and hyperalgesia in heartburn, functional dyspepsia and irritable bowel syndrome, cholera, hypomagnesemia with secondary hypocalcemia, infantile hypertrophic pyloric stenosis, esophageal, gastrointestinal and pancreatic cancer, and polycystic liver disease. These implications identify TRP channels as promising drug targets for the management of a number of gastrointestinal pathologies. As a result, major efforts are put into the development of selective TRP channel agonists and antagonists and the assessment of their therapeutic potential.

  8. Microbial P450 enzymes in bioremediation and drug discovery: Emerging potentials and challenges.

    Science.gov (United States)

    Bhattacharya, Sukanta S; Yadav, Jagjit S

    2016-11-21

    Cytochrome P450 enzymes are a structurally conserved but functionally diverse group of heme-containing mixed function oxidases found across both prokaryotic and eukaryotic forms of the microbial world. Microbial P450s are known to perform diverse functions ranging from the synthesis of cell wall components to xenobiotic/drug metabolism to biodegradation of environmental chemicals. Conventionally, many microbial systems have been reported to mimic mammalian P450-like activation of drugs and were proposed as the in-vitro models of mammalian drug metabolism. Recent reports suggest that native or engineered forms of specific microbial P450s from these and other microbial systems could be employed for desired specific biotransformation reactions toward natural and synthetic (drug) compounds underscoring their emerging potential in drug improvement and discovery. On the other hand, microorganisms particularly fungi and actinomycetes have been shown to possess catabolic P450s with unusual potential to degrade toxic environmental chemicals including persistent organic pollutants (POPs). Wood-rotting basidiomycete fungi in particular have revealed the presence of exceptionally large P450 repertoire (P450ome) in their genomes, majority of which are however orphan (with no known function). Our pre- and post-genomic studies have led to functional characterization of several fungal P450s inducible in response to exposure to several environmental toxicants and their potential in bioremediation of these chemicals. This review is an attempt to summarize the post-genomic unveiling of this versatile enzyme superfamily in microbial systems and investigation of their potential to synthesize new drugs and degrade persistent pollutants, among other biotechnological applications.

  9. [Potential antimicrobial drug interactions in clinical practice: consequences of polypharmacy and multidrug resistance].

    Science.gov (United States)

    Martínez-Múgica, Cristina

    2015-12-01

    Polypharmacy is a growing problem nowadays, which can increase the risk of potential drug interactions, and result in a loss of effectiveness. This is particularly relevant to the anti-infective therapy, especially when infection is produced by resistant bacteria, because therapeutic options are limited and interactions can cause treatment failure. All antimicrobial prescriptions were retrospectively reviewed during a week in the Pharmacy Department, in order to detect potential drug-interactions and analysing their clinical significance. A total of 314 antimicrobial prescriptions from 151 patients were checked. There was at least one potential interaction detected in 40% of patients, being more frequent and severe in those infected with multidrug-resistant microorganisms. Drugs most commonly involved were quinolones, azoles, linezolid and vancomycin. Potential drug interactions with antimicrobial agents are a frequent problem that can result in a loss of effectiveness. This is why they should be detected and avoided when possible, in order to optimize antimicrobial therapy, especially in case of multidrug resistant infections.

  10. Prediction of pharmacokinetics and drug-drug interaction potential using physiologically based pharmacokinetic (PBPK) modeling approach: A case study of caffeine and ciprofloxacin

    Science.gov (United States)

    Park, Min-Ho; Shin, Seok-Ho; Byeon, Jin-Ju; Lee, Gwan-Ho; Yu, Byung-Yong

    2017-01-01

    Over the last decade, physiologically based pharmacokinetics (PBPK) application has been extended significantly not only to predicting preclinical/human PK but also to evaluating the drug-drug interaction (DDI) liability at the drug discovery or development stage. Herein, we describe a case study to illustrate the use of PBPK approach in predicting human PK as well as DDI using in silico, in vivo and in vitro derived parameters. This case was composed of five steps such as: simulation, verification, understanding of parameter sensitivity, optimization of the parameter and final evaluation. Caffeine and ciprofloxacin were used as tool compounds to demonstrate the “fit for purpose” application of PBPK modeling and simulation for this study. Compared to caffeine, the PBPK modeling for ciprofloxacin was challenging due to several factors including solubility, permeability, clearance and tissue distribution etc. Therefore, intensive parameter sensitivity analysis (PSA) was conducted to optimize the PBPK model for ciprofloxacin. Overall, the increase in Cmax of caffeine by ciprofloxacin was not significant. However, the increase in AUC was observed and was proportional to the administered dose of ciprofloxacin. The predicted DDI and PK results were comparable to observed clinical data published in the literatures. This approach would be helpful in identifying potential key factors that could lead to significant impact on PBPK modeling and simulation for challenging compounds. PMID:28066147

