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Sample records for actual drug-drug interactions

  1. Transporter-mediated drug-drug interactions.

    PubMed

    Müller, Fabian; Fromm, Martin F

    2011-07-01

    Drug-drug interactions are a serious clinical issue. An important mechanism underlying drug-drug interactions is induction or inhibition of drug transporters that mediate the cellular uptake and efflux of xenobiotics. Especially drug transporters of the small intestine, liver and kidney are major determinants of the pharmacokinetic profile of drugs. Transporter-mediated drug-drug interactions in these three organs can considerably influence the pharmacokinetics and clinical effects of drugs. In this article, we focus on probe drugs lacking significant metabolism to highlight mechanisms of interactions of selected intestinal, hepatic and renal drug transporters (e.g., organic anion transporting polypeptide [OATP] 1A2, OATP2B1, OATP1B1, OATP1B3, P-gp, organic anion transporter [OAT] 1, OAT3, breast cancer resistance protein [BCRP], organic cation transporter [OCT] 2 and multidrug and toxin extrusion protein [MATE] 1). Genotype-dependent drug-drug interactions are also discussed.

  2. [Drug-drug interactions: interactions between xenobiotics].

    PubMed

    Haen, E

    2014-04-01

    Drug-drug interactions (DDI) are a major topic in programs for continuous medical education (CME). Many physicians are afraid of being trapped into charges of malpractice; however, DDI cannot be avoided in many cases. They belong to routine medical practice and it is often impossible to avoid them. Moreover, they do not just occur between drugs but between any kind of foreign substance (xenobiotica), such as food (e.g. grapefruit juice, broccoli, barbecue) as well as legal (e.g. tobacco smoke, caffeine and alcohol) and illegal drugs. Therefore, the medical challenge is not just to avoid any interaction. Instead the physician faces the question of how to proceed with drug treatment in the presence of such interactions. Based on the medical education a physician has to judge first of all whether there is a risk for interactions in the prescription being planned for an individual patient. The classification of interactions proposed in this article (PD1-PD4, PK1-PK3) might help as a sort of check list. For more detailed information the physician can then consult one of the many databases available on the internet, such as PSIAConline (http://www.psiac.de) and MediQ (http://www.mediq.ch). Pharmacokinetic interactions can be easily assessed, monitored and controlled by therapeutic drug monitoring (TDM). Besides these tools it is important to keep in mind that nobody knows everything; even physicians do not know everything. So take pride in asking someone who might help and for this purpose AGATE offers a drug information service AID (http://www.amuep-agate.de). Just good for nothing, without being based on any kind of medical approach are computer programs that judge prescriptions without taking into account a patient's individual peculiarities. In case these types of programs produce red exclamation marks or traffic lights to underline their judgment, they might even work in a contrapuntal way by just eliciting insecurity and fear.

  3. Text mining for drug-drug interaction.

    PubMed

    Wu, Heng-Yi; Chiang, Chien-Wei; Li, Lang

    2014-01-01

    In order to understand the mechanisms of drug-drug interaction (DDI), the study of pharmacokinetics (PK), pharmacodynamics (PD), and pharmacogenetics (PG) data are significant. In recent years, drug PK parameters, drug interaction parameters, and PG data have been unevenly collected in different databases and published extensively in literature. Also the lack of an appropriate PK ontology and a well-annotated PK corpus, which provide the background knowledge and the criteria of determining DDI, respectively, lead to the difficulty of developing DDI text mining tools for PK data collection from the literature and data integration from multiple databases.To conquer the issues, we constructed a comprehensive pharmacokinetics ontology. It includes all aspects of in vitro pharmacokinetics experiments, in vivo pharmacokinetics studies, as well as drug metabolism and transportation enzymes. Using our pharmacokinetics ontology, a PK corpus was constructed to present four classes of pharmacokinetics abstracts: in vivo pharmacokinetics studies, in vivo pharmacogenetic studies, in vivo drug interaction studies, and in vitro drug interaction studies. A novel hierarchical three-level annotation scheme was proposed and implemented to tag key terms, drug interaction sentences, and drug interaction pairs. The utility of the pharmacokinetics ontology was demonstrated by annotating three pharmacokinetics studies; and the utility of the PK corpus was demonstrated by a drug interaction extraction text mining analysis.The pharmacokinetics ontology annotates both in vitro pharmacokinetics experiments and in vivo pharmacokinetics studies. The PK corpus is a highly valuable resource for the text mining of pharmacokinetics parameters and drug interactions.

  4. Potential Drug - Drug Interactions among Medications Prescribed to Hypertensive Patients

    PubMed Central

    Ganguly, Barna

    2014-01-01

    Context: Drug-drug interactions(DDIs) are significant but avoidable causes of iatrogenic morbidity and hospital admission. Aim: To detect potential drug-drug interactions among medications received by hypertensive patients. Materials and Methods: Patients of both sex and all adult age groups, who were attending medicine out -patient department (OPD) of a tertiary care teaching rural hospital since last six months and were being prescribed antihypertensive drug/s for essential hypertension, were selected for the study. Hypertensive patient with co-morbities diabetes mellitus, ischemic heart diseases, congestive heart failure, and chronic renal diseases were also included in the study. Potential drug drug interactions were checked with medscape drug interaction software. Results: With the help of medscape drug interaction software, 71.50% prescriptions were identified having atleast one drug-drug interaction. Total 918 DDIs were found in between 58 drug pairs. 55.23% DDIs were pharmacodynamic, 4.79% pharmacokinetic type of DDIs. 32.24% DDIs were found affecting serum potassium level. 95.42% DDIs were found significant type of DDIs. Drug drug interaction between atenolol & amlodipine was the most common DDI (136) followed by metoprolol and amlodine (88) in this study. Atenolol and amlodipine ( 25.92%) was the most common drugs to cause DDIs in our study. Conclusion: We detected a significant number of drug drug interaction in hypertensive patients. These interactions were between antihypertensive agents or between hypertensive and drug for co-morbid condition. PMID:25584241

  5. Irreversible enzyme inhibition kinetics and drug-drug interactions.

    PubMed

    Mohutsky, Michael; Hall, Stephen D

    2014-01-01

    This chapter describes the types of irreversible inhibition of drug-metabolizing enzymes and the methods commonly employed to quantify the irreversible inhibition and subsequently predict the extent and time course of clinically important drug-drug interactions.

  6. Mechanisms and Consequences of Drug-Drug Interactions.

    PubMed

    Greenblatt, David J

    2017-03-01

    Medications used to treat human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections present a special challenge with respect to the management of potential and actual drug-drug interactions (DDIs). The HIV and HCV treatments may interact with each other, and also interact with drugs of abuse and/or with medications used to treat substance abuse. Possible mechanisms of these DDIs generally include induction or inhibition of activity/expression of human cytochromes P450, glucuronosyl transferases, or energy-dependent transport proteins. These DDIs can be complex and time-dependent in nature. Because time and resources available for new drug development are necessarily limited, not all potential DDIs can be evaluated via clinical pharmacokinetic studies in the course of development of HIV, HCV, and substance abuse treatments. Strategies are needed to refine existing in vitro models and screening techniques to allow more efficient targeting of resources to those clinical studies having the highest impact in terms of enhancing medication effectiveness and patient safety.

  7. Drug-drug interactions between clopidogrel and novel cardiovascular drugs.

    PubMed

    Pelliccia, Francesco; Rollini, Fabiana; Marazzi, Giuseppe; Greco, Cesare; Gaudio, Carlo; Angiolillo, Dominick J

    2015-10-15

    The combination of aspirin and the thienopyridine clopidogrel is a cornerstone in the prevention of atherothrombotic events. These two agents act in concert to ameliorate the prothrombotic processes stimulated by plaque rupture and vessel injury complicating cardiovascular disease. Guidelines recommend the use of clopidogrel in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention, and the drug remains the most utilized P2Y12 receptor inhibitor despite the fact that newer antiplatelet agents are now available. In recent years, numerous studies have shown inconsistency in the efficacy of clopidogrel to prevent atherothrombotic events. Studies of platelet function testing have shown variability in the response to clopidogrel. One of the major reason for this phenomenon lies in the interaction between clopidogrel and other drugs that may affect clopidogrel absorption, metabolism, and ultimately its antiplatelet action. Importantly, these drug-drug interactions have prognostic implications, since patients with high on-treatment platelet reactivity associated with reduced clopidogrel metabolism have an increased risk of ischemia. Previous systematic reviews have focused on drug-drug interactions between clopidogrel and specific pharmacologic classes, such as proton pump inhibitors, calcium channel blockers, and statins. However, more recent pieces of scientific evidence show that clopidogrel may also interact with newer drugs that are now available for the treatment of cardiovascular patients. Accordingly, the aim of this review is to highlight and discuss recent data on drug-drug interactions between clopidogrel and third-generation proton pump inhibitors, pantoprazole and lansoprazole, statins, pitavastatin, and antianginal drug, ranolazine.

  8. Enterprise-wide drug-drug interaction alerting system.

    PubMed

    Greim, Julie A; Shek, Caroline; Jones, Linda; Macauley, Robert; Paterno, Marilyn; Blumenfeld, Barry H; Kuperman, Gilad

    2003-01-01

    According to the Institute of Medicine's (IOM) 1999 report To Err is Human: Building a safer Health System, "medical errors kill some 44,000-98,0001 people in U.S. hospitals each year. Partners HealthCare System (PHS) is a large integrated delivery network in Boston, MA, which has as a goal improving patient care by preventing adverse drug events (ADE) and reducing medication errors enterprise-wide. PHS has developed a drug-drug Interaction (DDI) detection feature, for the suite of clinical applications currently used by its two major teaching institutions, Brigham & Women's Hospital (BWH) and Mass General Hospital (MGH). The following clinical applications will be using this drug-drug interaction feature: NICU Order Entry (OE) at BWH, MGH OE for pediatrics and adults, the Partners outpatient medical record, The LMR, and BICS OE at BWH.

  9. Participatory design for drug-drug interaction alerts.

    PubMed

    Luna, Daniel; Otero, Carlos; Almerares, Alfredo; Stanziola, Enrique; Risk, Marcelo; González Bernaldo de Quirós, Fernán

    2015-01-01

    The utilization of decision support systems, in the point of care, to alert drug-drug interactions has been shown to improve quality of care. Still, the use of these systems has not been as expected, it is believed, because of the difficulties in their knowledge databases; errors in the generation of the alerts and the lack of a suitable design. This study expands on the development of alerts using participatory design techniques based on user centered design process. This work was undertaken in three stages (inquiry, participatory design and usability testing) it showed that the use of these techniques improves satisfaction, effectiveness and efficiency in an alert system for drug-drug interactions, a fact that was evident in specific situations such as the decrease of errors to meet the specified task, the time, the workload optimization and users overall satisfaction in the system.

  10. Drug-drug plasma protein binding interactions of ivacaftor.

    PubMed

    Schneider, Elena K; Huang, Johnny X; Carbone, Vincenzo; Baker, Mark; Azad, Mohammad A K; Cooper, Matthew A; Li, Jian; Velkov, Tony

    2015-06-01

    Ivacaftor is a novel cystic fibrosis (CF) transmembrane conductance regulator (CFTR) potentiator that improves the pulmonary function for patients with CF bearing a G551D CFTR-protein mutation. Because ivacaftor is highly bound (>97%) to plasma proteins, there is the strong possibility that co-administered CF drugs may compete for the same plasma protein binding sites and impact the free drug concentration. This, in turn, could lead to drastic changes in the in vivo efficacy of ivacaftor and therapeutic outcomes. This biochemical study compares the binding affinity of ivacaftor and co-administered CF drugs for human serum albumin (HSA) and α1 -acid glycoprotein (AGP) using surface plasmon resonance and fluorimetric binding assays that measure the displacement of site-selective probes. Because of their ability to strongly compete for the ivacaftor binding sites on HSA and AGP, drug-drug interactions between ivacaftor are to be expected with ducosate, montelukast, ibuprofen, dicloxacillin, omeprazole, and loratadine. The significance of these plasma protein drug-drug interactions is also interpreted in terms of molecular docking simulations. This in vitro study provides valuable insights into the plasma protein drug-drug interactions of ivacaftor with co-administered CF drugs. The data may prove useful in future clinical trials for a staggered treatment that aims to maximize the effective free drug concentration and clinical efficacy of ivacaftor.

  11. A clinician's guide to statin drug-drug interactions.

    PubMed

    Kellick, Kenneth A; Bottorff, Michael; Toth, Peter P; The National Lipid Association's Safety Task Force

    2014-01-01

    The statins are widely used worldwide to reduce risk for cardiovascular events in both the primary and secondary prevention settings. Although generally quite safe, the statins can be associated with a variety of serious side adverse effects, including myalgia, myopathy, and changes in plasma enzymes of hepatic origin. Although rare, the most serious of these is rhabdomyolysis. Several drugs can interfere with the metabolism and disposal of the statins, thereby increasing risk for adverse events. It is important that clinicians treating patients with statins be aware of the potential for drug-drug interactions between each statin and specific other drugs and take measures to prevent them. The prediction of potential drug-drug interactions derives from basic pharmacokinetic principles. Certain drug interactions are predicted by measuring the effect of interacting drugs on blood plasma concentrations of the statin. Individual patient variations resulting in part from polymorphisms in the metabolizing enzymes confound some of these predictions. Based on these known effects, a new classification for predicting statin drug interactions is proposed. This report discusses likely prescription and nonprescription interactions as well as potential alternatives for special populations.

  12. Clinically relevant drug-drug interactions between antiretrovirals and antifungals

    PubMed Central

    Vadlapatla, Ramya Krishna; Patel, Mitesh; Paturi, Durga K; Pal, Dhananjay; Mitra, Ashim K

    2015-01-01

    Introduction Complete delineation of the HIV-1 life cycle has resulted in the development of several antiretroviral drugs. Twenty-five therapeutic agents belonging to five different classes are currently available for the treatment of HIV-1 infections. Advent of triple combination antiretroviral therapy has significantly lowered the mortality rate in HIV patients. However, fungal infections still represent major opportunistic diseases in immunocompromised patients worldwide. Areas covered Antiretroviral drugs that target enzymes and/or proteins indispensable for viral replication are discussed in this article. Fungal infections, causative organisms, epidemiology and preferred treatment modalities are also outlined. Finally, observed/predicted drug-drug interactions between antiretrovirals and antifungals are summarized along with clinical recommendations. Expert opinion Concomitant use of amphotericin B and tenofovir must be closely monitored for renal functioning. Due to relatively weak interactive potential with the CYP450 system, fluconazole is the preferred antifungal drug. High itraconazole doses (> 200 mg/day) are not advised in patients receiving booster protease inhibitor (PI) regimen. Posaconazole is contraindicated in combination with either efavirenz or fosamprenavir. Moreover, voriconazole is contraindicated with high-dose ritonavir-boosted PI. Echino-candins may aid in overcoming the limitations of existing antifungal therapy. An increasing number of documented or predicted drug-drug interactions and therapeutic drug monitoring may aid in the management of HIV-associated opportunistic fungal infections. PMID:24521092

  13. Drug-drug, drug-dietary supplement, and drug-citrus fruit and other food interactions: what have we learned?

    PubMed

    Huang, Shiew-Mei; Lesko, Lawrence J

    2004-06-01

    Serious drug-drug interactions have contributed to recent U.S. market withdrawals and also recent nonapprovals of a few new molecular entities. Many of these interactions involved the inhibition or induction of metabolizing enzymes and efflux transporters, resulting in altered systemic exposure and adverse drug reactions or loss of efficacy. In addition to drug-drug interactions, drug-dietary supplement and drug-citrus fruit interactions, among others, could also cause adverse drug reactions or loss of efficacy and are important issues to consider in the evaluation of new drug candidates. This commentary reviews (1). the current understanding of the mechanistic basis of these interactions, (2). issues to consider in the interpretation of study results, and (3). recent labeling examples to illustrate the translation of study results to information useful for patients and health care providers.

  14. Making Transporter Models for Drug-Drug Interaction Prediction Mobile.

    PubMed

    Ekins, Sean; Clark, Alex M; Wright, Stephen H

    2015-10-01

    The past decade has seen increased numbers of studies publishing ligand-based computational models for drug transporters. Although they generally use small experimental data sets, these models can provide insights into structure-activity relationships for the transporter. In addition, such models have helped to identify new compounds as substrates or inhibitors of transporters of interest. We recently proposed that many transporters are promiscuous and may require profiling of new chemical entities against multiple substrates for a specific transporter. Furthermore, it should be noted that virtually all of the published ligand-based transporter models are only accessible to those involved in creating them and, consequently, are rarely shared effectively. One way to surmount this is to make models shareable or more accessible. The development of mobile apps that can access such models is highlighted here. These apps can be used to predict ligand interactions with transporters using Bayesian algorithms. We used recently published transporter data sets (MATE1, MATE2K, OCT2, OCTN2, ASBT, and NTCP) to build preliminary models in a commercial tool and in open software that can deliver the model in a mobile app. In addition, several transporter data sets extracted from the ChEMBL database were used to illustrate how such public data and models can be shared. Predicting drug-drug interactions for various transporters using computational models is potentially within reach of anyone with an iPhone or iPad. Such tools could help prioritize which substrates should be used for in vivo drug-drug interaction testing and enable open sharing of models.