  11. Oral administration of drugs with hypersensitivity potential induces germinal center hyperplasia in secondary lymphoid organ/tissue in Brown Norway rats, and this histological lesion is a promising candidate as a predictive biomarker for drug hypersensitivity occurrence in humans

    Energy Technology Data Exchange (ETDEWEB)

    Tamura, Akitoshi, E-mail: akitoshi-tamura@ds-pharma.co.jp; Miyawaki, Izuru; Yamada, Toru; Kimura, Juki; Funabashi, Hitoshi

    2013-08-15

    It is important to evaluate the potential of drug hypersensitivity as well as other adverse effects during the preclinical stage of the drug development process, but validated methods are not available yet. In the present study we examined whether it would be possible to develop a new predictive model of drug hypersensitivity using Brown Norway (BN) rats. As representative drugs with hypersensitivity potential in humans, phenytoin (PHT), carbamazepine (CBZ), amoxicillin (AMX), and sulfamethoxazole (SMX) were orally administered to BN rats for 28 days to investigate their effects on these animals by examinations including observation of clinical signs, hematology, determination of serum IgE levels, histology, and flow cytometric analysis. Skin rashes were not observed in any animals treated with these drugs. Increases in the number of circulating inflammatory cells and serum IgE level did not necessarily occur in the animals treated with these drugs. However, histological examination revealed that germinal center hyperplasia was commonly induced in secondary lymphoid organs/tissues in the animals treated with these drugs. In cytometric analysis, changes in proportions of lymphocyte subsets were noted in the spleen of the animals treated with PHT or CBZ during the early period of administration. The results indicated that the potential of drug hypersensitivity was identified in BN rat by performing histological examination of secondary lymphoid organs/tissues. Data obtained herein suggested that drugs with hypersensitivity potential in humans gained immune reactivity in BN rat, and the germinal center hyperplasia induced by administration of these drugs may serve as a predictive biomarker for drug hypersensitivity occurrence. - Highlights: • We tested Brown Norway rats as a candidate model for predicting drug hypersensitivity. • The allergic drugs did not induce skin rash, whereas D-penicillamine did so in the rats. • Some of allergic drugs increased

  12. Potential hazards to embryo implantation: A human endometrial in vitro model to identify unwanted antigestagenic actions of chemicals

    Energy Technology Data Exchange (ETDEWEB)

    Fischer, L.; Deppert, W.R. [Department of Obstetrics and Gynecology, University Hospital Freiburg (Germany); Pfeifer, D. [Department of Hematology and Oncology, University Hospital Freiburg (Germany); Stanzel, S.; Weimer, M. [Department of Biostatistics, German Cancer Research Center, Heidelberg (Germany); Hanjalic-Beck, A.; Stein, A.; Straßer, M.; Zahradnik, H.P. [Department of Obstetrics and Gynecology, University Hospital Freiburg (Germany); Schaefer, W.R., E-mail: wolfgang.schaefer@uniklinik-freiburg.de [Department of Obstetrics and Gynecology, University Hospital Freiburg (Germany)

    2012-05-01

    Embryo implantation is a crucial step in human reproduction and depends on the timely development of a receptive endometrium. The human endometrium is unique among adult tissues due to its dynamic alterations during each menstrual cycle. It hosts the implantation process which is governed by progesterone, whereas 17β-estradiol regulates the preceding proliferation of the endometrium. The receptors for both steroids are targets for drugs and endocrine disrupting chemicals. Chemicals with unwanted antigestagenic actions are potentially hazardous to embryo implantation since many pharmaceutical antiprogestins adversely affect endometrial receptivity. This risk can be addressed by human tissue-specific in vitro assays. As working basis we compiled data on chemicals interacting with the PR. In our experimental work, we developed a flexible in vitro model based on human endometrial Ishikawa cells. Effects of antiprogestin compounds on pre-selected target genes were characterized by sigmoidal concentration–response curves obtained by RT-qPCR. The estrogen sulfotransferase (SULT1E1) was identified as the most responsive target gene by microarray analysis. The agonistic effect of progesterone on SULT1E1 mRNA was concentration-dependently antagonized by RU486 (mifepristone) and ZK137316 and, with lower potency, by 4-nonylphenol, bisphenol A and apigenin. The negative control methyl acetoacetate showed no effect. The effects of progesterone and RU486 were confirmed on the protein level by Western blotting. We demonstrated proof of principle that our Ishikawa model is suitable to study quantitatively effects of antiprogestin-like chemicals on endometrial target genes in comparison to pharmaceutical reference compounds. This test is useful for hazard identification and may contribute to reduce animal studies. -- Highlights: ► We compare progesterone receptor-mediated endometrial effects of chemicals and drugs. ► 4-Nonylphenol, bisphenol A and apigenin exert weak

  13. Hydro-geomorphic connectivity and landslide features extraction to identifying potential threats and hazardous areas

    Science.gov (United States)

    Tarolli, Paolo; Fuller, Ian C.; Basso, Federica; Cavalli, Marco; Sofia, Giulia

    2017-04-01

    Hydro-geomorphic connectivity has significantly emerged as a new concept to understand the transfer of surface water and sediment through landscapes. A further scientific challenge is determining how the concept can be used to enable sustainable land and water management. This research proposes an interesting approach to integrating remote sensing techniques, connectivity theory, and geomorphometry based on high-resolution digital terrain model (HR-DTMs) to automatically extract landslides crowns and gully erosion, to determine the different rate of connectivity among the main extracted features and the river network, and thus determine a possible categorization of hazardous areas. The study takes place in two mountainous regions in the Wellington Region (New Zealand). The methodology is a three step approach. Firstly, we performed an automatic detection of the likely landslides crowns through the use of thresholds obtained by the statistical analysis of the variability of landform curvature. After that, the research considered the Connectivity Index to analyse how a complex and rugged topography induces large variations in erosion and sediment delivery in the two catchments. Lastly, the two methods have been integrated to create a unique procedure able to classify the different rate of connectivity among the main features and the river network and thus identifying potential threats and hazardous areas. The methodology is fast, and it can produce a detailed and updated inventory map that could be a key tool for erosional and sediment delivery hazard mitigation. This fast and simple method can be a useful tool to manage emergencies giving priorities to more failure-prone zones. Furthermore, it could be considered to do a preliminary interpretations of geomorphological phenomena and more in general, it could be the base to develop inventory maps. References Cavalli M, Trevisani S, Comiti F, Marchi L. 2013. Geomorphometric assessment of spatial sediment connectivity

  14. Integrating Terrain and Vegetation Indices for Identifying Potential Soil Erosion Risk Area

    Institute of Scientific and Technical Information of China (English)

    Arabinda Sharma

    2010-01-01

    The present paper offers an innovative method to monitor the change in soil erosion potential by integrating terrain and vegetation indices derived from remote sensing data. Three terrain indices namely, topographic wetness index (TWI), stream power index (SPI) and slope length factor (LS), were derived from the digital elevation model. Normalized vegetation index (NDVI) was derived for the year 1988 and 2004 using remote sensing images. K-mean clustering was performed on staked indices to categorize the study area into four soil erosion potential classes. The validation of derived erosion potential map using USLE model showed a good agreement. Results indicated that there was a significant change in the erosion potential of the watershed and a gradual shifting of lower erosion potential class to next higher erosion potential class over the study period.

  15. Power to identify a genetic predictor of antihypertensive drug response using different methods to measure blood pressure response

    Directory of Open Access Journals (Sweden)

    Turner Stephen T

    2012-03-01

    Full Text Available Abstract Background To determine whether office, home, ambulatory daytime and nighttime blood pressure (BP responses to antihypertensive drug therapy measure the same signal and which method provides greatest power to identify genetic predictors of BP response. Methods We analyzed office, home, ambulatory daytime and nighttime BP responses in hypertensive adults randomized to atenolol (N = 242 or hydrochlorothiazide (N = 257 in the Pharmacogenomic Evaluation of Antihypertensive Responses Study. Since different measured BP responses may have different predictors, we tested the "same signal" model by using linear regression methods to determine whether known predictors of BP response depend on the method of BP measurement. We estimated signal-to-noise ratios and compared power to identify a genetic polymorphism predicting BP response measured by each method separately and by weighted averages of multiple methods. Results After adjustment for pretreatment BP level, known predictors of BP response including plasma renin activity, race, and sex were independent of the method of BP measurement. Signal-to-noise ratios were more than 2-fold greater for home and ambulatory daytime BP responses than for office and ambulatory nighttime BP responses and up to 11-fold greater for weighted averages of all four methods. Power to identify a genetic polymorphism predicting BP response was directly related to the signal-to-noise ratio and, therefore, greatest with the weighted averages. Conclusion Since different methods of measuring BP response to antihypertensive drug therapy measure the same signal, weighted averages of the BP responses measured by multiple methods minimize measurement error and optimize power to identify genetic predictors of BP response.