  15. Quantifying drug-drug interactions in pharmaco-EEG.

    PubMed

    Barbanoj, M J; Antonijoan, R M; Riba, J; Valle, M; Romero, S; Jané, F

    2006-04-01

    A drug interaction refers to an event in which the usual pharmacological effect of a drug is modified by other factors, most frequently additional drugs. When two drugs are administered simultaneously, or within a short time of each other, an interaction can occur that may increase or decrease the intended magnitude or duration of the effect of one or both drugs. Drugs may interact on a pharmaceutical, pharmacokinetic or pharmacodynamic basis. Pharmacodynamic interactions arise when the alteration of the effects occurs at the site of action. This is a wide field where not only interactions between different drugs are considered but also drug and metabolites (midazolam/alpha-hydroxy-midazolam), enantiomers (ketamine), as well as phenomena such as tolerance (nordiazepam) and sensitization (diazepam). Pharmacodynamic interactions can result in antagonism or synergism and can originate at a receptor level (antagonism, partial agonism, down-regulation, up-regulation), at an intraneuronal level (transduction, uptake), or at an interneuronal level (physiological pathways). Alternatively, psychotropic drug interactions assessed through quantitative pharmaco-EEG can be viewed according to the broad underlying objective of the study: safety-oriented (ketoprofen/theophylline, lorazepam/diphenhydramine, granisetron/haloperidol), strictly pharmacologically-oriented (benzodiazepine receptors), or broadly neuro-physiologically-oriented (diazepam/buspirone). Methodological issues are stressed, particularly drug plasma concentrations, dose-response relationships and time-course of effects (fluoxetine/buspirone), and unsolved questions are addressed (yohimbine/caffeine, hydroxizyne/alcohol).

  16. Drug-Drug Interaction Extraction via Convolutional Neural Networks

    PubMed Central

    Liu, Shengyu; Tang, Buzhou; Chen, Qingcai; Wang, Xiaolong

    2016-01-01

    Drug-drug interaction (DDI) extraction as a typical relation extraction task in natural language processing (NLP) has always attracted great attention. Most state-of-the-art DDI extraction systems are based on support vector machines (SVM) with a large number of manually defined features. Recently, convolutional neural networks (CNN), a robust machine learning method which almost does not need manually defined features, has exhibited great potential for many NLP tasks. It is worth employing CNN for DDI extraction, which has never been investigated. We proposed a CNN-based method for DDI extraction. Experiments conducted on the 2013 DDIExtraction challenge corpus demonstrate that CNN is a good choice for DDI extraction. The CNN-based DDI extraction method achieves an F-score of 69.75%, which outperforms the existing best performing method by 2.75%. PMID:26941831

  17. Prolonged Drug-Drug Interaction between Terbinafine and Perphenazine.

    PubMed

    Park, Young-Min

    2012-12-01

    I report here an elderly woman receiving perphenazine together with terbinafine. After 1 week of terbinafine treatment she experienced extrapyramidal symptoms and, in particular, akathisia. Her symptoms did not disappear for 6 weeks, and so at 2 weeks prior to this most recent admission she had stopped taking terbinafine. However, these symptoms persisted for 3 weeks after discontinuing terbinafine. It is well known that terbinafine inhibits CYP2D6 and that perphenazine is metabolized mainly by CYP2D6. Thus, when terbinafine and perphenazine are coadministrated, the subsequent increase in the concentration of perphenazine may induce extrapyramidal symptoms. Thus, terbinafine therapy may be associated with the induction and persistence of extrapyramidal symptoms, including akathisia. This case report emphasizes the importance of monitoring drug-drug interactions in patients undergoing terbinafine and perphenazine therapy.

  18. Drug-drug interactions: antiretroviral drugs and recreational drugs.

    PubMed

    Staltari, Orietta; Leporini, Christian; Caroleo, Benedetto; Russo, Emilio; Siniscalchi, Antonio; De Sarro, Giovambattista; Gallelli, Luca

    2014-01-01

    With the advances in antiretroviral (ARV) therapy, patients with Human Immunodeficiency Virus (HIV) infection are living longer, however, some patients encounter co- morbidities which sometimes require treatment. Therefore, during the treatment with ARV drugs these patients could take several recreational drugs (e.g. amphetamines, hallucinogenes, opiates, or alcohol) with a possible development of drug-drug interactions (DDIs). In particular, Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) are mainly excreted through the kidney and are not substrates of the cytochrome P450 or P-glycoprotein, therefore the DDIs during this treatment are minimal. In contrast, the other ARV drugs (i.e. non-nucleoside reversetranscriptase inhibitors, Protease inhibitors, Integrase inhibitors, chemokine receptor 5 antagonists and HIV-fusion inhibitors) are an important class of antiretroviral medications that are frequent components of HAART regimens but show several DDIs related to interaction with the cytochrome P450 or P-glycoprotein. In this paper we will review data concerning the possibility of DDI in HIV patients treated with ARV and taking recreational drugs.

  19. Mechanism of Drug-Drug Interactions Between Warfarin and Statins.

    PubMed

    Shaik, Abdul Naveed; Bohnert, Tonika; Williams, David A; Gan, Lawrence L; LeDuc, Barbara W

    2016-06-01

    The anticoagulant drug warfarin and the lipid-lowering statin drugs are commonly co-administered to patients with cardiovascular diseases. Clinically significant drug-drug interactions (DDIs) between these drugs have been recognized through case studies for many years, but the biochemical mechanisms causing these interactions have not been explained fully. Previous theories include kinetic alterations in cytochrome P-450-mediated drug metabolism or disturbances of drug-protein binding, leading to anticoagulant activity of warfarin; however, neither the enantioselective effects on warfarin metabolism nor the potential disruption of drug transporter function have been well investigated. This study investigated the etiology of the DDIs between warfarin and statins. Liquid chromatography-mass spectrometry methods were developed and validated to quantify racemic warfarin, 6 of its hydroxylated metabolites, and pure enantiomers of warfarin; these methods were applied to study the role of different absorption, distribution, metabolism, and excretion properties, leading to DDIs. Plasma protein binding displacement of warfarin was performed in the presence of statins using equilibrium dialysis method. Substrate kinetics of warfarin and pure enantiomers were performed with human liver microsomes to determine the kinetic parameters (Km and Vmax) for the formation of all 6 hydroxywarfarin metabolites, inhibition of warfarin metabolism in the presence of statins, was determined. Uptake transport studies of warfarin were performed using overexpressing HEK cell lines and efflux transport using human adenocarcinoma colonic cell line cells. Fluvastatin significantly displaced plasma protein binding of warfarin and pure enantiomers; no other statin resulted in significant displacement of warfarin. All the statins that inhibited the formation of 10-hydroxywarfarin, atorvastatin, pitavastatin, and simvastatin were highly potent compared to other statins; in contrast, only fluvastatin

  20. Clinical pharmacokinetics, metabolism, and drug-drug interaction of carfilzomib.

    PubMed

    Wang, Zhengping; Yang, Jinfu; Kirk, Christopher; Fang, Ying; Alsina, Melissa; Badros, Ashraf; Papadopoulos, Kyriakos; Wong, Alvin; Woo, Tina; Bomba, Darrin; Li, Jin; Infante, Jeffrey R

    2013-01-01

    Carfilzomib, an irreversible proteasome inhibitor, has a favorable safety profile and significant antitumor activity in patients with relapsed and refractory multiple myeloma (MM). Here we summarize the clinical pharmacokinetics (PK), metabolism, and drug-drug interaction (DDI) profile of carfilzomib. The PK of carfilzomib, infused over 2-10 minutes, was evaluated in patients with solid tumors or MM. Metabolites of carfilzomib were characterized in patient plasma and urine samples. In vitro drug metabolism and DDI studies were conducted in human liver microsomes and hepatocytes. A clinical DDI study was conducted in patients with solid tumors to evaluate the effect of carfilzomib on CYP3A activity. Plasma concentrations of carfilzomib declined rapidly and in a biphasic manner after intravenous administration. The systemic half-life was short and the systemic clearance rate was higher than hepatic blood flow. Carfilzomib was cleared largely extrahepatically via peptidase cleavage and epoxide hydrolysis. Cytochrome P450-mediated metabolism played a minor role, suggesting that coadministration of P450 inhibitors or inducers is unlikely to change its PK profile. Carfilzomib showed direct and time-dependent inhibition of CYP3A in human liver microsome preparations and exposure to carfilzomib resulted in reductions in CYP3A and 1A2 gene expression in cultured human hepatocytes. However, administration of carfilzomib did not affect the PK of midazolam in patients with solid tumors, and there were no safety signals indicative of potential drug interactions. We conclude that the rapid systemic clearance and short half-life of carfilzomib limit clinically significant DDI.

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

    PubMed Central

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

    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 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. PMID:26872079

  2. [Clinically significant drug-drug interactions between analgesics and psychotopics].

    PubMed

    Strobach, Dorothea

    2012-07-01

    Combining analgesic and psychotropic drugs can lead to pharmacodynamic and pharmacokinetic drug interactions. Under treatment with several serotonergic substances serotonin syndrome can occur, e.g., with certain opioids and antidepressant drugs. Serotonin reuptake inhibitors also affect the serotonin level in platelets, this can raise the risk for gastrointestinal bleeding especially in combination with non-steroidal antirheumatic drugs. Anticholinergic effects and sedation are common side effects of psychotropic but also analgesic drugs with possible additive results. A wide range of interactions between analgesics and psychotropics can occure during metabolism, especially via the cytochrome-P-system. The clinical relevance of warnings on drug interactions from data banks has always to be judged for the individual patient.

  3. USING SEMANTIC PREDICATIONS TO UNCOVER DRUG-DRUG INTERACTIONS IN CLINICAL DATA

    PubMed Central

    Zhang, Rui; Cairelli, Michael J.; Fiszman, Marcelo; Rosemblat, Graciela; Kilicoglu, Halil; Rindflesch, Thomas C.; Pakhomov, Serguei V.; Melton, Genevieve B.

    2014-01-01

    In this study we report on potential drug-drug interactions between drugs occurring in patient clinical data. Results are based on relationships in SemMedDB, a database of structured knowledge extracted from all MEDLINE citations (titles and abstracts) using SemRep. The core of our methodology is to construct two potential drug-drug interaction schemas, based on relationships extracted from SemMedDB. In the first schema, Drug1 and Drug2 interact through Drug1’s effect on some gene, which in turn affects Drug2. In the second, Drug1 affects Gene1, while Drug2 affects Gene2. Gene1 and Gene2, together, then have an effect on some biological function. After checking each drug pair from the medication lists of each of 22 patients, we found 19 known and 62 unknown drug-drug interactions using both schemas. For example, our results suggest that the interaction of Lisinopril, an ACE inhibitor commonly prescribed for hypertension, and the antidepressant sertraline can potentially increase the likelihood and possibly the severity of psoriasis. We also assessed the relationships extracted by SemRep from a linguistic perspective and found that the precision of SemRep was 0.58 for 300 randomly selected sentences from MEDLINE. Our study demonstrates that the use of structured knowledge in the form of relationships from the biomedical literature can support the discovery of potential drug-drug interactions occurring in patient clinical data. Moreover, SemMedDB provides a good knowledge resource for expanding the range of drugs, genes, and biological functions considered as elements in various drug-drug interaction pathways. PMID:24448204

  4. DRUG-DRUG INTERACTION PROFILES OF MEDICATION REGIMENS EXTRACTED FROM A DE-IDENTIFIED ELECTRONIC MEDICAL RECORDS SYSTEM

    PubMed Central

    Butkiewicz, Mariusz; Restrepo, Nicole A.; Haines, Jonathan L.; Crawford, Dana C.

    2016-01-01

    With age, the number of prescribed medications increases and subsequently raises the risk for adverse drug-drug interactions. These adverse effects lower quality of life and increase health care costs. Quantifying the potential burden of adverse effects before prescribing medications can be a valuable contribution to health care. This study evaluated medication lists extracted from a subset of the Vanderbilt de-identified electronic medical record system. Reported drugs were cross-referenced with the Kyoto Encyclopedia of Genes and Genomes DRUG database to identify known drug-drug interactions. On average, a medication regimen contained 6.58 medications and 2.68 drug-drug interactions. Here, we quantify the burden of potential adverse events from drug-drug interactions through drug-drug interaction profiles and include a number of alternative medications as provided by the Anatomical Therapeutic Chemical Classification System. PMID:27570646

  5. Drug-drug interactions between HMG-CoA reductase inhibitors (statins) and antiviral protease inhibitors.

    PubMed

    Chauvin, Benoit; Drouot, Sylvain; Barrail-Tran, Aurélie; Taburet, Anne-Marie

    2013-10-01

    The HMG-CoA reductase inhibitors are a class of drugs also known as statins. These drugs are effective and widely prescribed for the treatment of hypercholesterolemia and prevention of cardiovascular morbidity and mortality. Seven statins are currently available: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Although these drugs are generally well tolerated, skeletal muscle abnormalities from myalgia to severe lethal rhabdomyolysis can occur. Factors that increase statin concentrations such as drug-drug interactions can increase the risk of these adverse events. Drug-drug interactions are dependent on statins' pharmacokinetic profile: simvastatin, lovastatin and atorvastatin are metabolized through cytochrome P450 (CYP) 3A, while the metabolism of the other statins is independent of this CYP. All statins are substrate of organic anion transporter polypeptide 1B1, an uptake transporter expressed in hepatocyte membrane that may also explain some drug-drug interactions. Many HIV-infected patients have dyslipidemia and comorbidities that may require statin treatment. HIV-protease inhibitors (HIV PIs) are part of recommended antiretroviral treatment in combination with two reverse transcriptase inhibitors. All HIV PIs except nelfinavir are coadministered with a low dose of ritonavir, a potent CYP3A inhibitor to improve their pharmacokinetic properties. Cobicistat is a new potent CYP3A inhibitor that is combined with elvitegravir and will be combined with HIV-PIs in the future. The HCV-PIs boceprevir and telaprevir are both, to different extents, inhibitors of CYP3A. This review summarizes the pharmacokinetic properties of statins and PIs with emphasis on their metabolic pathways explaining clinically important drug-drug interactions. Simvastatin and lovastatin metabolized through CYP3A have the highest potency for drug-drug interaction with potent CYP3A inhibitors such as ritonavir- or cobicistat-boosted HIV-PI or the

  6. Bedaquiline: a review of human pharmacokinetics and drug-drug interactions.

    PubMed

    van Heeswijk, R P G; Dannemann, B; Hoetelmans, R M W

    2014-09-01

    Bedaquiline has recently been approved for the treatment of pulmonary multidrug-resistant tuberculosis (TB) as part of combination therapy in adults. It is metabolized primarily by the cytochrome P450 isoenzyme 3A4 (CYP3A4) to a less-active N-monodesmethyl metabolite. Phase I and Phase II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant TB have assessed the pharmacokinetics and drug-drug interaction profile of bedaquiline. Potential interactions have been assessed between bedaquiline and first- and second-line anti-TB drugs (rifampicin, rifapentine, isoniazid, pyrazinamide, ethambutol, kanamycin, ofloxacin and cycloserine), commonly used antiretroviral agents (lopinavir/ritonavir, nevirapine and efavirenz) and a potent CYP3A inhibitor (ketoconazole). This review summarizes the pharmacokinetic profile of bedaquiline as well as the results of the drug-drug interaction studies.

  7. Using linked data for mining drug-drug interactions in electronic health records.

    PubMed

    Pathak, Jyotishman; Kiefer, Richard C; Chute, Christopher G

    2013-01-01

    By nature, healthcare data is highly complex and voluminous. While on one hand, it provides unprecedented opportunities to identify hidden and unknown relationships between patients and treatment outcomes, or drugs and allergic reactions for given individuals, representing and querying large network datasets poses significant technical challenges. In this research, we study the use of Semantic Web and Linked Data technologies for identifying drug-drug interaction (DDI) information from publicly available resources, and determining if such interactions were observed using real patient data. Specifically, we apply Linked Data principles and technologies for representing patient data from electronic health records (EHRs) at Mayo Clinic as Resource Description Framework (RDF), and identify potential drug-drug interactions (PDDIs) for widely prescribed cardiovascular and gastroenterology drugs. Our results from the proof-of-concept study demonstrate the potential of applying such a methodology to study patient health outcomes as well as enabling genome-guided drug therapies and treatment interventions.

  8. Using Linked Data for Mining Drug-Drug Interactions in Electronic Health Records

    PubMed Central

    Pathak, Jyotishman; Kiefer, Richard C.; Chute, Christopher G.

    2014-01-01

    By nature, healthcare data is highly complex and voluminous. While on one hand, it provides unprecedented opportunities to identify hidden and unknown relationships between patients and treatment outcomes, or drugs and allergic reactions for given individuals, representing and querying large network datasets poses significant technical challenges. In this research, we study the use of Semantic Web and Linked Data technologies for identifying drug-drug interaction (DDI) information from publicly available resources, and determining if such interactions were observed using real patient data. Specifically, we apply Linked Data principles and technologies for representing patient data from electronic health records (EHRs) at Mayo Clinic as Resource Description Framework (RDF), and identify potential drug-drug interactions (PDDIs) for widely prescribed cardiovascular and gastroenterology drugs. Our results from the proof-of-concept study demonstrate the potential of applying such a methodology to study patient health outcomes as well as enabling genome-guided drug therapies and treatment interventions. PMID:23920643

  9. Drug-drug interactions with tyrosine-kinase inhibitors: a clinical perspective.

    PubMed

    van Leeuwen, Roelof W F; van Gelder, Teun; Mathijssen, Ron H J; Jansman, Frank G A

    2014-07-01

    In the past decade, many tyrosine-kinase inhibitors have been introduced in oncology and haemato-oncology. Because this new class of drugs is extensively used, serious drug-drug interactions are an increasing risk. In this Review, we give a comprehensive overview of known or suspected drug-drug interactions between tyrosine-kinase inhibitors and other drugs. We discuss all haemato-oncological and oncological tyrosine-kinase inhibitors that had been approved by Aug 1, 2013, by the US Food and Drug Administration or the European Medicines Agency. Various clinically relevant drug interactions with tyrosine-kinase inhibitors have been identified. Most interactions concern altered bioavailability due to altered stomach pH, metabolism by cytochrome P450 isoenzymes, and prolongation of the QTc interval. To guarantee the safe use of tyrosine-kinase inhibitors, a drugs review for each patient is needed. This Review provides specific recommendations to guide haemato-oncologists, oncologists, and clinical pharmacists, through the process of managing drug-drug interactions during treatment with tyrosine-kinase inhibitors in daily clinical practice.