  16. Modified local diatomite as potential functional drug carrier--A model study for diclofenac sodium.

    Science.gov (United States)

    Janićijević, Jelena; Krajišnik, Danina; Čalija, Bojan; Vasiljević, Bojana Nedić; Dobričić, Vladimir; Daković, Aleksandra; Antonijević, Milan D; Milić, Jela

    2015-12-30

    Diatomite makes a promising candidate for a drug carrier because of its high porosity, large surface area, modifiable surface chemistry and biocompatibility. Herein, refined diatomite from Kolubara coal basin, which complied with the pharmacopoeial requirements for heavy metals content and microbiological quality, was used as a starting material. Inorganic modification of the starting material was performed through a simple, one-step procedure. Significant increase in adsorbent loading with diclofenac sodium (DS) was achieved after the modification process (∼373mg/g) which enabled the preparation of comprimates containing therapeutic dose of the adsorbed drug. Adsorption of DS onto modified diatomite resulted in the alteration of the drug's XRD pattern and FTIR spectrum. In vitro drug release studies in phosphate buffer pH 7.5 demonstrated prolonged DS release over 8h from comprimates containing DS adsorbed on modified diatomite (up to 37% after 8h) and those containing physical mixture of the same composition (up to 45% after 8h). The results of in vivo toxicity testing on mice pointed on potential safety of both unmodified (starting) and modified diatomite. All these findings favor the application of diatomite as a potential functional drug carrier. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. A hadoop-based method to predict potential effective drug combination.

    Science.gov (United States)

    Sun, Yifan; Xiong, Yi; Xu, Qian; Wei, Dongqing

    2014-01-01

    Combination drugs that impact multiple targets simultaneously are promising candidates for combating complex diseases due to their improved efficacy and reduced side effects. However, exhaustive screening of all possible drug combinations is extremely time-consuming and impractical. Here, we present a novel Hadoop-based approach to predict drug combinations by taking advantage of the MapReduce programming model, which leads to an improvement of scalability of the prediction algorithm. By integrating the gene expression data of multiple drugs, we constructed data preprocessing and the support vector machines and naïve Bayesian classifiers on Hadoop for prediction of drug combinations. The experimental results suggest that our Hadoop-based model achieves much higher efficiency in the big data processing steps with satisfactory performance. We believed that our proposed approach can help accelerate the prediction of potential effective drugs with the increasing of the combination number at an exponential rate in future. The source code and datasets are available upon request.

  18. A Hadoop-Based Method to Predict Potential Effective Drug Combination

    Directory of Open Access Journals (Sweden)

    Yifan Sun

    2014-01-01

    Full Text Available Combination drugs that impact multiple targets simultaneously are promising candidates for combating complex diseases due to their improved efficacy and reduced side effects. However, exhaustive screening of all possible drug combinations is extremely time-consuming and impractical. Here, we present a novel Hadoop-based approach to predict drug combinations by taking advantage of the MapReduce programming model, which leads to an improvement of scalability of the prediction algorithm. By integrating the gene expression data of multiple drugs, we constructed data preprocessing and the support vector machines and naïve Bayesian classifiers on Hadoop for prediction of drug combinations. The experimental results suggest that our Hadoop-based model achieves much higher efficiency in the big data processing steps with satisfactory performance. We believed that our proposed approach can help accelerate the prediction of potential effective drugs with the increasing of the combination number at an exponential rate in future. The source code and datasets are available upon request.

  19. Porous metal-organic-framework nanoscale carriers as a potential platform for drug delivery and imaging

    Science.gov (United States)

    Horcajada, Patricia; Chalati, Tamim; Serre, Christian; Gillet, Brigitte; Sebrie, Catherine; Baati, Tarek; Eubank, Jarrod F.; Heurtaux, Daniela; Clayette, Pascal; Kreuz, Christine; Chang, Jong-San; Hwang, Young Kyu; Marsaud, Veronique; Bories, Phuong-Nhi; Cynober, Luc; Gil, Sophie; Férey, Gérard; Couvreur, Patrick; Gref, Ruxandra

    2010-02-01

    In the domain of health, one important challenge is the efficient delivery of drugs in the body using non-toxic nanocarriers. Most of the existing carrier materials show poor drug loading (usually less than 5wt% of the transported drug versus the carrier material) and/or rapid release of the proportion of the drug that is simply adsorbed (or anchored) at the external surface of the nanocarrier. In this context, porous hybrid solids, with the ability to tune their structures and porosities for better drug interactions and high loadings, are well suited to serve as nanocarriers for delivery and imaging applications. Here we show that specific non-toxic porous iron(III)-based metal-organic frameworks with engineered cores and surfaces, as well as imaging properties, function as superior nanocarriers for efficient controlled delivery of challenging antitumoural and retroviral drugs (that is, busulfan, azidothymidine triphosphate, doxorubicin or cidofovir) against cancer and AIDS. In addition to their high loadings, they also potentially associate therapeutics and diagnostics, thus opening the way for theranostics, or personalized patient treatments.

  20. Natural Non-Mulberry Silk Nanoparticles for Potential-Controlled Drug Release.

    Science.gov (United States)

    Wang, Juan; Yin, Zhuping; Xue, Xiang; Kundu, Subhas C; Mo, Xiumei; Lu, Shenzhou

    2016-12-01

    Natural silk protein nanoparticles are a promising biomaterial for drug delivery due to their pleiotropic properties, including biocompatibility, high bioavailability, and biodegradability. Chinese oak tasar Antheraea pernyi silk fibroin (ApF) nanoparticles are easily obtained using cations as reagents under mild conditions. The mild conditions are potentially advantageous for the encapsulation of sensitive drugs and therapeutic molecules. In the present study, silk fibroin protein nanoparticles are loaded with differently-charged small-molecule drugs, such as doxorubicin hydrochloride, ibuprofen, and ibuprofen-Na, by simple absorption based on electrostatic interactions. The structure, morphology and biocompatibility of the silk nanoparticles in vitro are investigated. In vitro release of the drugs from the nanoparticles depends on charge-charge interactions between the drugs and the nanoparticles. The release behavior of the compounds from the nanoparticles demonstrates that positively-charged molecules are released in a more prolonged or sustained manner. Cell viability studies with L929 demonstrated that the ApF nanoparticles significantly promoted cell growth. The results suggest that Chinese oak tasar Antheraea pernyi silk fibroin nanoparticles can be used as an alternative matrix for drug carrying and controlled release in diverse biomedical applications.

  1. Natural Non-Mulberry Silk Nanoparticles for Potential-Controlled Drug Release

    Science.gov (United States)

    Wang, Juan; Yin, Zhuping; Xue, Xiang; Kundu, Subhas C.; Mo, Xiumei; Lu, Shenzhou

    2016-01-01

    Natural silk protein nanoparticles are a promising biomaterial for drug delivery due to their pleiotropic properties, including biocompatibility, high bioavailability, and biodegradability. Chinese oak tasar Antheraea pernyi silk fibroin (ApF) nanoparticles are easily obtained using cations as reagents under mild conditions. The mild conditions are potentially advantageous for the encapsulation of sensitive drugs and therapeutic molecules. In the present study, silk fibroin protein nanoparticles are loaded with differently-charged small-molecule drugs, such as doxorubicin hydrochloride, ibuprofen, and ibuprofen-Na, by simple absorption based on electrostatic interactions. The structure, morphology and biocompatibility of the silk nanoparticles in vitro are investigated. In vitro release of the drugs from the nanoparticles depends on charge-charge interactions between the drugs and the nanoparticles. The release behavior of the compounds from the nanoparticles demonstrates that positively-charged molecules are released in a more prolonged or sustained manner. Cell viability studies with L929 demonstrated that the ApF nanoparticles significantly promoted cell growth. The results suggest that Chinese oak tasar Antheraea pernyi silk fibroin nanoparticles can be used as an alternative matrix for drug carrying and controlled release in diverse biomedical applications. PMID:27916946

  2. Potential of surface-eroding poly(ethylene carbonate) for drug delivery to macrophages

    DEFF Research Database (Denmark)

    Bohr, Adam; Water, Jorrit J; Wang, Yingya

    2016-01-01

    Films composed of poly(ethylene carbonate) (PEC), a biodegradable polymer, were compared with poly(lactide-co-glycolide) (PLGA) films loaded with and without the tuberculosis drug rifampicin to study the characteristics and performance of PEC as a potential carrier for controlled drug delivery...... degradation products the murine macrophage cell line J774A.1 showed less susceptibility to PEC than to PLGA. However, when seeding the macrophages on PLGA and PEC films no relevant difference in cell proliferation/growth kinetics was observed. Overall, this study emphasizes that PEC is an attractive polymer...

  3. Biological characteristics of dengue virus and potential targets for drug design

    Institute of Scientific and Technical Information of China (English)

    Rui-feng Qi; Ling Zhang; Cheng-wu Chi

    2008-01-01

    Dengue infection is a major cause of morbidity in tropical and subtropical regions, bringing nearly 40% of the world population at risk and causing more than 20,000 deaths per year. But there is neither a vaccine for dengue disease nor antiviral drugs to treat the infection. In recent years, dengue infection has been particularly prevalent in India, Southeast Asia, Brazil, and Guangdong Province, China. In this article, we present a brief summary of the biological characteristics of dengue virus and associated flaviviruses, and outline the progress on studies of vaccines and drugs based on potential targets of the dengue virus.