  10. Roles of rifampicin in drug-drug interactions: underlying molecular mechanisms involving the nuclear pregnane X receptor

    PubMed Central

    Chen, Jiezhong; Raymond, Kenneth

    2006-01-01

    Rifampicin, an important drug in the treatment of tuberculosis, is used extensively despite its broad effects on drug-drug interactions, creating serious problems. The clinical importance of such interactions includes autoinduction leading to suboptimal or failed treatment. The concomitantly administered effects of rifampicin on other drugs can result in their altered metabolism or transportation that are metabolised by cytochromes P450 or transported by p-glycoprotein in the gastrointestinal tract and liver. This review paper summarises recent findings with emphases on the molecular mechanisms used to explain these broad drug-drug interactions. In general, rifampicin can act on a pattern: rifampicin activates the nuclear pregnane X receptor that in turn affects cytochromes P450, glucuronosyltransferases and p-glycoprotein activities. This pattern of action may explain many of the rifampicin inducing drug-drug interactions. However, effects through other mechanisms have also been reported and these make any explanation of such drug-drug interactions more complex. PMID:16480505

  11. Roles of rifampicin in drug-drug interactions: underlying molecular mechanisms involving the nuclear pregnane X receptor.

    PubMed

    Chen, Jiezhong; Raymond, Kenneth

    2006-02-15

    Rifampicin, an important drug in the treatment of tuberculosis, is used extensively despite its broad effects on drug-drug interactions, creating serious problems. The clinical importance of such interactions includes autoinduction leading to suboptimal or failed treatment. The concomitantly administered effects of rifampicin on other drugs can result in their altered metabolism or transportation that are metabolised by cytochromes P450 or transported by p-glycoprotein in the gastrointestinal tract and liver. This review paper summarises recent findings with emphases on the molecular mechanisms used to explain these broad drug-drug interactions. In general, rifampicin can act on a pattern: rifampicin activates the nuclear pregnane X receptor that in turn affects cytochromes P450, glucuronosyltransferases and p-glycoprotein activities. This pattern of action may explain many of the rifampicin inducing drug-drug interactions. However, effects through other mechanisms have also been reported and these make any explanation of such drug-drug interactions more complex.

  12. Predicting Pharmacodynamic Drug-Drug Interactions through Signaling Propagation Interference on Protein-Protein Interaction Networks

    PubMed Central

    Park, Kyunghyun; Kim, Docyong; Ha, Suhyun; Lee, Doheon

    2015-01-01

    As pharmacodynamic drug-drug interactions (PD DDIs) could lead to severe adverse effects in patients, it is important to identify potential PD DDIs in drug development. The signaling starting from drug targets is propagated through protein-protein interaction (PPI) networks. PD DDIs could occur by close interference on the same targets or within the same pathways as well as distant interference through cross-talking pathways. However, most of the previous approaches have considered only close interference by measuring distances between drug targets or comparing target neighbors. We have applied a random walk with restart algorithm to simulate signaling propagation from drug targets in order to capture the possibility of their distant interference. Cross validation with DrugBank and Kyoto Encyclopedia of Genes and Genomes DRUG shows that the proposed method outperforms the previous methods significantly. We also provide a web service with which PD DDIs for drug pairs can be analyzed at http://biosoft.kaist.ac.kr/targetrw. PMID:26469276

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

    PubMed

    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.

  14. Clustering drug-drug interaction networks with energy model layouts: community analysis and drug repurposing

    PubMed Central

    Udrescu, Lucreţia; Sbârcea, Laura; Topîrceanu, Alexandru; Iovanovici, Alexandru; Kurunczi, Ludovic; Bogdan, Paul; Udrescu, Mihai

    2016-01-01

    Analyzing drug-drug interactions may unravel previously unknown drug action patterns, leading to the development of new drug discovery tools. We present a new approach to analyzing drug-drug interaction networks, based on clustering and topological community detection techniques that are specific to complex network science. Our methodology uncovers functional drug categories along with the intricate relationships between them. Using modularity-based and energy-model layout community detection algorithms, we link the network clusters to 9 relevant pharmacological properties. Out of the 1141 drugs from the DrugBank 4.1 database, our extensive literature survey and cross-checking with other databases such as Drugs.com, RxList, and DrugBank 4.3 confirm the predicted properties for 85% of the drugs. As such, we argue that network analysis offers a high-level grasp on a wide area of pharmacological aspects, indicating possible unaccounted interactions and missing pharmacological properties that can lead to drug repositioning for the 15% drugs which seem to be inconsistent with the predicted property. Also, by using network centralities, we can rank drugs according to their interaction potential for both simple and complex multi-pathology therapies. Moreover, our clustering approach can be extended for applications such as analyzing drug-target interactions or phenotyping patients in personalized medicine applications. PMID:27599720

  15. Integration of heterogeneous clinical decision support systems and their knowledge sets: feasibility study with Drug-Drug Interaction alerts.

    PubMed

    Kam, Hye Jin; Kim, Jeong Ah; Cho, InSook; Kim, Yoon; Park, Rae Woong

    2011-01-01

    There exist limitations in both commercial and in-house clinical decision support systems (CDSSs) and issues related to the integration of different knowledge sources and CDSSs. We chose Standard-based Shareable Active Guideline Environment (SAGE) as a new architecture with knowledge integration and a centralized knowledge base which includes authoring/management functions and independent CDSS, and applied it to Drug-Drug Interaction (DDI) CDSS. The aim of this study was to evaluate the feasibility of the newly integrated DDI alerting CDSS into a real world hospital information system involving construction of an integrated CDSS derived from two heterogeneous systems and their knowledge sets. The proposed CDSS was successfully implemented and compensated for the weaknesses of the old CDSS from knowledge integration and management, and its applicability in actual situations was verified. Although the DDI CDSS was constructed as an example case, the new CDS architecture might prove applicable to areas of CDSSs.

  16. Addressing drug-drug and drug-food interactions through personalized empowerment services for healthcare.

    PubMed

    Spanakis, Marios; Spanakis, Emmanouil G; Kondylakis, Haridimos; Sfakianakis, Stelios; Genitsaridi, Irini; Sakkalis, Vangelis; Tsiknakis, Manolis; Marias, Kostas

    2016-08-01

    Personalized healthcare systems support the provision of timely and appropriate information regarding healthcare options and treatment alternatives. Especially for patients that receive multi-drug treatments a key issue is the minimization of the risk of adverse effects due to drug-drug interactions (DDIs). DDIs may be the result of doctor prescribed drugs but also due to self-medication of conventional drugs, alternative medicines, food habits, alcohol or smoking. It is therefore crucial for personalized health systems, apart from assisting physicians for optimal prescription practices, to also provide appropriate information for individual users for drug-drug interactions or similar information regarding risks for modulation of the ensuing treatment. In this manuscript we describe a DDI service including drug-food, drug-herb and other lifestyle-related factors, developed in the context of a personalized patient empowerment platform. The solution enables guidance to patients for their medication on how to reduce the risk of unwanted drug interactions and side effects in a seamless and transparent way. We present and analyze the implemented services and provide examples on using an alerting service to identify potential DDIs in two different chronic diseases, congestive heart failure and osteoarthritis.

  17. Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin.

    PubMed

    Kwon, Mihwa; Choi, Young A; Choi, Min-Koo; Song, Im-Sook

    2015-01-01

    Berberine, the main active component of the herbal medicine Rhizoma Coptidis, has been reported to have hypoglycemic and insulin-sensitizing effects and, therefore, could be combined with metformin therapy. Thus, we assessed the potential drug-drug interactions between berberine and metformin. We investigated the in vitro inhibitory potency of berberine on metformin uptake in HEK293 cells overexpressing organic cation transporter (OCT) 1 and 2. To investigate whether this inhibitory effect of berberine on OCT1 and OCT2 could change the pharmacokinetics of metformin in vivo, we measured the effect of berberine co-administration on the pharmacokinetics of metformin at a single intravenous dose of 2 mg/kg metformin and 10 mg/kg berberine. In HEK293 cells, berberine inhibited OCT1- and OCT2-mediated metformin uptake in a concentration dependent manner and IC50 values for OCT1 and OCT2 were 7.28 and 11.3 μM, respectively. Co-administration of berberine increased the initial plasma concentration and AUC of metformin and decreased systemic clearance and volume of distribution of metformin in rats, suggesting that berberine inhibited disposition of metformin, which is governed by OCT1 and OCT2. Berberine inhibited the transport activity of OCT1 and OCT2 and showed significant potential drug-drug interactions with metformin in in vivo rats.

  18. Pharmacokinetic and pharmacodynamic drug-drug interaction assessment between pradigastat and digoxin or warfarin.

    PubMed

    Yan, Jing-He; Meyers, Dan; Lee, Zachary; Danis, Kate; Neelakantham, Srikanth; Majumdar, Tapan; Rebello, Sam; Sunkara, Gangadhar; Chen, Jin

    2014-07-01

    Pradigastat, a novel diacylglycerol acyltransferase-1 inhibitor, was evaluated for both pharmacokinetic (PK) and pharmacodynamic (PD) drug-drug interactions when co-administered with digoxin or warfarin in healthy subjects. This open-label study included two parallel subject cohorts each with three sequential treatment periods. Forty subjects were enrolled in the study with 20 subjects allocated to each cohort. PK and PD (PT/INR for warfarin only) samples were collected in each period. The statistical analysis results showed that the 90% CIs of the geometric mean ratios of digoxin, R-warfarin, and S-warfarin PK parameters (AUC and Cmax) were all within 0.80-1.25 interval. The 90% CIs of the geometric mean ratios of pradigastat PK parameters (AUC and Cmax) were within 0.80-1.25 interval when co-administered with warfarin; while co-administration with digoxin slightly reduced pradigastat exposure (∼15%). The results also showed that 90% CIs of the geometric mean ratios of warfarin PD parameters (AUC(PT), PTmax, AUC(INR), and INRmax) were within 0.80-1.25 interval. Pradigastat and digoxin or warfarin had no relevant clinical PK or PD drug-drug interactions. Administration of pradigastat and warfarin or pradigastat and digoxin as a mono or combined treatment appears to be safe and tolerated.

  19. Inhibition of human liver aldehyde oxidase: implications for potential drug-drug interactions.

    PubMed

    Barr, John T; Jones, Jeffrey P

    2011-12-01

    During the course of our research efforts to understand the kinetics of human aldehyde oxidase as a xenobiotic-clearing enzyme, we investigated the effect of eight different inhibitors on the oxidation of the probe substrate phthalazine. Saturation kinetic parameters for phthalazine oxidation in human liver cytosol were found to be the following: K(m) = 8.0 ± 0.4 μM and V(max) = 4.3 ± 0.1 nmol · min(-1) · mg protein(-1). Inhibitory potency of the inhibitors tested ranged from 0.1 to 5 μM. Of the eight different inhibitor compounds tested, seven were observed to inhibit through a mixed mode and one through a strictly competitive mode. A ratio of the K(ii) and K(is) values was used to assess the relative competitiveness of each inhibitor. For the mixed inhibitors, the mode of inhibition varied from mostly uncompetitive to predominantly competitive (K(ii)/K(is) values ranging from 0.1 to 15). The implications for potential drug-drug interactions and inhibition mechanism are discussed. We found two inhibitors, clozapine and chlorpromazine, that have a moderate predicted risk of drug-drug interactions based on the K(i) value relative to the inhibitor concentration in human plasma, having a calculated [I]/K(i) value of 0.4 and 0.8, respectively.

  20. A Single Kernel-Based Approach to Extract Drug-Drug Interactions from Biomedical Literature

    PubMed Central

    Zhang, Yijia; Lin, Hongfei; Yang, Zhihao; Wang, Jian; Li, Yanpeng

    2012-01-01

    When one drug influences the level or activity of another drug this is known as a drug-drug interaction (DDI). Knowledge of such interactions is crucial for patient safety. However, the volume and content of published biomedical literature on drug interactions is expanding rapidly, making it increasingly difficult for DDIs database curators to detect and collate DDIs information manually. In this paper, we propose a single kernel-based approach to extract DDIs from biomedical literature. This novel kernel-based approach can effectively make full use of syntactic structural information of the dependency graph. In particular, our approach can efficiently represent both single subgraph topological information and the relation of two subgraphs in the dependency graph. Experimental evaluations showed that our single kernel-based approach can achieve state-of-the-art performance on the publicly available DDI corpus without exploiting multiple kernels or additional domain resources. PMID:23133662

  1. Resolving anaphoras for the extraction of drug-drug interactions in pharmacological documents

    PubMed Central

    2010-01-01

    Background Drug-drug interactions are frequently reported in the increasing amount of biomedical literature. Information Extraction (IE) techniques have been devised as a useful instrument to manage this knowledge. Nevertheless, IE at the sentence level has a limited effect because of the frequent references to previous entities in the discourse, a phenomenon known as 'anaphora'. DrugNerAR, a drug anaphora resolution system is presented to address the problem of co-referring expressions in pharmacological literature. This development is part of a larger and innovative study about automatic drug-drug interaction extraction. Methods The system uses a set of linguistic rules drawn by Centering Theory over the analysis provided by a biomedical syntactic parser. Semantic information provided by the Unified Medical Language System (UMLS) is also integrated in order to improve the recognition and the resolution of nominal drug anaphors. Besides, a corpus has been developed in order to analyze the phenomena and evaluate the current approach. Each possible case of anaphoric expression was looked into to determine the most effective way of resolution. Results An F-score of 0.76 in anaphora resolution was achieved, outperforming significantly the baseline by almost 73%. This ad-hoc reference line was developed to check the results as there is no previous work on anaphora resolution in pharmalogical documents. The obtained results resemble those found in related-semantic domains. Conclusions The present approach shows very promising results in the challenge of accounting for anaphoric expressions in pharmacological texts. DrugNerAr obtains similar results to other approaches dealing with anaphora resolution in the biomedical domain, but, unlike these approaches, it focuses on documents reflecting drug interactions. The Centering Theory has proved being effective at the selection of antecedents in anaphora resolution. A key component in the success of this framework is the

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

    PubMed

    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

  3. Venetoclax (ABT-199) Might Act as a Perpetrator in Pharmacokinetic Drug-Drug Interactions.

    PubMed

    Weiss, Johanna; Gajek, Thomas; Köhler, Bruno Christian; Haefeli, Walter Emil

    2016-02-24

    Venetoclax (ABT-199) represents a specific B-cell lymphoma 2 (Bcl-2) inhibitor that is currently under development for the treatment of lymphoid malignancies. So far, there is no published information on its interaction potential with important drug metabolizing enzymes and drug transporters, or its efficacy in multidrug resistant (MDR) cells. We therefore scrutinized its drug-drug interaction potential in vitro. Inhibition of cytochrome P450 enzymes (CYPs) was quantified by commercial kits. Inhibition of drug transporters (P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP), and organic anion transporting polypeptides (OATPs)) was evaluated by the use of fluorescent probe substrates. Induction of drug transporters and drug metabolizing enzymes was quantified by real-time RT-PCR. The efficacy of venetoclax in MDR cells lines was evaluated with proliferation assays. Venetoclax moderately inhibited P-gp, BCRP, OATP1B1, OATP1B3, CYP3A4, and CYP2C19, whereas CYP2B6 activity was increased. Venetoclax induced the mRNA expression of CYP1A1, CYP1A2, UGT1A3, and UGT1A9. In contrast, expression of ABCB1 was suppressed, which might revert tumor resistance towards antineoplastic P-gp substrates. P-gp over-expression led to reduced antiproliferative effects of venetoclax. Effective concentrations for inhibition and induction lay in the range of maximum plasma concentrations of venetoclax, indicating that it might act as a perpetrator drug in pharmacokinetic drug-drug interactions.

  4. Pregnane X receptor and natural products: beyond drug-drug interactions.

    PubMed

    Staudinger, Jeff L; Ding, Xunshan; Lichti, Kristin

    2006-12-01

    The pregnane X receptor (PXR, NR1I2) is a member of the nuclear receptor superfamily that is activated by a myriad of compounds and natural products in clinical use. Activation of PXR represents the basis for several clinically important drug-drug interactions. Although PXR activation has undesirable effects in patients on combination therapy, it also mediates the hepatoprotective effects exhibited by some herbal remedies. This review focuses on PXR activation by natural products and the potential therapeutic opportunities presented. In particular, the biological effects of St. John's Wort, gugulipid, kava kava, Coleus forskolii, Hypoxis, Sutherlandia, qing hao, wu wei zi, gan cao and other natural products are discussed. The impact of these natural products on drug metabolism and hepatoprotection is highlighted in the context of activation and antagonism of PXR.

  5. Drug-drug Interaction Discovery Using Abstraction Networks for "National Drug File - Reference Terminology" Chemical Ingredients.

    PubMed

    Ochs, Christopher; Zheng, Ling; Gu, Huanying; Perl, Yehoshua; Geller, James; Kapusnik-Uner, Joan; Zakharchenko, Aleksandr

    2015-01-01

    The National Drug File - Reference Terminology (NDF-RT) is a large and complex drug terminology. NDF-RT provides important information about clinical drugs, e.g., their chemical ingredients, mechanisms of action, dosage form and physiological effects. Within NDF-RT such information is represented using tens of thousands of roles. It is difficult to comprehend large, complex terminologies like NDF-RT. In previous studies, we introduced abstraction networks to summarize the content and structure of terminologies. In this paper, we introduce the Ingredient Abstraction Network to summarize NDF-RT's Chemical Ingredients and their associated drugs. Additionally, we introduce the Aggregate Ingredient Abstraction Network, for controlling the granularity of summarization provided by the Ingredient Abstraction Network. The Ingredient Abstraction Network is used to support the discovery of new candidate drug-drug interactions (DDIs) not appearing in First Databank, Inc.'s DDI knowledgebase.

  6. Renal drug transporters and their significance in drug-drug interactions.

    PubMed

    Yin, Jia; Wang, Joanne

    2016-09-01

    The kidney is a vital organ for the elimination of therapeutic drugs and their metabolites. Renal drug transporters, which are primarily located in the renal proximal tubules, play an important role in tubular secretion and reabsorption of drug molecules in the kidney. Tubular secretion is characterized by high clearance capacities, broad substrate specificities, and distinct charge selectivity for organic cations and anions. In the past two decades, substantial progress has been made in understanding the roles of transporters in drug disposition, efficacy, toxicity and drug-drug interactions (DDIs). In the kidney, several transporters are involved in renal handling of organic cation (OC) and organic anion (OA) drugs. These transporters are increasingly recognized as the target for clinically significant DDIs. This review focuses on the functional characteristics of major human renal drug transporters and their involvement in clinically significant DDIs.

  7. Enhancing Extraction of Drug-Drug Interaction from Literature Using Neutral Candidates, Negation, and Clause Dependency

    PubMed Central

    Bokharaeian, Behrouz; Diaz, Alberto; Chitsaz, Hamidreza

    2016-01-01

    Motivation Supervised biomedical relation extraction plays an important role in biomedical natural language processing, endeavoring to obtain the relations between biomedical entities. Drug-drug interactions, which are investigated in the present paper, are notably among the critical biomedical relations. Thus far many methods have been developed with the aim of extracting DDI relations. However, unfortunately there has been a scarcity of comprehensive studies on the effects of negation, complex sentences, clause dependency, and neutral candidates in the course of DDI extraction from biomedical articles. Results Our study proposes clause dependency features and a number of features for identifying neutral candidates as well as negation cues and scopes. Furthermore, our experiments indicate that the proposed features significantly improve the performance of the relation extraction task combined with other kernel methods. We characterize the contribution of each category of features and finally conclude that neutral candidate features have the most prominent role among all of the three categories. PMID:27695078

  8. Pharmacokinetic drug-drug interaction and their implication in clinical management

    PubMed Central

    Palleria, Caterina; Di Paolo, Antonello; Giofrè, Chiara; Caglioti, Chiara; Leuzzi, Giacomo; Siniscalchi, Antonio; De Sarro, Giovambattista; Gallelli, Luca

    2013-01-01

    Drug-drug interactions (DDIs) are one of the commonest causes of medication error in developed countries, particularly in the elderly due to poly-therapy, with a prevalence of 20-40%. In particular, poly-therapy increases the complexity of therapeutic management and thereby the risk of clinically important DDIs, which can both induce the development of adverse drug reactions or reduce the clinical efficacy. DDIs can be classify into two main groups: pharmacokinetic and pharmacodynamic. In this review, using Medline, PubMed, Embase, Cochrane library and Reference lists we searched articles published until June 30 2012, and we described the mechanism of pharmacokinetic DDIs focusing the interest on their clinical implications. PMID:24516494

  9. Drug-drug and food-drug pharmacokinetic interactions with new insulinotropic agents repaglinide and nateglinide.

    PubMed

    Scheen, André J

    2007-01-01

    This review describes the current knowledge on drug-drug and food-drug interactions with repaglinide and nateglinide. These two meglitinide derivatives, commonly called glinides, have been developed for improving insulin secretion of patients with type 2 diabetes mellitus. They are increasingly used either in monotherapy or in combination with other oral antihyperglycaemic agents for the treatment of type 2 diabetes. Compared with sulfonylureas, glinides have been shown to (i) provide a better control of postprandial hyperglycaemia, (ii) overcome some adverse effects, such as hypoglycaemia, and (iii) have a more favourable safety profile, especially in patients with renal failure. The meal-related timing of administration of glinides and the potential influence of food and meal composition on their bioavailability may be important. In addition, some food components (e.g. grapefruit juice) may cause pharmacokinetic interactions. Because glinides are metabolised via cytochrome P450 (CYP) 3A4 isoenzyme, they are indeed exposed to pharmacokinetic interactions. In addition to CYP3A4, repaglinide is metabolised via CYP2C8, while nateglinide metabolism also involves CYP2C9. Furthermore, both compounds and their metabolites may undergo specialised transport/uptake in the intestine, another source of pharmacokinetic interactions. Clinically relevant drug-drug interactions are those that occur when glinides are administered together with other glucose-lowering agents or compounds widely coadministered to diabetic patients (e.g. lipid-lowering agents), with drugs that are known to induce (risk of lower glinide plasma levels and thus of deterioration of glucose control) or inhibit (risk of higher glinide plasma levels leading to hypoglycaemia) CYP isoenzymes concerned in their metabolism, or with drugs that have a narrow efficacy : toxicity ratio. Pharmacokinetic interactions reported in the literature appear to be more frequent and more important with repaglinide than with

  10. Identification and Mechanistic Investigation of Drug-Drug Interactions Associated With Myopathy: A Translational Approach.

    PubMed

    Han, X; Quinney, S K; Wang, Z; Zhang, P; Duke, J; Desta, Z; Elmendorf, J S; Flockhart, D A; Li, L

    2015-09-01

    Myopathy is a group of muscle diseases that can be induced or exacerbated by drug-drug interactions (DDIs). We sought to identify clinically important myopathic DDIs and elucidate their underlying mechanisms. Five DDIs were found to increase the risk of myopathy based on analysis of observational data from the Indiana Network of Patient Care. Loratadine interacted with simvastatin (relative risk 95% confidence interval [CI] = [1.39, 2.06]), alprazolam (1.50, 2.31), ropinirole (2.06, 5.00), and omeprazole (1.15, 1.38). Promethazine interacted with tegaserod (1.94, 4.64). In vitro investigation showed that these DDIs were unlikely to result from inhibition of drug metabolism by CYP450 enzymes or from inhibition of hepatic uptake via the membrane transporter OATP1B1/1B3. However, we did observe in vitro synergistic myotoxicity of simvastatin and desloratadine, suggesting a role in loratadine-simvastatin interaction. This interaction was epidemiologically confirmed (odds ratio 95% CI = [2.02, 3.65]) using the data from the US Food and Drug Administration Adverse Event Reporting System.

  11. Drug-Drug Interaction Associated with Mold-Active Triazoles among Hospitalized Patients.

    PubMed

    Andes, David; Azie, Nkechi; Yang, Hongbo; Harrington, Rachel; Kelley, Caroline; Tan, Ruo-Ding; Wu, Eric Q; Franks, Billy; Kristy, Rita; Lee, Edward; Khandelwal, Nikhil; Spalding, James

    2016-06-01

    The majority of hospitalized patients receiving mold-active triazoles are at risk of drug-drug interactions (DDIs). Efforts are needed to increase awareness of DDIs that pose a serious risk of adverse events. Triazoles remain the most commonly utilized antifungals. Recent developments have included the mold-active triazoles (MATs) itraconazole, voriconazole, and posaconazole, which are first-line agents for the treatment of filamentous fungal infections but have the potential for DDIs. This objective of this study was to evaluate the prevalence of triazole DDIs. Hospitalized U.S. adults with MAT use were identified in the Cerner HealthFacts database, which contained data from over 150 hospitals (2005 to 2013). The severities of DDIs with MATs were categorized, using drug labels and the drug information from the Drugdex system (Thompson Micromedex), into four groups (contraindicated, major, moderate, and minor severity). DDIs of minor severity were not counted. A DDI event was considered to have occurred if the following two conditions were met: (i) the patient used at least one drug with a classification of at least a moderate interaction with the MAT during the hospitalization and (ii) there was a period of overlap between the administration of the MAT and that of the interacting drug of at least 1 day. A total of 6,962 hospitalizations with MAT use were identified. Among them, 88% of hospitalizations with voriconazole use, 86% of hospitalizations with itraconazole use, and 93% of hospitalizations with posaconazole use included the use of a concomitant interacting drug. A total of 68% of hospitalizations with posaconazole use, 34% of hospitalizations with itraconazole use, and 20% of hospitalizations with voriconazole use included the use of at least one drug with a DDI of contraindicated severity. A total of 83% of hospitalizations with posaconazole use, 61% of hospitalizations with itraconazole use, and 82% of hospitalizations with voriconazole use included the

  12. Drug-Drug Interaction Associated with Mold-Active Triazoles among Hospitalized Patients

    PubMed Central

    Azie, Nkechi; Yang, Hongbo; Harrington, Rachel; Kelley, Caroline; Tan, Ruo-Ding; Wu, Eric Q.; Franks, Billy; Kristy, Rita; Lee, Edward; Khandelwal, Nikhil; Spalding, James

    2016-01-01

    The majority of hospitalized patients receiving mold-active triazoles are at risk of drug-drug interactions (DDIs). Efforts are needed to increase awareness of DDIs that pose a serious risk of adverse events. Triazoles remain the most commonly utilized antifungals. Recent developments have included the mold-active triazoles (MATs) itraconazole, voriconazole, and posaconazole, which are first-line agents for the treatment of filamentous fungal infections but have the potential for DDIs. This objective of this study was to evaluate the prevalence of triazole DDIs. Hospitalized U.S. adults with MAT use were identified in the Cerner HealthFacts database, which contained data from over 150 hospitals (2005 to 2013). The severities of DDIs with MATs were categorized, using drug labels and the drug information from the Drugdex system (Thompson Micromedex), into four groups (contraindicated, major, moderate, and minor severity). DDIs of minor severity were not counted. A DDI event was considered to have occurred if the following two conditions were met: (i) the patient used at least one drug with a classification of at least a moderate interaction with the MAT during the hospitalization and (ii) there was a period of overlap between the administration of the MAT and that of the interacting drug of at least 1 day. A total of 6,962 hospitalizations with MAT use were identified. Among them, 88% of hospitalizations with voriconazole use, 86% of hospitalizations with itraconazole use, and 93% of hospitalizations with posaconazole use included the use of a concomitant interacting drug. A total of 68% of hospitalizations with posaconazole use, 34% of hospitalizations with itraconazole use, and 20% of hospitalizations with voriconazole use included the use of at least one drug with a DDI of contraindicated severity. A total of 83% of hospitalizations with posaconazole use, 61% of hospitalizations with itraconazole use, and 82% of hospitalizations with voriconazole use included the

  13. Similarity-based modeling in large-scale prediction of drug-drug interactions

    PubMed Central

    Vilar, Santiago; Uriarte, Eugenio; Santana, Lourdes; Lorberbaum, Tal; Hripcsak, George; Friedman, Carol; Tatonetti, Nicholas P

    2015-01-01

    Drug-drug interactions (DDIs) are a major cause of adverse drug effects and a public health concern, as they increase hospital care expenses and reduce patients’ quality of life. DDI detection is, therefore, an important objective in patient safety, one whose pursuit affects drug development and pharmacovigilance. In this article, we describe a protocol applicable on a large scale to predict novel DDIs based on similarity of drug interaction candidates to drugs involved in established DDIs. the method integrates a reference standard database of known DDIs with drug similarity information extracted from different sources, such as 2D and 3D molecular structure, interaction profile, target and side-effect similarities. the method is interpretable in that it generates drug interaction candidates that are traceable to pharmacological or clinical effects. We describe a protocol with applications in patient safety and preclinical toxicity screening. the time frame to implement this protocol is 5–7 h, with additional time potentially necessary, depending on the complexity of the reference standard DDI database and the similarity measures implemented. PMID:25122524

  14. MDR- and CYP3A4-mediated drug-drug interactions.

    PubMed

    Pal, Dhananjay; Mitra, Ashim K

    2006-09-01

    P-glycoprotein (P-gp), multiple drug resistance associated proteins (MRPs), and cytochrome P450 3A4 together constitute a highly efficient barrier for many orally absorbed drugs. Multidrug regimens and corresponding drug-drug interactions are known to cause many adverse drug reactions and treatment failures. Available literature, clinical reports, and in vitro studies from our laboratory indicate that many drugs are substrates for both P-gp and CYP3A4. Our primary hypothesis is that transport and metabolism of protease inhibitors (PIs) and NNRTIs will be altered when administered in combination with azole antifungals, macrolide, fluroquinolone antibiotics, statins, cardiovascular agents, immune modulators, and recreational drugs [benzodiazepines, cocaine, lysergic acid dithylamide (LSD), marijuana, amphetamine (Meth), 3,4-methylenedioxymethamphetamine (MDMA), and opiates] due to efflux, and/or metabolism at cellular targets. Therefore, such drug combinations could be a reason for the unexpected and unexplainable therapeutic outcomes. A number of clinical reports on drug interaction between PIs and other classes (macrolide antibiotics, azole antifungals, cholesterol lowering statins, cardiovascular medicines, and immunomodulators) are discussed in this article. MDCKII-MDR1 was employed as an in vitro model to evaluate the effects of antiretrovirals, azole antifungals, macrolide, and fluroquinolone antibiotics on efflux transporters. Ketoconazole (50 muM) enhanced the intracellular concentration of (3)H ritonavir. The inhibitory effects of ketoconazole and MK 571 on the efflux of (3)H ritonavir were comparable. An additive effect was observed with simultaneous incorporation of ketoconazole and MK 571. Results of (3)H ritonavir uptake studies were confirmed with transcellular transport studies. Several fluroquinolones were also evaluated on P-gp-mediated efflux of (3)H cyclosporin and 14C erythromycin. These in vitro studies indicate that grepafloxacin, levofloxacin

  15. The Effect of CYP2D6 Drug-Drug Interactions on Hydrocodone Effectiveness

    PubMed Central

    Monte, Andrew A.; Heard, Kennon J.; Campbell, Jenny; Hamamura, D.; Weinshilboum, Richard M.; Vasiliou, Vasilis

    2014-01-01

    Objectives The hepatic cytochrome 2D6 (CYP2D6) is a saturable enzyme responsible for metabolism of approximately 25% of known pharmaceuticals. CYP interactions can alter the efficacy of prescribed medications. Hydrocodone is largely dependent on CYP2D6 metabolism for analgesia, ondansetron is inactivated by CYP2D6, and oxycodone analgesia is largely independent of CYP2D6. The objective was to determine if CYP2D6 medication co-ingestion decreases the effectiveness of hydrocodone. Methods This was a prospective observational study conducted in an academic U.S. emergency department (ED). Subjects were included if they had self-reported pain or nausea; and were excluded if they were unable to speak English, were less than 18 years of age, had liver or renal failure, or carried diagnoses of chronic pain or cyclic vomiting. Detailed drug ingestion histories for the preceding 48 hours prior to the ED visit were obtained. The patient's pain and nausea were quantified using a 100-millimeter visual analogue scale (VAS) at baseline prior to drug administration and following doses of hydrocodone, oxycodone, or ondansetron. We used a mixed model with random subject effect to determine the interaction between CYP2D6 drug ingestion and study drug effectiveness. Odds ratios (OR) were calculated to compare clinically significant VAS changes between CYP2D6 users and non-users. Results Two hundred fifty (49.8%) of the 502 subjects enrolled had taken at least one CYP2D6 substrate, inhibitor, or inducing pharmaceutical, supplement, or illicit drug in the 48 hours prior to ED presentation. CYP2D6-drug users were one third as likely to respond to hydrocodone (OR 0.33, 95% CI = 0.1 to 0.8), and more than three times as likely as non-users to respond to ondansetron (OR 3.4, 95% CI = 1.3 to 9.1). There was no significant difference in oxycodone effectiveness between CYP2D6 users and non-users (OR 0.53, 95% CI = 0.3 to 1.1). Conclusions CYP2D6 drug-drug interactions appear to change

  16. Pharmacokinetic and Pharmacodynamic Analyses of Drug-Drug Interactions between Iguratimod and Warfarin.

    PubMed

    Yamamoto, Tetsuya; Hasegawa, Kyoko; Onoda, Makoto; Tanaka, Keiichi

    2016-01-01

    Iguratimod (IGU), a disease-modifying antirheumatic drug launched in September 2012, has been reported to carry a risk of severe hemorrhages through a suspected interaction with warfarin (WF) in the all-case surveillance and early postmarketing-phase vigilance. To elucidate possible mechanisms of adverse interaction between IGU and WF, we analyzed the effects of IGU on the pharmacodynamics and pharmacokinetics of WF in rats. IGU was orally administered to male Wistar rats once daily for 5 d at 10 or 30 mg/kg in combination with WF at an oral dose of 0.25 mg/kg. Coadministration of IGU 30 mg/kg enhanced the anticoagulant activity of WF; prolonged blood coagulation time (prothrombin time and activated partial thromboplastin time) and decreased levels of vitamin K (VK)-dependent blood coagulation factors (II, VII, IX, and X) were observed. On the other hand, the pharmacokinetic parameters of WF including maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to 24 h (AUC0-24 h) were not affected by the combination with IGU. IGU alone did not change blood coagulation time at doses up to 100 mg/kg, while VK-dependent blood coagulation factors decreased slightly at 30 and 100 mg/kg. These results suggest that the pharmacodynamic effect of IGU on VK-dependent blood coagulation factors is involved in the mechanism of drug-drug interaction of IGU with WF.

  17. Effects of Shared Electronic Health Record Systems on Drug-Drug Interaction and Duplication Warning Detection.

    PubMed

    Rinner, Christoph; Grossmann, Wilfried; Sauter, Simone Katja; Wolzt, Michael; Gall, Walter

    2015-01-01

    Shared electronic health records (EHRs) systems can offer a complete medication overview of the prescriptions of different health care providers. We use health claims data of more than 1 million Austrians in 2006 and 2007 with 27 million prescriptions to estimate the effect of shared EHR systems on drug-drug interaction (DDI) and duplication warnings detection and prevention. The Austria Codex and the ATC/DDD information were used as a knowledge base to detect possible DDIs. DDIs are categorized as severe, moderate, and minor interactions. In comparison to the current situation where only DDIs between drugs issued by a single health care provider can be checked, the number of warnings increases significantly if all drugs of a patient are checked: severe DDI warnings would be detected for 20% more persons, and the number of severe DDI warnings and duplication warnings would increase by 17%. We show that not only do shared EHR systems help to detect more patients with warnings but DDIs are also detected more frequently. Patient safety can be increased using shared EHR systems.