  4. Differences in abuse potential of ADHD drugs measured by contrasting poison centre and therapeutic use data

    DEFF Research Database (Denmark)

    Jensen, Louise; Pagsberg, Anne Katrine; Dalhoff, Kim Peder

    2015-01-01

    CONTEXT: Atomoxetine (ATX) is the treatment of choice for attention deficit hyperactivity disorders with co-morbid risk of drug abuse, although its abuse potential needs to be qualified. The purpose of this study is to analyse ATX misuse in relation to therapeutic use and compare our results.......018), but not the enquiries/sale relationship. The proportion of exposures motivated by recreational drug use was significantly lower for ATX (19%) than that for MPH (40%) (p = 0.038). DISCUSSION AND CONCLUSION: These results suggest that ATX is used by adults for non-medical purposes including recreational use...

  5. A case of a potential drug interaction between clobazam and etravirine-based antiretroviral therapy.

    Science.gov (United States)

    Naccarato, Mark; Yoong, Deborah; Kovacs, Colin; Gough, Kevin

    2012-01-01

    The cytochrome P450 isoforms primarily involved in clobazam metabolism are CYP3A4 and 2C19. Drugs that modulate these enzymes would then be expected to alter the exposure of clobazam and its major metabolites. Etravirine, a second-generation non-nucleoside reverse transcriptase inhibitor has been shown to induce CYP3A4, while inhibiting CYP2C9 and CYP2C19. We report a case in which a potential drug interaction between clobazam and etravirine may have led to increased concentrations of clobazam and its pharmacologically active metabolite, N-desmethylclobazam, causing neurotoxic symptoms.

  6. Diagnosis of Lynch Syndrome: Genetic Testing Identifies a Potentially Deadly Hereditary Disease

    Science.gov (United States)

    ... the sequencing can identify variants in a person’s genes—places where their genetic sequence differs from an expected sequence,” says Katie Lewis, a research coordinator at NIH’s National Human Genome ...

  7. Reduction in hepatic drug metabolizing CYP3A4 activities caused by P450 oxidoreductase mutations identified in patients with disordered steroid metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Flueck, Christa E.; Mullis, Primus E. [Pediatric Endocrinology, Diabetology and Metabolism, Department of Clinical Research, University of Bern, Tiefenaustrasse 120c, CH 3004 Bern (Switzerland); Pandey, Amit V., E-mail: amit@pandeylab.org [Pediatric Endocrinology, Diabetology and Metabolism, Department of Clinical Research, University of Bern, Tiefenaustrasse 120c, CH 3004 Bern (Switzerland)

    2010-10-08

    Research highlights: {yields} Cytochrome P450 3A4 (CYP3A4), metabolizes 50% of drugs in clinical use and requires NADPH-P450 reductase (POR). {yields} Mutations in human POR cause congenital adrenal hyperplasia from diminished activities of steroid metabolizing P450s. {yields} We are reporting that mutations in POR may reduce CYP3A4 activity. {yields} POR mutants Y181D, A457H, Y459H, V492E and R616X lost 99%, while A287P, C569Y and V608F lost 60-85% CYP3A4 activity. {yields} Reduction of CYP3A4 activity may cause increased risk of drug toxicities/adverse drug reactions in patients with POR mutations. -- Abstract: Cytochrome P450 3A4 (CYP3A4), the major P450 present in human liver metabolizes approximately half the drugs in clinical use and requires electrons supplied from NADPH through NADPH-P450 reductase (POR, CPR). Mutations in human POR cause a rare form of congenital adrenal hyperplasia from diminished activities of steroid metabolizing P450s. In this study we examined the effect of mutations in POR on CYP3A4 activity. We used purified preparations of wild type and mutant human POR and in vitro reconstitution with purified CYP3A4 to perform kinetic studies. We are reporting that mutations in POR identified in patients with disordered steroidogenesis/Antley-Bixler syndrome (ABS) may reduce CYP3A4 activity, potentially affecting drug metabolism in individuals carrying mutant POR alleles. POR mutants Y181D, A457H, Y459H, V492E and R616X had more than 99% loss of CYP3A4 activity, while POR mutations A287P, C569Y and V608F lost 60-85% activity. Loss of CYP3A4 activity may result in increased risk of drug toxicities and adverse drug reactions in patients with POR mutations.