  18. Label Propagation Prediction of Drug-Drug Interactions Based on Clinical Side Effects.

    PubMed

    Zhang, Ping; Wang, Fei; Hu, Jianying; Sorrentino, Robert

    2015-07-21

    Drug-drug interaction (DDI) is an important topic for public health, and thus attracts attention from both academia and industry. Here we hypothesize that clinical side effects (SEs) provide a human phenotypic profile and can be translated into the development of computational models for predicting adverse DDIs. We propose an integrative label propagation framework to predict DDIs by integrating SEs extracted from package inserts of prescription drugs, SEs extracted from FDA Adverse Event Reporting System, and chemical structures from PubChem. Experimental results based on hold-out validation demonstrated the effectiveness of the proposed algorithm. In addition, the new algorithm also ranked drug information sources based on their contributions to the prediction, thus not only confirming that SEs are important features for DDI prediction but also paving the way for building more reliable DDI prediction models by prioritizing multiple data sources. By applying the proposed algorithm to 1,626 small-molecule drugs which have one or more SE profiles, we obtained 145,068 predicted DDIs. The predicted DDIs will help clinicians to avoid hazardous drug interactions in their prescriptions and will aid pharmaceutical companies to design large-scale clinical trial by assessing potentially hazardous drug combinations. All data sets and predicted DDIs are available at http://astro.temple.edu/~tua87106/ddi.html.

  19. Potential P-glycoprotein-mediated drug-drug interactions of antimalarial agents in Caco-2 cells.

    PubMed

    Oga, Enoche F; Sekine, Shuichi; Shitara, Yoshihisa; Horie, Toshiharu

    2012-07-01

    Antimalarials are widely used in African and Southeast Asian countries, where they are combined with other drugs for the treatment of concurrent ailments. The potential for P-glycoprotein (P-gp)-mediated drug-drug interactions (DDIs) between antimalarials and P-gp substrates was examined using a Caco-2 cell-based model. Selected antimalarials were initially screened for their interaction with P-gp based on the inhibition of rhodamine-123 (Rho-123) transport in Caco-2 cells. Verapamil (100 μM) and quinidine (1 μM) were used as positive inhibition controls. Lumefantrine, amodiaquin, and artesunate all showed blockade of Rho-123 transport. Subsequently, the inhibitory effect of these antimalarials on the bi-directional passage of digoxin (DIG) was examined. All of the drugs decreased basal-to-apical (B-A) P-gp-mediated DIG transport at concentrations of 100 μM and 1 mM. These concentrations may reflect therapeutic doses for amodiaquin and artesunate. Therefore, clinically relevant DDIs may occur between certain antimalarials and P-gp substrates in general.

  20. Drug-drug interaction prediction: a Bayesian meta-analysis approach.

    PubMed

    Li, Lang; Yu, Menggang; Chin, Raymond; Lucksiri, Aroonrut; Flockhart, David A; Hall, Stephen D

    2007-09-10

    In drug-drug interaction (DDI) research, a two drug interaction is usually predicted by individual drug pharmacokinetics (PK). Although subject-specific drug concentration data from clinical PK studies on inhibitor/inducer or substrate's PK are not usually published, sample mean plasma drug concentrations and their standard deviations have been routinely reported. In this paper, an innovative DDI prediction method based on a three-level hierarchical Bayesian meta-analysis model is developed. The first level model is a study-specific sample mean model; the second level model is a random effect model connecting different PK studies; and all priors of PK parameters are specified in the third level model. A Monte Carlo Markov chain (MCMC) PK parameter estimation procedure is developed, and DDI prediction for a future study is conducted based on the PK models of two drugs and posterior distributions of the PK parameters. The performance of Bayesian meta-analysis in DDI prediction is demonstrated through a ketoconazole-midazolam example. The biases of DDI prediction are evaluated through statistical simulation studies. The DDI marker, ratio of area under the concentration curves, is predicted with little bias (less than 5 per cent), and its 90 per cent credible interval coverage rate is close to the nominal level. Sensitivity analysis is conducted to justify prior distribution selections.

  1. Extracting Drug-Drug Interaction from the Biomedical Literature Using a Stacked Generalization-Based Approach

    PubMed Central

    He, Linna; Yang, Zhihao; Zhao, Zhehuan; Lin, Hongfei; Li, Yanpeng

    2013-01-01

    Drug-drug interaction (DDI) detection is particularly important for patient safety. However, the amount of biomedical literature regarding drug interactions is increasing rapidly. Therefore, there is a need to develop an effective approach for the automatic extraction of DDI information from the biomedical literature. In this paper, we present a Stacked Generalization-based approach for automatic DDI extraction. The approach combines the feature-based, graph and tree kernels and, therefore, reduces the risk of missing important features. In addition, it introduces some domain knowledge based features (the keyword, semantic type, and DrugBank features) into the feature-based kernel, which contribute to the performance improvement. More specifically, the approach applies Stacked generalization to automatically learn the weights from the training data and assign them to three individual kernels to achieve a much better performance than each individual kernel. The experimental results show that our approach can achieve a better performance of 69.24% in F-score compared with other systems in the DDI Extraction 2011 challenge task. PMID:23785452

  2. Extracting drug-drug interactions from literature using a rich feature-based linear kernel approach

    PubMed Central

    Kim, Sun; Yeganova, Lana; Wilbur, W. John

    2015-01-01

    Identifying unknown drug interactions is of great benefit in the early detection of adverse drug reactions. Despite existence of several resources for drug-drug interaction (DDI) information, the wealth of such information is buried in a body of unstructured medical text which is growing exponentially. This calls for developing text mining techniques for identifying DDIs. The state-of-the-art DDI extraction methods use Support Vector Machines (SVMs) with non-linear composite kernels to explore diverse contexts in literature. While computationally less expensive, linear kernel-based systems have not achieved a comparable performance in DDI extraction tasks. In this work, we propose an efficient and scalable system using a linear kernel to identify DDI information. The proposed approach consists of two steps: identifying DDIs and assigning one of four different DDI types to the predicted drug pairs. We demonstrate that when equipped with a rich set of lexical and syntactic features, a linear SVM classifier is able to achieve a competitive performance in detecting DDIs. In addition, the one-against-one strategy proves vital for addressing an imbalance issue in DDI type classification. Applied to the DDIExtraction 2013 corpus, our system achieves an F1 score of 0.670, as compared to 0.651 and 0.609 reported by the top two participating teams in the DDIExtraction 2013 challenge, both based on non-linear kernel methods. PMID:25796456

  3. A novel algorithm for analyzing drug-drug interactions from MEDLINE literature.

    PubMed

    Lu, Yin; Shen, Dan; Pietsch, Maxwell; Nagar, Chetan; Fadli, Zayd; Huang, Hong; Tu, Yi-Cheng; Cheng, Feng

    2015-11-27

    Drug-drug interaction (DDI) is becoming a serious clinical safety issue as the use of multiple medications becomes more common. Searching the MEDLINE database for journal articles related to DDI produces over 330,000 results. It is impossible to read and summarize these references manually. As the volume of biomedical reference in the MEDLINE database continues to expand at a rapid pace, automatic identification of DDIs from literature is becoming increasingly important. In this article, we present a random-sampling-based statistical algorithm to identify possible DDIs and the underlying mechanism from the substances field of MEDLINE records. The substances terms are essentially carriers of compound (including protein) information in a MEDLINE record. Four case studies on warfarin, ibuprofen, furosemide and sertraline implied that our method was able to rank possible DDIs with high accuracy (90.0% for warfarin, 83.3% for ibuprofen, 70.0% for furosemide and 100% for sertraline in the top 10% of a list of compounds ranked by p-value). A social network analysis of substance terms was also performed to construct networks between proteins and drug pairs to elucidate how the two drugs could interact.

  4. Drug-drug interaction studies: regulatory guidance and an industry perspective.

    PubMed

    Prueksaritanont, Thomayant; Chu, Xiaoyan; Gibson, Christopher; Cui, Donghui; Yee, Ka Lai; Ballard, Jeanine; Cabalu, Tamara; Hochman, Jerome

    2013-07-01

    Recently, the US Food and Drug Administration and European Medicines Agency have issued new guidance for industry on drug interaction studies, which outline comprehensive recommendations on a broad range of in vitro and in vivo studies to evaluate drug-drug interaction (DDI) potential. This paper aims to provide an overview of these new recommendations and an in-depth scientifically based perspective on issues surrounding some of the recommended approaches in emerging areas, particularly, transporters and complex DDIs. We present a number of theoretical considerations and several case examples to demonstrate complexities in applying (1) the proposed transporter decision trees and associated criteria for studying a broad spectrum of transporters to derive actionable information and (2) the recommended model-based approaches at an early stage of drug development to prospectively predict DDIs involving time-dependent inhibition and mixed inhibition/induction of drug metabolizing enzymes. We hope to convey the need for conducting DDI studies on a case-by-case basis using a holistic scientifically based interrogative approach and to communicate the need for additional research to fill in knowledge gaps in these areas where the science is rapidly evolving to better ensure the safety and efficacy of new therapeutic agents.

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

    PubMed Central

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

    2015-01-01

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

  6. Optimizing hepatitis C virus treatment through pharmacist interventions: Identification and management of drug-drug interactions

    PubMed Central

    Langness, Jacob A; Nguyen, Matthew; Wieland, Amanda; Everson, Gregory T; Kiser, Jennifer J

    2017-01-01

    AIM To quantify drug-drug-interactions (DDIs) encountered in patients prescribed hepatitis C virus (HCV) treatment, the interventions made, and the time spent in this process. METHODS As standard of care, a clinical pharmacist screened for DDIs in patients prescribed direct acting antiviral (DAA) HCV treatment between November 2013 and July 2015 at the University of Colorado Hepatology Clinic. HCV regimens prescribed included ledipasvir/sofosbuvir (LDV/SOF), paritaprevir/ritonavir/ombitasvir/dasabuvir (OBV/PTV/r + DSV), simeprevir/sofosbuvir (SIM/SOF), and sofosbuvir/ribavirin (SOF/RBV). This retrospective analysis reviewed the work completed by the clinical pharmacist in order to measure the aims identified for the study. The number and type of DDIs identified were summarized with descriptive statistics. RESULTS Six hundred and sixty four patients (83.4% Caucasian, 57% male, average 56.7 years old) were identified; 369 for LDV/SOF, 48 for OBV/PTV/r + DSV, 114 for SIM/SOF, and 133 for SOF/RBV. Fifty-one point five per cent of patients were cirrhotic. Overall, 5217 medications were reviewed (7.86 medications per patient) and 781 interactions identified (1.18 interactions per patient). The number of interactions were fewest for SOF/RBV (0.17 interactions per patient) and highest for OBV/PTV/r + DSV (2.48 interactions per patient). LDV/SOF and SIM/SOF had similar number of interactions (1.28 and 1.48 interactions per patient, respectively). Gastric acid modifiers and vitamin/herbal supplements commonly caused interactions with LDV/SOF. Hypertensive agents, analgesics, and psychiatric medications frequently caused interactions with OBV/PTV/r + DSV and SIM/SOF. To manage these interactions, the pharmacists most often recommended discontinuing the medication (28.9%), increasing monitoring for toxicities (24.1%), or separating administration times (18.2%). The pharmacist chart review for each patient usually took approximately 30 min, with additional time for more complex

  7. Absence of pharmacokinetic drug-drug interaction of pertuzumab with trastuzumab and docetaxel.

    PubMed

    Cortés, Javier; Swain, Sandra M; Kudaba, Iveta; Hauschild, Maik; Patel, Taral; Grincuka, Elza; Masuda, Norikazu; McNally, Virginia; Ross, Graham; Brewster, Mike; Marier, Jean-François; Trinh, My My; Garg, Amit; Nijem, Ihsan; Visich, Jennifer; Lum, Bert L; Baselga, José

    2013-11-01

    Pertuzumab is a novel antihuman epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody. Combined with trastuzumab plus docetaxel, pertuzumab improved progression-free and overall survival versus trastuzumab plus docetaxel in the phase III CLEOPATRA trial (NCT00567190) in first-line HER2-positive metastatic breast cancer. Thirty-seven patients participated in a pharmacokinetic (PK)/corrected QT interval substudy of CLEOPATRA, which evaluated potential PK drug-drug interaction (DDI). PK parameters were calculated using noncompartmental methods, and DDI analyses were carried out. In the presence of trastuzumab and docetaxel, the mean pertuzumab Cmin and Cmax in cycle 3 were 63.6 and 183 µg/ml, respectively. The pertuzumab concentrations observed were consistent with simulations from a validated population PK model, indicating that trastuzumab and docetaxel did not alter pertuzumab PK. Comparison of geometric least-squares mean PK parameters between arms showed no impact of pertuzumab on the PK of trastuzumab or docetaxel. In conclusion, no PK DDI was observed when pertuzumab, trastuzumab, and docetaxel were combined for the treatment of HER2-positive metastatic breast cancer.

  8. A Topic-modeling Based Framework for Drug-drug Interaction Classification from Biomedical Text.

    PubMed

    Li, Dingcheng; Liu, Sijia; Rastegar-Mojarad, Majid; Wang, Yanshan; Chaudhary, Vipin; Therneau, Terry; Liu, Hongfang

    2016-01-01

    Classification of drug-drug interaction (DDI) from medical literatures is significant in preventing medication-related errors. Most of the existing machine learning approaches are based on supervised learning methods. However, the dynamic nature of drug knowledge, combined with the enormity and rapidly growing of the biomedical literatures make supervised DDI classification methods easily overfit the corpora and may not meet the needs of real-world applications. In this paper, we proposed a relation classification framework based on topic modeling (RelTM) augmented with distant supervision for the task of DDI from biomedical text. The uniqueness of RelTM lies in its two-level sampling from both DDI and drug entities. Through this design, RelTM take both relation features and drug mention features into considerations. An efficient inference algorithm for the model using Gibbs sampling is also proposed. Compared to the previous supervised models, our approach does not require human efforts such as annotation and labeling, which is its advantage in trending big data applications. Meanwhile, the distant supervision combination allows RelTM to incorporate rich existing knowledge resources provided by domain experts. The experimental results on the 2013 DDI challenge corpus reach 48% in F1 score, showing the effectiveness of RelTM.

  9. A Topic-modeling Based Framework for Drug-drug Interaction Classification from Biomedical Text

    PubMed Central

    Li, Dingcheng; Liu, Sijia; Rastegar-Mojarad, Majid; Wang, Yanshan; Chaudhary, Vipin; Therneau, Terry; Liu, Hongfang

    2016-01-01

    Classification of drug-drug interaction (DDI) from medical literatures is significant in preventing medication-related errors. Most of the existing machine learning approaches are based on supervised learning methods. However, the dynamic nature of drug knowledge, combined with the enormity and rapidly growing of the biomedical literatures make supervised DDI classification methods easily overfit the corpora and may not meet the needs of real-world applications. In this paper, we proposed a relation classification framework based on topic modeling (RelTM) augmented with distant supervision for the task of DDI from biomedical text. The uniqueness of RelTM lies in its two-level sampling from both DDI and drug entities. Through this design, RelTM take both relation features and drug mention features into considerations. An efficient inference algorithm for the model using Gibbs sampling is also proposed. Compared to the previous supervised models, our approach does not require human efforts such as annotation and labeling, which is its advantage in trending big data applications. Meanwhile, the distant supervision combination allows RelTM to incorporate rich existing knowledge resources provided by domain experts. The experimental results on the 2013 DDI challenge corpus reach 48% in F1 score, showing the effectiveness of RelTM. PMID:28269875

  10. Physiologically based pharmacokinetic modeling of disposition and drug-drug interactions for atorvastatin and its metabolites.

    PubMed

    Zhang, Tao

    2015-09-18

    Atorvastatin is the most commonly used of all statins to lower cholesterol. Atorvastatin is extensively metabolized in both gut and liver to produce several active metabolites. The purpose of the present study is to develop a physiologically based pharmacokinetic (PBPK) model for atorvastatin and its two primary metabolites, 2-hydroxy-atorvastatin acid and atorvastatin lactone, using in vitro and in vivo data. The model was used to predict the pharmacokinetic profiles and drug-drug interaction (DDI) effect for atorvastatin and its metabolites in different DDI scenarios. The predictive performance of the model was assessed by comparing predicted results to observed data after coadministration of atorvastatin with different medications such as itraconazole, clarithromycin, cimetidine, rifampin and phenytoin. This population based PBPK model was able to describe the concentration-time profiles of atorvastatin and its two metabolites reasonably well in the absence or presence of those drugs at different dose regimens. The predicted maximum concentration (Cmax), area under the concentration-time curve (AUC) values and between-phase ratios were in good agreement with clinically observed data. The model has also revealed the importance of different metabolic pathways on the disposition of atorvastatin metabolites. This PBPK model can be utilized to assess the safety and efficacy of atorvastatin in the clinic. This study demonstrated the feasibility of applying PBPK approach to predict the DDI potential of drugs undergoing complex metabolism.

  11. Drug drug interaction extraction from biomedical literature using syntax convolutional neural network

    PubMed Central

    Zhao, Zhehuan; Yang, Zhihao; Luo, Ling; Lin, Hongfei; Wang, Jian

    2016-01-01

    Motivation: Detecting drug-drug interaction (DDI) has become a vital part of public health safety. Therefore, using text mining techniques to extract DDIs from biomedical literature has received great attentions. However, this research is still at an early stage and its performance has much room to improve. Results: In this article, we present a syntax convolutional neural network (SCNN) based DDI extraction method. In this method, a novel word embedding, syntax word embedding, is proposed to employ the syntactic information of a sentence. Then the position and part of speech features are introduced to extend the embedding of each word. Later, auto-encoder is introduced to encode the traditional bag-of-words feature (sparse 0–1 vector) as the dense real value vector. Finally, a combination of embedding-based convolutional features and traditional features are fed to the softmax classifier to extract DDIs from biomedical literature. Experimental results on the DDIExtraction 2013 corpus show that SCNN obtains a better performance (an F-score of 0.686) than other state-of-the-art methods. Availability and Implementation: The source code is available for academic use at http://202.118.75.18:8080/DDI/SCNN-DDI.zip. Contact: yangzh@dlut.edu.cn Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27466626

  12. Computerized techniques pave the way for drug-drug interaction prediction and interpretation

    PubMed Central

    Safdari, Reza; Ferdousi, Reza; Aziziheris, Kamal; Niakan-Kalhori, Sharareh R.; Omidi, Yadollah

    2016-01-01

    Introduction: Health care industry also patients penalized by medical errors that are inevitable but highly preventable. Vast majority of medical errors are related to adverse drug reactions, while drug-drug interactions (DDIs) are the main cause of adverse drug reactions (ADRs). DDIs and ADRs have mainly been reported by haphazard case studies. Experimental in vivo and in vitro researches also reveals DDI pairs. Laboratory and experimental researches are valuable but also expensive and in some cases researchers may suffer from limitations. Methods: In the current investigation, the latest published works were studied to analyze the trend and pattern of the DDI modelling and the impacts of machine learning methods. Applications of computerized techniques were also investigated for the prediction and interpretation of DDIs. Results: Computerized data-mining in pharmaceutical sciences and related databases provide new key transformative paradigms that can revolutionize the treatment of diseases and hence medical care. Given that various aspects of drug discovery and pharmacotherapy are closely related to the clinical and molecular/biological information, the scientifically sound databases (e.g., DDIs, ADRs) can be of importance for the success of pharmacotherapy modalities. Conclusion: A better understanding of DDIs not only provides a robust means for designing more effective medicines but also grantees patient safety. PMID:27525223

  13. A novel approach to the prediction of drug-drug interactions in humans based on the serum incubation method.

    PubMed

    Shibata, Yoshihiro; Takahashi, Hiroyuki; Chiba, Masato; Ishii, Yasuyuki

    2008-01-01

    A novel method for the prediction of drug-drug interaction has been established based on the in vitro metabolic stability in the "serum incubation method" using cryopreserved human hepatocytes suspended in 100% human serum. As a novel approach, the inhibitory effect of inhibitors on the metabolism of substrates during the first-pass elimination process in the liver (hepatic availability) and in the elimination process from the systemic circulation (hepatic clearance) were separately predicted with the anticipated inhibitor/substrate concentrations during absorption and in the systemic circulation, respectively. Ketoconazole strongly inhibited CYP3A4-mediated terfenadine metabolism in vitro, and the method predicted 6- to 37-fold increase of terfenadine AUC by the concomitant dosing of ketoconazole, which reasonably well agreed with the observed 13- to 59-fold increase of AUC in clinical studies. The CYP3A4-mediated metabolism of indinavir was also subject to the inhibition by ketoconazole in vitro at the lower indinavir concentration (2 microM), whereas no substantial inhibition was observed at 12 microM due to the saturation of indinavir metabolism. Predicted no interaction between ketoconazole and indinavir was consistent with the minimal increase (1.3-fold increase) of indinavir AUC by ketoconazole observed in clinical study. In addition, the method was applied to the CYP2D6-mediated desipramine-quinidine interaction: the predicted 6.4-fold increase of desipramine AUC by quinidine was consistent with the observed 6.7-fold increase of AUC in the clinical drug-drug interaction study. On the other hand, desipramine metabolism was little affected by ketoconazole in vitro, and consequently, it predicted no drug-drug interaction between desipramine and ketoconazole in humans, which agreed with the negligible interaction observed in clinical study. The accuracy of predictions for drug-drug interaction by the serum incubation method was evaluated by comparing the

  14. Adverse events caused by potential drug-drug interactions in an intensive care unit of a teaching hospital

    PubMed Central

    Alvim, Mariana Macedo; da Silva, Lidiane Ayres; Leite, Isabel Cristina Gonçalves; Silvério, Marcelo Silva

    2015-01-01

    Objective To evaluate the incidence of potential drug-drug interactions in an intensive care unit of a hospital, focusing on antimicrobial drugs. Methods This cross-sectional study analyzed electronic prescriptions of patients admitted to the intensive care unit of a teaching hospital between January 1 and March 31, 2014 and assessed potential drug-drug interactions associated with antimicrobial drugs. Antimicrobial drug consumption levels were expressed in daily doses per 100 patient-days. The search and classification of the interactions were based on the Micromedex® system. Results The daily prescriptions of 82 patients were analyzed, totaling 656 prescriptions. Antimicrobial drugs represented 25% of all prescription drugs, with meropenem, vancomycin and ceftriaxone being the most prescribed medications. According to the approach of daily dose per 100 patient-days, the most commonly used antimicrobial drugs were cefepime, meropenem, sulfamethoxazole + trimethoprim and ciprofloxacin. The mean number of interactions per patient was 2.6. Among the interactions, 51% were classified as contraindicated or significantly severe. Highly significant interactions (clinical value 1 and 2) were observed with a prevalence of 98%. Conclusion The current study demonstrated that antimicrobial drugs are frequently prescribed in intensive care units and present a very high number of potential drug-drug interactions, with most of them being considered highly significant. PMID:26761473

  15. Drug-Drug Interactions with the NS3/4A Protease Inhibitor Simeprevir.

    PubMed

    Ouwerkerk-Mahadevan, Sivi; Snoeys, Jan; Peeters, Monika; Beumont-Mauviel, Maria; Simion, Alexandru

    2016-02-01

    Simeprevir is an NS3/4A protease inhibitor approved for the treatment of hepatitis C infection, as a component of combination therapy. Simeprevir is metabolized by the cytochrome P450 (CYP) system, primarily CYP3A, and is a substrate for several drug transporters, including the organic anion transporting polypeptides (OATPs). It is susceptible to metabolic drug-drug interactions with drugs that are moderate or strong CYP3A inhibitors (e.g. ritonavir and erythromycin) or CYP3A inducers (e.g. rifampin and efavirenz); coadministration of these drugs may increase or decrease plasma concentrations of simeprevir, respectively, and should be avoided. Clinical studies have shown that simeprevir is a mild inhibitor of CYP1A2 and intestinal CYP3A but does not inhibit hepatic CYP3A. The effects of simeprevir on these enzymes are of clinical relevance only for narrow-therapeutic-index drugs that are metabolized solely by these enzymes (e.g. oral midazolam). Simeprevir does not have a clinically relevant effect on the pharmacokinetics of rilpivirine, tacrolimus, oral contraceptives and several other drugs metabolized by CYP enzymes. Simeprevir is a substrate and inhibitor of the transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and OATP1B1/3. Cyclosporine is an inhibitor of OATP1B1/3, BCRP and P-gp, and a mild inhibitor of CYP3A; cyclosporine causes a significant increase in simeprevir plasma concentrations, and coadministration is not recommended. Clinical studies have demonstrated increases in coadministered drug concentrations for drugs that are substrates of the OATP1B1/3, BRCP (e.g. rosuvastatin) and P-gp (e.g. digoxin) transporters; these drugs should be administered with dose titration and or/close monitoring.

  16. Prediction of Drug Clearance and Drug-Drug Interactions in Microscale Cultures of Human Hepatocytes.

    PubMed

    Lin, Christine; Shi, Julianne; Moore, Amanda; Khetani, Salman R

    2016-01-01

    Accurate prediction of in vivo hepatic drug clearance using in vitro assays is important to properly estimate clinical dosing regimens. Clearance of low-turnover compounds is especially difficult to predict using short-lived suspensions of unpooled primary human hepatocytes (PHHs) and functionally declining PHH monolayers. Micropatterned cocultures (MPCCs) of PHHs and 3T3-J2 fibroblasts have been shown previously to display major liver functions for several weeks in vitro. In this study, we first characterized long-term activities of major cytochrome P450 enzymes in MPCCs created from unpooled cryopreserved PHH donors. MPCCs were then used to predict the clearance of 26 drugs that exhibit a wide range of turnover rates in vivo (0.05-19.5 ml/min per kilogram). MPCCs predicted 73, 92, and 96% of drug clearance values for all tested drugs within 2-fold, 3-fold, and 4-fold of in vivo values, respectively. There was good correlation (R(2) = 0.94, slope = 1.05) of predictions between the two PHH donors. On the other hand, suspension hepatocytes and conventional monolayers created from the same donor had significantly reduced predictive capacity (i.e., 30-50% clearance values within 4-fold of in vivo), and were not able to metabolize several drugs. Finally, we modulated drug clearance in MPCCs by inducing or inhibiting P450s. Rifampin-mediated CYP3A4 induction increased midazolam clearance by 73%, while CYP3A4 inhibition with ritonavir decreased midazolam clearance by 79%. Similarly, quinidine-mediated CYP2D6 inhibition reduced clearance of dextromethorphan and desipramine by 71 and 22%, respectively. In conclusion, MPCCs created using cryopreserved unpooled PHHs can be used for drug clearance predictions and to model drug-drug interactions.

  17. Drug-Drug Interaction Potentials of Tyrosine Kinase Inhibitors via Inhibition of UDP-Glucuronosyltransferases

    PubMed Central

    Zhang, Nan; Liu, Yong; Jeong, Hyunyoung

    2015-01-01

    Tyrosine kinase inhibitors (TKIs) are anticancer drugs that may be co-administered with other drugs. The aims of this study are to investigate the inhibitory effects of TKIs on UDP-glucuronosyltransferase (UGT) activities, and to quantitatively evaluate their potential to cause drug-drug interactions (DDIs). Inhibition kinetic profiles of a panel of UGT enzymes (UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, and 2B17) by four TKIs (axitinib, imatinib, lapatinib and vandetanib) were characterized by using hepatic microsomes and recombinant proteins. Lapatinib exhibited potent competitive inhibition against UGT1A1 activity with a Ki of 0.5 μM. Imatinib was found to exhibit broad inhibition on several UGTs, particularly potent competitive inhibition against UGT2B17 with a Ki of 0.4 μM. The TKIs also exerted intermediate inhibition against several UGTs (i.e., UGT1A7 by lapatinib; UGT1A1 by imatinib; UGT1A4, 1A7 and 1A9 by axitinib; and UGT1A9 by vandetanib). Results from modeling for the quantitative prediction of DDI risk indicated that the coadministration of lapatinib or imatinib at clinical doses could result in a significant increase in AUC of drugs primarily cleared by UGT1A1 or 2B17. Lapatinib and imatinib may cause clinically significant DDIs when co-administered UGT1A1 or 2B17 substrates. PMID:26642944

  18. A linguistic rule-based approach to extract drug-drug interactions from pharmacological documents

    PubMed Central

    2011-01-01

    Background A drug-drug interaction (DDI) occurs when one drug influences the level or activity of another drug. The increasing volume of the scientific literature overwhelms health care professionals trying to be kept up-to-date with all published studies on DDI. Methods This paper describes a hybrid linguistic approach to DDI extraction that combines shallow parsing and syntactic simplification with pattern matching. Appositions and coordinate structures are interpreted based on shallow syntactic parsing provided by the UMLS MetaMap tool (MMTx). Subsequently, complex and compound sentences are broken down into clauses from which simple sentences are generated by a set of simplification rules. A pharmacist defined a set of domain-specific lexical patterns to capture the most common expressions of DDI in texts. These lexical patterns are matched with the generated sentences in order to extract DDIs. Results We have performed different experiments to analyze the performance of the different processes. The lexical patterns achieve a reasonable precision (67.30%), but very low recall (14.07%). The inclusion of appositions and coordinate structures helps to improve the recall (25.70%), however, precision is lower (48.69%). The detection of clauses does not improve the performance. Conclusions Information Extraction (IE) techniques can provide an interesting way of reducing the time spent by health care professionals on reviewing the literature. Nevertheless, no approach has been carried out to extract DDI from texts. To the best of our knowledge, this work proposes the first integral solution for the automatic extraction of DDI from biomedical texts. PMID:21489220

  19. Drug-drug interaction between voriconazole and oral hypoglycemic agents in diabetic rats

    PubMed Central

    Kumar, Boyina Hemanth; Joshi, Bheemachari; Singh, Jayasingh Chellammal Hanish; Diwan, Prakash V.

    2013-01-01

    Objective: The objective was to study the of drug-drug interaction between voriconazole and oral hypoglycemic agents in normal and alloxan induced diabetic rats. Materials and Methods: The study was designed in two phases. In the first phase, influence of glibenclamide (0.45 mg/kg, p.o.) and pioglitazone (2.7 mg/kg, p.o. once daily) on blood glucose levels in normoglycemic rats was studied and then influence of voriconazole (18 mg/kg, p.o. twice daily.) pre-treatment on the hypoglycemic activity studied. Simultaneously the influence of voriconazole treatment for seven consecutive days (per se effect) on blood glucose levels was also studied in normoglycemic rats. In the second phase of the study alloxan-induced diabetic rats were used to find out the influence of voriconazole pre-treatment on glibenclamide and pioglitazone induced hypoglycemic effect in pathophysiological condition. Blood samples were collected from retro orbital plexus at regular intervals of 0.0, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 18.0 and 24.0 h after drug treatment. All the blood samples were analyzed for plasma glucose by glucose oxidase peroxidase method (GOD/POD). Results: The therapeutic dose of voriconazole potentiates the hypoglycemic activity of glibenclamide and pioglitazone both in normoglycemic and diabetic rats respectively. Conclusion: The results indicate that the dose of oral hypoglycemic agents needs to be adjusted if co-administered with voriconazole. PMID:23716892

  20. User-centered design improves the usability of drug-drug interaction alerts: Experimental comparison of interfaces.

    PubMed

    Luna, Daniel R; Rizzato Lede, Daniel A; Otero, Carlos M; Risk, Marcelo R; González Bernaldo de Quirós, Fernán

    2017-02-01

    Clinical Decision Support Systems can alert health professionals about drug interactions when they prescribe medications. The Hospital Italiano de Buenos Aires in Argentina developed an electronic health record with drug-drug interaction alerts, using traditional software engineering techniques and requirements. Despite enhancing the drug-drug interaction knowledge database, the alert override rate of this system was very high. We redesigned the alert system using user-centered design (UCD) and participatory design techniques to enhance the drug-drug interaction alert interface. This paper describes the methodology of our UCD. We used crossover method with realistic, clinical vignettes to compare usability of the standard and new software versions in terms of efficiency, effectiveness, and user satisfaction. Our study showed that, compared to the traditional alert system, the UCD alert system was more efficient (alerts faster resolution), more effective (tasks completed with fewer errors), and more satisfying. These results indicate that UCD techniques that follow ISO 9241-210 can generate more usable alerts than traditional design.

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

    PubMed

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

    2013-11-01

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

  2. Drug-Drug Interactions between Sofosbuvir and Ombitasvir-Paritaprevir-Ritonavir with or without Dasabuvir.

    PubMed

    King, Jennifer R; Dutta, Sandeep; Cohen, Daniel; Podsadecki, Thomas J; Ding, Bifeng; Awni, Walid M; Menon, Rajeev M

    2016-02-01

    The combination of ombitasvir (an NS5A inhibitor), paritaprevir (an NS3/4A inhibitor) coadministered with ritonavir (r), and dasabuvir (an NS5B nonnucleoside polymerase inhibitor), referred to as the 3D regimen, and the combination of ombitasvir-paritaprevir-r, referred to as the 2D regimen, have demonstrated high efficacy with and without ribavirin in hepatitis C virus (HCV)-infected subjects. These regimens have potential for coadministration with sofosbuvir (nucleoside NS5B inhibitor) in the treatment of HCV. This phase 1, drug-drug interaction, open-label, multiple-dose study enrolled 32 healthy subjects to receive the 3D or 2D regimen in combination with sofosbuvir. Doses of study drugs were as follows: ombitasvir-paritaprevir-r, 25/150/100 mg daily (QD); dasabuvir, 250 mg twice daily (BID); and sofosbuvir, 400 mg QD. Blood samples were collected on study days 7, 14, and 21 for evaluating drug interaction at steady state. The effect of the 3D and 2D regimens on the pharmacokinetics of sofosbuvir and its circulating metabolite GS-331007 and vice versa was assessed by a repeated-measures analysis. Exposures of the 3D and 2D regimens were similar (≤20% change) during coadministration with sofosbuvir and during administration alone. Sofosbuvir exposures were 61% to 112% higher with the 3D regimen and 64% to 93% higher with the 2D regimen than with sofosbuvir alone. GS-331007 total exposures were 27% and 32% higher with the 3D and 2D regimens, respectively, than with sofosbuvir alone. Increases in sofosbuvir and GS-331007 exposures likely resulted from breast cancer resistance protein (BCRP) and/or P glycoprotein (P-gp) transporter inhibition by paritaprevir and ritonavir. No subjects discontinued the study due to study drug-related adverse events. No dose adjustment is recommended for 3D, 2D, or sofosbuvir in clinical trials exploring the safety and efficacy of the combination. (This study has been registered at ClinicalTrials.gov under registration no. NCT

  3. Drug-Drug Interactions between Sofosbuvir and Ombitasvir-Paritaprevir-Ritonavir with or without Dasabuvir

    PubMed Central

    Dutta, Sandeep; Cohen, Daniel; Podsadecki, Thomas J.; Ding, Bifeng; Awni, Walid M.; Menon, Rajeev M.