  8. A potential causal association mining algorithm for screening adverse drug reactions in postmarketing surveillance.

    Science.gov (United States)

    Ji, Yanqing; Ying, Hao; Dews, Peter; Mansour, Ayman; Tran, John; Miller, Richard E; Massanari, R Michael

    2011-05-01

    Early detection of unknown adverse drug reactions (ADRs) in postmarketing surveillance saves lives and prevents harmful consequences. We propose a novel data mining approach to signaling potential ADRs from electronic health databases. More specifically, we introduce potential causal association rules (PCARs) to represent the potential causal relationship between a drug and ICD-9 (CDC. (2010). International Classification of Diseases, Ninth Revision (ICD-9). [Online]. Available: http://www.cdc.gov/nchs/icd/icd9.html) coded signs or symptoms representing potential ADRs. Due to the infrequent nature of ADRs, the existing frequency-based data mining methods cannot effectively discover PCARs. We introduce a new interestingness measure, potential causal leverage, to quantify the degree of association of a PCAR. This measure is based on the computational, experience-based fuzzy recognition-primed decision (RPD) model that we developed previously (Y. Ji, R. M. Massanari, J. Ager, J. Yen, R. E. Miller, and H. Ying, "A fuzzy logic-based computational recognition-primed decision model," Inf. Sci., vol. 177, pp. 4338-4353, 2007) on the basis of the well-known, psychology-originated qualitative RPD model (G. A. Klein, "A recognition-primed decision making model of rapid decision making," in Decision Making in Action: Models and Methods, 1993, pp. 138-147). The potential causal leverage assesses the strength of the association of a drug-symptom pair given a collection of patient cases. To test our data mining approach, we retrieved electronic medical data for 16,206 patients treated by one or more than eight drugs of our interest at the Veterans Affairs Medical Center in Detroit between 2007 and 2009. We selected enalapril as the target drug for this ADR signal generation study. We used our algorithm to preliminarily evaluate the associations between enalapril and all the ICD-9 codes associated with it. The experimental results indicate that our approach has a potential to

  9. Potential of calcium isotopes to identify fractionations in vegetation: experimental approach

    Science.gov (United States)

    Cobert, F.; Schmitt, A.; Bourgade, P.; Stille, P.; Chabaux, F. J.; Badot, P.; Jaegler, T.

    2010-12-01

    This study aims to better understand the role of vegetation on the Ca cycle at the level of the critical zone of the Earth, in order to specify the mechanisms controlling the Ca absorption by plants at the rock/plant interface. To do this, we performed experiments using hydroponic plant cultures in a way that we could control the cooccuring geochemical and biological processes and determine the impact of the nutritive solution on the Ca cycle within plants. A dicotyledon and calcicole plant with rapid growth, the French bean (Phaseolus vulgaris L.), has been chosen to have access to one complete growth cycle. Several experiments have been conducted with two Ca concentrations, 5 (L) and 60 (H) ppm and two pH values (4 and 6) in the nutritive solution, for which the Ca concentration was maintained constant, so its Ca content is considered to be infinite. We determined Ca concentrations and isotopic ratios in the nutritive solution and in different organs (main roots, secondary roots, old and young stems, old and young leaves and fruits) at two different growth stages (10 days and 6 weeks). Our results show, in accord with previously published field studies, that the bean organs are all enriched in the light 40Ca isotope compared to the nutritive solution (e.g. Wigand et al., 2005; Page et al., 2008; Cenki-Tok et al., 2009; Holmden and Bélanger, 2010). We identify two fractionation levels. The first occurs during the uptake of the nutrient elements by the lateral roots. This implies that the main mechanisms of light isotope enrichments in the plant are due to electrochemical gradient transport processes taking place at this interface. The second fractionation can be observed within the plant itself and is due to the nature of the considered organ itself. Indeed structural reservoirs (primary roots, stem, reproductive organs) incorporate more the light 40Ca isotope compared to the transfer reservoirs (lateral roots, xylem sap, leaves). This could be linked to ion

  10. Sequence Analysis of Hypothetical Proteins from 26695 to Identify Potential Virulence Factors

    Directory of Open Access Journals (Sweden)

    Ahmad Abu Turab Naqvi

    2016-09-01

    Full Text Available Helicobacter pylori is a Gram-negative bacteria that is responsible for gastritis in human. Its spiral flagellated body helps in locomotion and colonization in the host environment. It is capable of living in the highly acidic environment of the stomach with the help of acid adaptive genes. The genome of H. pylori 26695 strain contains 1,555 coding genes that encode 1,445 proteins. Out of these, 340 proteins are characterized as hypothetical proteins (HP. This study involves extensive analysis of the HPs using an established pipeline which comprises various bioinformatics tools and databases to find out probable functions of the HPs and identification of virulence factors. After extensive analysis of all the 340 HPs, we found that 104 HPs are showing characteristic similarities with the proteins with known functions. Thus, on the basis of such similarities, we assigned probable functions to 104 HPs with high confidence and precision. All the predicted HPs contain representative members of diverse functional classes of proteins such as enzymes, transporters, binding proteins, regulatory proteins, proteins involved in cellular processes and other proteins with miscellaneous functions. Therefore, we classified 104 HPs into aforementioned functional groups. During the virulence factors analysis of the HPs, we found 11 HPs are showing significant virulence. The identification of virulence proteins with the help their predicted functions may pave the way for drug target estimation and development of effective drug to counter the activity of that protein.