    2015-01-01

    The combination of ombitasvir (an NS5A inhibitor), paritaprevir (an NS3/4A inhibitor) coadministered with ritonavir (r), and dasabuvir (an NS5B nonnucleoside polymerase inhibitor), referred to as the 3D regimen, and the combination of ombitasvir-paritaprevir-r, referred to as the 2D regimen, have demonstrated high efficacy with and without ribavirin in hepatitis C virus (HCV)-infected subjects. These regimens have potential for coadministration with sofosbuvir (nucleoside NS5B inhibitor) in the treatment of HCV. This phase 1, drug-drug interaction, open-label, multiple-dose study enrolled 32 healthy subjects to receive the 3D or 2D regimen in combination with sofosbuvir. Doses of study drugs were as follows: ombitasvir-paritaprevir-r, 25/150/100 mg daily (QD); dasabuvir, 250 mg twice daily (BID); and sofosbuvir, 400 mg QD. Blood samples were collected on study days 7, 14, and 21 for evaluating drug interaction at steady state. The effect of the 3D and 2D regimens on the pharmacokinetics of sofosbuvir and its circulating metabolite GS-331007 and vice versa was assessed by a repeated-measures analysis. Exposures of the 3D and 2D regimens were similar (≤20% change) during coadministration with sofosbuvir and during administration alone. Sofosbuvir exposures were 61% to 112% higher with the 3D regimen and 64% to 93% higher with the 2D regimen than with sofosbuvir alone. GS-331007 total exposures were 27% and 32% higher with the 3D and 2D regimens, respectively, than with sofosbuvir alone. Increases in sofosbuvir and GS-331007 exposures likely resulted from breast cancer resistance protein (BCRP) and/or P glycoprotein (P-gp) transporter inhibition by paritaprevir and ritonavir. No subjects discontinued the study due to study drug-related adverse events. No dose adjustment is recommended for 3D, 2D, or sofosbuvir in clinical trials exploring the safety and efficacy of the combination. (This study has been registered at ClinicalTrials.gov under registration no. NCT

  4. Toward a complete dataset of drug-drug interaction information from publicly available sources.

    PubMed

    Ayvaz, Serkan; Horn, John; Hassanzadeh, Oktie; Zhu, Qian; Stan, Johann; Tatonetti, Nicholas P; Vilar, Santiago; Brochhausen, Mathias; Samwald, Matthias; Rastegar-Mojarad, Majid; Dumontier, Michel; Boyce, Richard D

    2015-06-01

    Although potential drug-drug interactions (PDDIs) are a significant source of preventable drug-related harm, there is currently no single complete source of PDDI information. In the current study, all publically available sources of PDDI information that could be identified using a comprehensive and broad search were combined into a single dataset. The combined dataset merged fourteen different sources including 5 clinically-oriented information sources, 4 Natural Language Processing (NLP) Corpora, and 5 Bioinformatics/Pharmacovigilance information sources. As a comprehensive PDDI source, the merged dataset might benefit the pharmacovigilance text mining community by making it possible to compare the representativeness of NLP corpora for PDDI text extraction tasks, and specifying elements that can be useful for future PDDI extraction purposes. An analysis of the overlap between and across the data sources showed that there was little overlap. Even comprehensive PDDI lists such as DrugBank, KEGG, and the NDF-RT had less than 50% overlap with each other. Moreover, all of the comprehensive lists had incomplete coverage of two data sources that focus on PDDIs of interest in most clinical settings. Based on this information, we think that systems that provide access to the comprehensive lists, such as APIs into RxNorm, should be careful to inform users that the lists may be incomplete with respect to PDDIs that drug experts suggest clinicians be aware of. In spite of the low degree of overlap, several dozen cases were identified where PDDI information provided in drug product labeling might be augmented by the merged dataset. Moreover, the combined dataset was also shown to improve the performance of an existing PDDI NLP pipeline and a recently published PDDI pharmacovigilance protocol. Future work will focus on improvement of the methods for mapping between PDDI information sources, identifying methods to improve the use of the merged dataset in PDDI NLP algorithms

  5. ITC commentary on the prediction of digoxin clinical drug-drug interactions from in vitro transporter assays.

    PubMed

    Lee, C A; Kalvass, J C; Galetin, A; Zamek-Gliszczynski, M J

    2014-09-01

    The "P-glycoprotein" IC50 working group reported an 18- to 796-fold interlaboratory range in digoxin transport IC50 (inhibitor concentration achieving 50% of maximal inhibition), raising concerns about the predictability of clinical transporter-based drug-drug interactions (DDIs) from in vitro data. This Commentary describes complexities of digoxin transport, which involve both uptake and efflux processes. We caution against attributing digoxin transport IC50 specifically to P-glycoprotein (P-gp) or extending this composite uptake/efflux IC50 variability to individual transporters. Clinical digoxin interaction studies should be interpreted as evaluation of digoxin safety, not P-gp DDIs.

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

    PubMed

    Petersen, Karl-Uwe

    2011-08-01

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

  7. Improving Detection of Arrhythmia Drug-Drug Interactions in Pharmacovigilance Data through the Implementation of Similarity-Based Modeling.

    PubMed

    Vilar, Santiago; Lorberbaum, Tal; Hripcsak, George; Tatonetti, Nicholas P

    2015-01-01

    Identification of Drug-Drug Interactions (DDIs) is a significant challenge during drug development and clinical practice. DDIs are responsible for many adverse drug effects (ADEs), decreasing patient quality of life and causing higher care expenses. DDIs are not systematically evaluated in pre-clinical or clinical trials and so the FDA U. S. Food and Drug Administration relies on post-marketing surveillance to monitor patient safety. However, existing pharmacovigilance algorithms show poor performance for detecting DDIs exhibiting prohibitively high false positive rates. Alternatively, methods based on chemical structure and pharmacological similarity have shown promise in adverse drug event detection. We hypothesize that the use of chemical biology data in a post hoc analysis of pharmacovigilance results will significantly improve the detection of dangerous interactions. Our model integrates a reference standard of DDIs known to cause arrhythmias with drug similarity data. To compare similarity between drugs we used chemical structure (both 2D and 3D molecular structure), adverse drug side effects, chemogenomic targets, drug indication classes, and known drug-drug interactions. We evaluated the method on external reference standards. Our results showed an enhancement of sensitivity, specificity and precision in different top positions with the use of similarity measures to rank the candidates extracted from pharmacovigilance data. For the top 100 DDI candidates, similarity-based modeling yielded close to twofold precision enhancement compared to the proportional reporting ratio (PRR). Moreover, the method helps in the DDI decision making through the identification of the DDI in the reference standard that generated the candidate.

  8. First case of stress cardiomyopathy as a result of methadone withdrawal secondary to drug-drug interaction.

    PubMed

    Lemesle, Frédéric; Lemesle, Florence; Nicola, Walid; Pierre Jonville-Béra, Annie

    2010-03-01

    We describe the first case of stress cardiomyopathy secondary to a drug-drug interaction. A 44-year-old man was admitted for acute agitation, hallucinations, tachycardia, and fever within 2 hours of ingestion of naltrexone prescribed to stop alcohol consumption. He had been receiving methadone (120 mg/d) for several months for a history of heroin use; thus, acute opiate withdrawal syndrome secondary to naltrexone treatment was diagnosed. Because electrocardiography showed diffuse ST-segment elevation, a transthoracic echocardiography was performed. It revealed apical akinesia of the left ventricle with a reduction in systolic function. The echocardiogram showed an ejection fraction of 35%, apical and midventricular wall motion abnormalities of the left ventricle, and a cardiac output of 4 L/min without coronary stenosis. The patient was transferred to the cardiologic intensive care unit with a diagnosis of transient left ventricular apical ballooning syndrome secondary to acute opiate withdrawal syndrome. It is likely that opioid withdrawal, inducing a marked increase in catecholamine plasma concentrations, contributed to the development of stress cardiomyopathy. To our knowledge, this is the first case of stress cardiomyopathy described after abrupt opiate withdrawal secondary to a drug-drug interaction.

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

    PubMed

    Bohnert, Tonika; Patel, Aarti; Templeton, Ian; Chen, Yuan; Lu, Chuang; Lai, George; Leung, Louis; Tse, Susanna; Einolf, Heidi J; Wang, Ying-Hong; Sinz, Michael; Stearns, Ralph; Walsky, Robert; Geng, Wanping; Sudsakorn, Sirimas; Moore, David; He, Ling; Wahlstrom, Jan; Keirns, Jim; Narayanan, Rangaraj; Lang, Dieter; Yang, Xiaoqing

    2016-08-01

    Under the guidance of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), scientists from 20 pharmaceutical companies formed a Victim Drug-Drug Interactions Working Group. This working group has conducted a review of the literature and the practices of each company on the approaches to clearance pathway identification (fCL), estimation of fractional contribution of metabolizing enzyme toward metabolism (fm), along with modeling and simulation-aided strategy in predicting the victim drug-drug interaction (DDI) liability due to modulation of drug metabolizing enzymes. Presented in this perspective are the recommendations from this working group on: 1) strategic and experimental approaches to identify fCL and fm, 2) whether those assessments may be quantitative for certain enzymes (e.g., cytochrome P450, P450, and limited uridine diphosphoglucuronosyltransferase, UGT enzymes) or qualitative (for most of other drug metabolism enzymes), and the impact due to the lack of quantitative information on the latter. Multiple decision trees are presented with stepwise approaches to identify specific enzymes that are involved in the metabolism of a given drug and to aid the prediction and risk assessment of drug as a victim in DDI. Modeling and simulation approaches are also discussed to better predict DDI risk in humans. Variability and parameter sensitivity analysis were emphasized when applying modeling and simulation to capture the differences within the population used and to characterize the parameters that have the most influence on the prediction outcome.

  10. Assessment of Drug-Drug Interactions among Renal Failure Patients of Nephrology Ward in a South Indian Tertiary Care Hospital.

    PubMed

    Rama, Mylapuram; Viswanathan, Gayathri; Acharya, Leelavathi D; Attur, R P; Reddy, P N; Raghavan, S V

    2012-01-01

    Polypharmacy is common in drug prescriptions of chronic kidney disease patients. A study of the prescription patterns of drugs with potential interactions would be of interest to prevent drug related adverse events. A prospective observational study of six months (Dec 2009-May 2010) was carried out among the chronic kidney disease patients admitted to the nephrology ward of a South Indian tertiary care hospital. The pattern and rates of drug-drug interactions seen in the prescriptions of these patients was studied. Among the 205 prescriptions included, a total of 474 interactions were reported, making 2.7 interactions per prescription with incidence rates of 76.09%. Around 19.62% of interactions were of major severity. Most common interactions were found between ascorbic acid and cyanocobalamine (12.45%), clonidine and metoprolol (3.80%) respectively. Hypo or hypertension (31.65%), decreased drug efficacy (29.11%) and hypo or hyperglycemia (14.14%), were the most commonly reported clinical outcomes of the drug interactions. Cardiovascular drugs (calcium channel blockers and beta blockers; 52%) constitute the major class of drugs involved in interactions. As most of the interactions had a delayed onset, long term follow-up is essential to predict the clinically significant outcomes of these interactions. Hence, drug interactions are commonly seen in the prescriptions of chronic kidney disease patients which can lead to serious adverse events if not detected early. Need for collaboration with a clinical pharmacist and electronic surveillance, which are absent in developing countries like India, is emphatic.

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

    PubMed

    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.

  12. Delamanid Coadministered with Antiretroviral Drugs or Antituberculosis Drugs Shows No Clinically Relevant Drug-Drug Interactions in Healthy Subjects

    PubMed Central

    Wells, Charles; Petersen, Carolyn; Paccaly, Anne; Shoaf, Susan E.; Patil, Shiva; Geiter, Lawrence

    2016-01-01

    Delamanid is a medicinal product approved for treatment of multidrug-resistant tuberculosis. Three studies were conducted to evaluate the potential drug-drug interactions between delamanid and antiretroviral drugs, including ritonavir, a strong inhibitor of CYP3A4, and selected anti-TB drugs, including rifampin, a strong inducer of cytochrome P450 (CYP) isozymes. Multiple-dose studies were conducted in parallel groups of healthy subjects. Plasma samples were analyzed for delamanid, delamanid metabolite, and coadministered drug concentrations, and pharmacokinetic (PK) parameters were determined. The magnitude of the interaction was assessed by the ratio of the geometric means and 90% confidence intervals. Coadministration of delamanid with tenofovir or efavirenz did not affect the PK characteristics of delamanid. Coadministration of Kaletra (lopinavir/ritonavir) with delamanid resulted in an approximately 25% higher delamanid area under the concentration-time curve from time 0 to the end of the dosing interval (AUCτ). Tenofovir, efavirenz, lopinavir, and ritonavir exposure were not affected by delamanid. Coadministration of delamanid with the TB drugs (ethambutol plus Rifater [rifampin, pyrazinamide, and isoniazid]) resulted in lower delamanid exposures (47 and 42% for the AUCτ and Cmax [maximum concentration of a drug in plasma] values, respectively), as well as decreased exposure of three primary metabolites (approximately 30 to 50% lower AUCτ values). Delamanid did not affect rifampin, pyrazinamide, and isoniazid exposure; the ethambutol AUCτ and Cmax values were about 25% higher with delamanid coadministration. The lack of clinically significant drug-drug interactions between delamanid and selected antiretroviral agents (including the strong CYP inhibitor ritonavir) and a combination of anti-TB drugs was demonstrated. Although there was a decrease in the delamanid concentrations when coadministered with ethambutol plus Rifater, this is likely related to

  13. Improving Detection of Arrhythmia Drug-Drug Interactions in Pharmacovigilance Data through the Implementation of Similarity-Based Modeling

    PubMed Central

    Vilar, Santiago; Lorberbaum, Tal; Hripcsak, George; Tatonetti, Nicholas P.

    2015-01-01

    Identification of Drug-Drug Interactions (DDIs) is a significant challenge during drug development and clinical practice. DDIs are responsible for many adverse drug effects (ADEs), decreasing patient quality of life and causing higher care expenses. DDIs are not systematically evaluated in pre-clinical or clinical trials and so the FDA U. S. Food and Drug Administration relies on post-marketing surveillance to monitor patient safety. However, existing pharmacovigilance algorithms show poor performance for detecting DDIs exhibiting prohibitively high false positive rates. Alternatively, methods based on chemical structure and pharmacological similarity have shown promise in adverse drug event detection. We hypothesize that the use of chemical biology data in a post hoc analysis of pharmacovigilance results will significantly improve the detection of dangerous interactions. Our model integrates a reference standard of DDIs known to cause arrhythmias with drug similarity data. To compare similarity between drugs we used chemical structure (both 2D and 3D molecular structure), adverse drug side effects, chemogenomic targets, drug indication classes, and known drug-drug interactions. We evaluated the method on external reference standards. Our results showed an enhancement of sensitivity, specificity and precision in different top positions with the use of similarity measures to rank the candidates extracted from pharmacovigilance data. For the top 100 DDI candidates, similarity-based modeling yielded close to twofold precision enhancement compared to the proportional reporting ratio (PRR). Moreover, the method helps in the DDI decision making through the identification of the DDI in the reference standard that generated the candidate. PMID:26068584

  14. Drug-drug Interaction Discovery Using Abstraction Networks for “National Drug File – Reference Terminology” Chemical Ingredients

    PubMed Central

    Ochs, Christopher; Zheng, Ling; Gu, Huanying; Perl, Yehoshua; Geller, James; Kapusnik-Uner, Joan; Zakharchenko, Aleksandr

    2015-01-01

    The National Drug File – Reference Terminology (NDF-RT) is a large and complex drug terminology. NDF-RT provides important information about clinical drugs, e.g., their chemical ingredients, mechanisms of action, dosage form and physiological effects. Within NDF-RT such information is represented using tens of thousands of roles. It is difficult to comprehend large, complex terminologies like NDF-RT. In previous studies, we introduced abstraction networks to summarize the content and structure of terminologies. In this paper, we introduce the Ingredient Abstraction Network to summarize NDF-RT’s Chemical Ingredients and their associated drugs. Additionally, we introduce the Aggregate Ingredient Abstraction Network, for controlling the granularity of summarization provided by the Ingredient Abstraction Network. The Ingredient Abstraction Network is used to support the discovery of new candidate drug-drug interactions (DDIs) not appearing in First Databank, Inc.’s DDI knowledgebase. PMID:26958234

  15. The prevalence of major potential drug-drug interactions at a University health centre pharmacy in Jamaica

    PubMed Central

    Kennedy-Dixon, Tracia-Gay; Gossell-Williams, Maxine; Hall, Jannel; Anglin-Brown, Blossom

    2015-01-01

    Objective: To identify major potential drug-drug interactions (DDIs) on prescriptions filled at the University Health Centre Pharmacy, Mona Campus, Jamaica. Methods: This investigation utilised a cross-sectional analysis on all prescriptions with more than one drug that were filled at the Health Centre Pharmacy between November 2012 and February 2013. Potential DDIs were identified using the online Drug Interactions Checker database of Drugs.com. Results: During the period of the study, a total of 2814 prescriptions were analysed for potential DDIs. The prevalence of potential DDIs found during the study period was 49.82%. Major potential DDIs accounted for 4.7 % of the total number of interactions detected, while moderate potential DDIs and minor potential DDIs were 80.8 % and 14.5 % respectively. The three most frequently occurring major potential DDIs were amlodipine and simvastatin (n=46), amiloride and losartan (n=27) and amiloride and lisinopril (n=16). Conclusion: This study has highlighted the need for educational initiatives to ensure that physicians and pharmacists collaborate in an effort to minimise the risks to the patients. These interactions are avoidable for the most part, as the use of online tools can facilitate the selection of therapeutic alternatives or guide decisions for closer patient monitoring and thus reduce the risks of adverse events. PMID:26759615

  16. Use of physiologically based pharmacokinetic modeling for assessment of drug-drug interactions.

    PubMed

    Baneyx, Guillaume; Fukushima, Yumi; Parrott, Neil

    2012-04-01

    Interactions between co-administered medicines can reduce efficacy or lead to adverse effects. Understanding and managing such interactions is essential in bringing safe and effective medicines to the market. Ideally, interaction potential should be recognized early and minimized in compounds that reach late stages of drug development. Physiologically based pharmacokinetic models combine knowledge of physiological factors with compound-specific properties to simulate how a drug behaves in the human body. These software tools are increasingly used during drug discovery and development and, when integrating relevant in vitro data, can simulate drug interaction potential. This article provides some background and presents illustrative examples. Physiologically based models are an integral tool in the discovery and development of drugs, and can significantly aid our understanding and prediction of drug interactions.