  11. Sequence Analysis of Hypothetical Proteins from Helicobacter pylori 26695 to Identify Potential Virulence Factors

    Science.gov (United States)

    Naqvi, Ahmad Abu Turab; Anjum, Farah; Khan, Faez Iqbal; Islam, Asimul; Ahmad, Faizan

    2016-01-01

    Helicobacter pylori is a Gram-negative bacteria that is responsible for gastritis in human. Its spiral flagellated body helps in locomotion and colonization in the host environment. It is capable of living in the highly acidic environment of the stomach with the help of acid adaptive genes. The genome of H. pylori 26695 strain contains 1,555 coding genes that encode 1,445 proteins. Out of these, 340 proteins are characterized as hypothetical proteins (HP). This study involves extensive analysis of the HPs using an established pipeline which comprises various bioinformatics tools and databases to find out probable functions of the HPs and identification of virulence factors. After extensive analysis of all the 340 HPs, we found that 104 HPs are showing characteristic similarities with the proteins with known functions. Thus, on the basis of such similarities, we assigned probable functions to 104 HPs with high confidence and precision. All the predicted HPs contain representative members of diverse functional classes of proteins such as enzymes, transporters, binding proteins, regulatory proteins, proteins involved in cellular processes and other proteins with miscellaneous functions. Therefore, we classified 104 HPs into aforementioned functional groups. During the virulence factors analysis of the HPs, we found 11 HPs are showing significant virulence. The identification of virulence proteins with the help their predicted functions may pave the way for drug target estimation and development of effective drug to counter the activity of that protein. PMID:27729842

  12. Anisotropic coarse-grained statistical potentials improve the ability to identify native-like protein structures

    CERN Document Server

    Buchete, N V; Thirumalai, D

    2003-01-01

    We present a new method to extract distance and orientation dependent potentials between amino acid side chains using a database of protein structures and the standard Boltzmann device. The importance of orientation dependent interactions is first established by computing orientational order parameters for proteins with alpha-helical and beta-sheet architecture. Extraction of the anisotropic interactions requires defining local reference frames for each amino acid that uniquely determine the coordinates of the neighboring residues. Using the local reference frames and histograms of the radial and angular correlation functions for a standard set of non-homologue protein structures, we construct the anisotropic pair potentials. The performance of the orientation dependent potentials was studied using a large database of decoy proteins. The results demonstrate that the new distance and orientation dependent residue-residue potentials present a significantly improved ability to recognize native folds from a set o...

  13. Drug addiction: targeting dynamic neuroimmune receptor interactions as a potential therapeutic strategy.

    Science.gov (United States)

    Jacobsen, Jonathan Henry W; Hutchinson, Mark R; Mustafa, Sanam

    2016-02-01

    Drug addiction and dependence have proven to be difficult psychiatric disorders to treat. The limited efficacy of neuronally acting medications, such as acamprosate and naltrexone, highlights the need to identify novel targets. Recent research has underscored the importance of the neuroimmune system in many behavioural manifestations of drug addiction. In this review, we propose that our appreciation for complex phenotypes such as drug addiction and dependence will come with a greater understanding that these disorders are the result of intricate, interconnected signalling pathways that are, if only partially, determined at the receptor level. The idea of receptor heteromerisation and receptor mosaics will be introduced to explain cross talk between the receptors and signalling molecules implicated in neuroimmune signalling pathways. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. The SADI Personal Health Lens: A Web Browser-Based System for Identifying Personally Relevant Drug Interactions.

    Science.gov (United States)

    Vandervalk, Ben; McCarthy, E Luke; Cruz-Toledo, José; Klein, Artjom; Baker, Christopher J O; Dumontier, Michel; Wilkinson, Mark D

    2013-04-05

    The Web provides widespread access to vast quantities of health-related information that can improve quality-of-life through better understanding of personal symptoms, medical conditions, and available treatments. Unfortunately, identifying a credible and personally relevant subset of information can be a time-consuming and challenging task for users without a medical background. The objective of the Personal Health Lens system is to aid users when reading health-related webpages by providing warnings about personally relevant drug interactions. More broadly, we wish to present a prototype for a novel, generalizable approach to facilitating interactions between a patient, their practitioner(s), and the Web. We utilized a distributed, Semantic Web-based architecture for recognizing personally dangerous drugs consisting of: (1) a private, local triple store of personal health information, (2) Semantic Web services, following the Semantic Automated Discovery and Integration (SADI) design pattern, for text mining and identifying substance interactions, (3) a bookmarklet to trigger analysis of a webpage and annotate it with personalized warnings, and (4) a semantic query that acts as an abstract template of the analytical workflow to be enac