  17. Potential drug-drug interactions in medical intensive care unit of a tertiary care hospital in Pakistan.

    PubMed

    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.

  18. Drug-drug interactions between antiretroviral and immunosuppressive agents in HIV-infected patients after solid organ transplantation: a review.

    PubMed

    van Maarseveen, Erik M; Rogers, Christin C; Trofe-Clark, Jennifer; van Zuilen, Arjan D; Mudrikova, Tania

    2012-10-01

    Since the introduction of combination antiretroviral therapy (cART) resulting in the prolonged survival of HIV-infected patients, HIV infection is no longer considered to be a contraindication for solid organ transplantation (SOT). The combined management of antiretroviral and immunosuppressive therapy proved to be extremely challenging, as witnessed by high rates of allograft rejection and drug toxicity, but the profound drug-drug interactions between immunosuppressants and cART, especially protease inhibitors (PIs) also play an important role. Caution and frequent drug level monitoring of calcineurin inhibitors, such as tacrolimus are necessary when PIs are (re)introduced or withdrawn in HIV-infected recipients. Furthermore, the pharmacokinetics of glucocorticoids and mTOR inhibitors are seriously affected by PIs. With the introduction of integrase inhibitors, CCR5-antagonists and fusion inhibitors which cause significantly less pharmacokinetic interactions, have minor overlapping toxicity, and offer the advantage of pharmacodynamic synergy, it is time to revaluate what may be considered the optimal antiretroviral regimen in SOT recipients. In this review we provide a brief overview of the recent success of SOT in the HIV population, and an update on the pharmacokinetic and pharmacodynamic interactions between currently available cART and immunosuppressants in HIV-infected patients, who underwent SOT.

  19. DDI-CPI, a server that predicts drug-drug interactions through implementing the chemical-protein interactome.

    PubMed

    Luo, Heng; Zhang, Ping; Huang, Hui; Huang, Jialiang; Kao, Emily; Shi, Leming; He, Lin; Yang, Lun

    2014-07-01

    Drug-drug interactions (DDIs) may cause serious side-effects that draw great attention from both academia and industry. Since some DDIs are mediated by unexpected drug-human protein interactions, it is reasonable to analyze the chemical-protein interactome (CPI) profiles of the drugs to predict their DDIs. Here we introduce the DDI-CPI server, which can make real-time DDI predictions based only on molecular structure. When the user submits a molecule, the server will dock user's molecule across 611 human proteins, generating a CPI profile that can be used as a feature vector for the pre-constructed prediction model. It can suggest potential DDIs between the user's molecule and our library of 2515 drug molecules. In cross-validation and independent validation, the server achieved an AUC greater than 0.85. Additionally, by investigating the CPI profiles of predicted DDI, users can explore the PK/PD proteins that might be involved in a particular DDI. A 3D visualization of the drug-protein interaction will be provided as well. The DDI-CPI is freely accessible at http://cpi.bio-x.cn/ddi/.

  20. Detection of drug-drug interactions through data mining studies using clinical sources, scientific literature and social media.

    PubMed

    Vilar, Santiago; Friedman, Carol; Hripcsak, George

    2017-02-17

    Drug-drug interactions (DDIs) constitute an important concern in drug development and postmarketing pharmacovigilance. They are considered the cause of many adverse drug effects exposing patients to higher risks and increasing public health system costs. Methods to follow-up and discover possible DDIs causing harm to the population are a primary aim of drug safety researchers. Here, we review different methodologies and recent advances using data mining to detect DDIs with impact on patients. We focus on data mining of different pharmacovigilance sources, such as the US Food and Drug Administration Adverse Event Reporting System and electronic health records from medical institutions, as well as on the diverse data mining studies that use narrative text available in the scientific biomedical literature and social media. We pay attention to the strengths but also further explain challenges related to these methods. Data mining has important applications in the analysis of DDIs showing the impact of the interactions as a cause of adverse effects, extracting interactions to create knowledge data sets and gold standards and in the discovery of novel and dangerous DDIs.

  1. Analysis and prediction of drug-drug interaction by minimum redundancy maximum relevance and incremental feature selection.

    PubMed

    Liu, Lili; Chen, Lei; Zhang, Yu-Hang; Wei, Lai; Cheng, Shiwen; Kong, Xiangyin; Zheng, Mingyue; Huang, Tao; Cai, Yu-Dong

    2017-02-01

    Drug-drug interaction (DDI) defines a situation in which one drug affects the activity of another when both are administered together. DDI is a common cause of adverse drug reactions and sometimes also leads to improved therapeutic effects. Therefore, it is of great interest to discover novel DDIs according to their molecular properties and mechanisms in a robust and rigorous way. This paper attempts to predict effective DDIs using the following properties: (1) chemical interaction between drugs; (2) protein interactions between the targets of drugs; and (3) target enrichment of KEGG pathways. The data consisted of 7323 pairs of DDIs collected from the DrugBank and 36,615 pairs of drugs constructed by randomly combining two drugs. Each drug pair was represented by 465 features derived from the aforementioned three categories of properties. The random forest algorithm was adopted to train the prediction model. Some feature selection techniques, including minimum redundancy maximum relevance and incremental feature selection, were used to extract key features as the optimal input for the prediction model. The extracted key features may help to gain insights into the mechanisms of DDIs and provide some guidelines for the relevant clinical medication developments, and the prediction model can give new clues for identification of novel DDIs.

  2. Hypericum perforatum: pharmacokinetic, mechanism of action, tolerability, and clinical drug-drug interactions.

    PubMed

    Russo, Emilio; Scicchitano, Francesca; Whalley, Benjamin J; Mazzitello, Carmela; Ciriaco, Miriam; Esposito, Stefania; Patanè, Marinella; Upton, Roy; Pugliese, Michela; Chimirri, Serafina; Mammì, Maria; Palleria, Caterina; De Sarro, Giovambattista

    2014-05-01

    Hypericum perforatum (HP) belongs to the Hypericaceae family and is one of the oldest used and most extensively investigated medicinal herbs. The medicinal form comprises the leaves and flowering tops of which the primary ingredients of interest are naphthodianthrones, xanthones, flavonoids, phloroglucinols (e.g. hyperforin), and hypericin. Although several constituents elicit pharmacological effects that are consistent with HP's antidepressant activity, no single mechanism of action underlying these effects has thus far been found. Various clinical trials have shown that HP has a comparable antidepressant efficacy as some currently used antidepressant drugs in the treatment of mild/moderate depression. Interestingly, low-hyperforin-content preparations are effective in the treatment of depression. Moreover, HP is also used to treat certain forms of anxiety. However, HP can induce various cytochrome P450s isozymes and/or P-glycoprotein, of which many drugs are substrates and which are the main origin of HP-drug interactions. Here, we analyse the existing evidence describing the clinical consequence of HP-drug interactions. Although some of the reported interactions are based on findings from in vitro studies, the clinical importance of which remain to be demonstrated, others are based on case reports where causality can, in some cases, be determined to reveal clinically significant interactions that suggest caution, consideration, and disclosure of potential interactions prior to informed use of HP.

  3. Unravelling the complex drug-drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein.

    PubMed

    Ledwitch, Kaitlyn V; Barnes, Robert W; Roberts, Arthur G

    2016-01-28

    Drug-drug interactions (DDIs) and associated toxicity from cardiovascular drugs represents a major problem for effective co-administration of cardiovascular therapeutics. A significant amount of drug toxicity from DDIs occurs because of drug interactions and multiple cardiovascular drug binding to the efflux transporter P-glycoprotein (Pgp), which is particularly problematic for cardiovascular drugs because of their relatively low therapeutic indexes. The calcium channel antagonist, verapamil and the cardiac glycoside, digoxin, exhibit DDIs with Pgp through non-competitive inhibition of digoxin transport, which leads to elevated digoxin plasma concentrations and digoxin toxicity. In the present study, verapamil-induced ATPase activation kinetics were biphasic implying at least two verapamil-binding sites on Pgp, whereas monophasic digoxin activation of Pgp-coupled ATPase kinetics suggested a single digoxin-binding site. Using intrinsic protein fluorescence and the saturation transfer double difference (STDD) NMR techniques to probe drug-Pgp interactions, verapamil was found to have little effect on digoxin-Pgp interactions at low concentrations of verapamil, which is consistent with simultaneous binding of the drugs and non-competitive inhibition. Higher concentrations of verapamil caused significant disruption of digoxin-Pgp interactions that suggested overlapping and competing drug-binding sites. These interactions correlated to drug-induced conformational changes deduced from acrylamide quenching of Pgp tryptophan fluorescence. Also, Pgp-coupled ATPase activity kinetics measured with a range of verapamil and digoxin concentrations fit well to a DDI model encompassing non-competitive and competitive inhibition of digoxin by verapamil. The results and previous transport studies were combined into a comprehensive model of verapamil-digoxin DDIs encompassing drug binding, ATP hydrolysis, transport and conformational changes.

  4. Biological products for the treatment of psoriasis: therapeutic targets, pharmacodynamics and disease-drug-drug interaction implications.

    PubMed

    Wang, Jie; Wang, Yow-Ming C; Ahn, Hae-Young

    2014-09-01

    Psoriasis is a chronic inflammatory skin disease condition that involves altered expression of a broad spectrum of proinflammatory cytokines which are associated with activation of T cells and proliferation of keratinocytes. Currently approved biological products for psoriasis treatment fall into two main classes: cytokine modulators and biologics targeting T cells. In psoriatic patients, elevated levels of proinflammatory cytokines are observed. Elevated proinflammatory cytokines can suppress some cytochrome P450 (CYP) enzymes, and the treatment of psoriasis with biological products can reduce proinflammatory cytokine levels. Therefore, the exposure of CYP substrate drugs is anticipated to be affected by the psoriasis disease resulting in a higher exposure than in healthy state (named disease-drug interaction) as well as by the biological treatments due to disease improvements resulting in a decrease in exposure (named disease-drug-drug interaction, disease-DDI). However, the quantitative impact on CYP substrate exposure due to disease or due to treatment with biological products remains to be evaluated. The objective of the current review is to provide an overview of the therapeutic targets and cytokine-related pharmacodynamic effects of biological products in psoriasis treatment with a particular focus on their implications for disease-DDI. The clinical study design considerations for psoriasis disease-DDI evaluation are also discussed.

  5. Time-dependent drug-drug interaction alerts in care provider order entry: software may inhibit medication error reductions.

    PubMed

    van der Sijs, Heleen; Lammers, Laureen; van den Tweel, Annemieke; Aarts, Jos; Berg, Marc; Vulto, Arnold; van Gelder, Teun

    2009-01-01

    Time-dependent drug-drug interactions (TDDIs) are drug combinations that result in a decreased drug effect due to coadministration of a second drug. Such interactions can be prevented by separately administering the drugs. This study attempted to reduce drug administration errors due to overridden TDDIs in a care provider order entry (CPOE) system. In four periods divided over two studies, logged TDDIs were investigated by reviewing the time intervals prescribed in the CPOE and recorded on the patient chart. The first study showed significant drug administration error reduction from 56.4 to 36.2% (p<0.05), whereas the second study was not successful (46.7 and 45.2%; p>0.05). Despite interventions, drug administration errors still occurred in more than one third of cases and prescribing errors in 79-87%. Probably the low alert specificity, the unclear alert information content, and the inability of the software to support safe and efficient TDDI alert handling all diminished correct prescribing, and consequently, insufficiently reduced drug administration errors.

  6. Drug-Drug Interactions and Diagnostics for Drug Users With HIV and HIV/HCV Coinfections: Introduction.

    PubMed

    Khalsa, Jag H; Talal, Andrew H; Morse, Gene

    2017-03-01

    Substance use and pharmacologic treatment of co-occurring infections such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are associated with many adverse consequences including pharmacokinetic and pharmacodynamic drug-drug interactions (DDIs). The National Institute on Drug Abuse sponsored a 2-day conference on DDIs at which clinicians/scientists from government, academia, and the pharmaceutical industry presented the most current research findings to formulate a comprehensive overview of DDIs. Specific topics discussed included drug metabolism; drug interactions between medications used in the treatment of HIV, HCV, and substance use disorders; intrahepatic concentrations and methods of assessment of drugs in liver disease of varying etiologies and degrees of impairment; and minimally invasive sampling techniques for the assessment of intrahepatic drug concentrations, viral replication, and changes in gene expression in response to treatment. Finally, the speakers identified research targets and priorities on DDIs. Areas of emphasis included development of diagnostic assays for drug concentration assessment in different organs, an enhanced understanding of factors responsible for alterations in drug metabolism and excretion, and establishment of clinical trials and work groups to study DDIs. Our long-term objective is to broaden investigation in the field of DDIs in substance users.

  7. A novel algorithm for analyzing drug-drug interactions from MEDLINE literature

    PubMed Central

    Lu, Yin; Shen, Dan; Pietsch, Maxwell; Nagar, Chetan; Fadli, Zayd; Huang, Hong; Tu, Yi-Cheng; Cheng, Feng

    2015-01-01

    Drug–drug interaction (DDI) is becoming a serious clinical safety issue as the use of multiple medications becomes more common. Searching the MEDLINE database for journal articles related to DDI produces over 330,000 results. It is impossible to read and summarize these references manually. As the volume of biomedical reference in the MEDLINE database continues to expand at a rapid pace, automatic identification of DDIs from literature is becoming increasingly important. In this article, we present a random-sampling-based statistical algorithm to identify possible DDIs and the underlying mechanism from the substances field of MEDLINE records. The substances terms are essentially carriers of compound (including protein) information in a MEDLINE record. Four case studies on warfarin, ibuprofen, furosemide and sertraline implied that our method was able to rank possible DDIs with high accuracy (90.0% for warfarin, 83.3% for ibuprofen, 70.0% for furosemide and 100% for sertraline in the top 10% of a list of compounds ranked by p-value). A social network analysis of substance terms was also performed to construct networks between proteins and drug pairs to elucidate how the two drugs could interact. PMID:26612138

  8. Drug-drug interactions related to altered absorption and plasma protein binding: theoretical and regulatory considerations, and an industry perspective.

    PubMed

    Hochman, Jerome; Tang, Cuyue; Prueksaritanont, Thomayant

    2015-03-01

    Drug-drug interactions (DDIs) related to altered drug absorption and plasma protein binding have received much less attention from regulatory agencies relative to DDIs mediated via drug metabolizing enzymes and transporters. In this review, a number of theoretical bases and regulatory framework are presented for these DDI aspects. Also presented is an industry perspective on how to approach these issues in support of drug development. Overall, with the exception of highly permeable and highly soluble (BCS 1) drugs, DDIs related to drug-induced changes in gastrointestinal (GI) physiology can be substantial, thus warranting more attentions. For a better understanding of absorption-associated DDI potential in a clinical setting, mechanistic studies should be conducted based on holistic integration of the pharmaceutical profiles (e.g., pH-dependent solubility) and pharmacological properties (e.g., GI physiology and therapeutic margin) of drug candidates. Although majority of DDI events related to altered plasma protein binding are not expected to be of clinical significance, exceptions exist for a subset of compounds with certain pharmacokinetic and pharmacological properties. Knowledge of the identity of binding proteins and the binding extent in various clinical setting (including disease states) can be valuable in aiding clinical DDI data interpretations, and ensuring safe and effective use of new drugs.

  9. Comparison of the Drug-Drug Interactions Potential of Erlotinib and Gefitinib via Inhibition of UDP-Glucuronosyltransferases

    PubMed Central

    Liu, Yong; Ramírez, Jacqueline; House, Larry

    2010-01-01

    We aimed to investigate and compare the effects of erlotinib and gefitinib on UDP-glucuronosyltransferase (UGT) activities and to quantitatively evaluate their drug-drug interaction (DDI) potential due to UGT inhibition. The inhibitory effects of erlotinib and gefitinib on UGTs were determined using high-performance liquid chromatography by measuring the formation rates for 4-methylumbelliferone (4-MU) glucuronide, imipramine N-glucuronide, and bilirubin glucuronides using recombinant human UGT isoforms and human liver microsomes (HLMs) in the absence or presence of erlotinib and gefitinib. Inhibition kinetic studies were conducted. Area under the curve (AUC) ratios were used to predict the risk of potential DDI in vivo. Erlotinib exhibited selective potent competitive inhibition against 4-MU glucuronidation by UGT1A1, and gefitinib demonstrated a wide range of inhibition against UGT-mediated 4-MU glucuronidation, particularly against UGT1A1, UGT1A7, UGT1A9, and UGT2B7. Erlotinib also exerted potent mixed inhibition against bilirubin glucuronidation in HLMs. We estimated that coadministration of erlotinib at 100 mg/day or higher doses may result in at least a 30% increase in the AUC of drugs predominantly cleared by UGT1A1. Thus, the coadministration of erlotinib with drugs primarily cleared by UGT1A1 may result in potential DDI. In contrast, gefitinib is unlikely to cause a clinically significant DDI through inhibition of glucuronidation. PMID:19850672

  10. Drug-drug interactions and adverse drug reactions in polypharmacy among older adults: an integrative review 1

    PubMed Central

    Rodrigues, Maria Cristina Soares; de Oliveira, Cesar

    2016-01-01

    ABSTRACT Objective: to identify and summarize studies examining both drug-drug interactions (DDI) and adverse drug reactions (ADR) in older adults polymedicated. Methods: an integrative review of studies published from January 2008 to December 2013, according to inclusion and exclusion criteria, in MEDLINE and EMBASE electronic databases were performed. Results: forty-seven full-text studies including 14,624,492 older adults (≥ 60 years) were analyzed: 24 (51.1%) concerning ADR, 14 (29.8%) DDI, and 9 studies (19.1%) investigating both DDI and ADR. We found a variety of methodological designs. The reviewed studies reinforced that polypharmacy is a multifactorial process, and predictors and inappropriate prescribing are associated with negative health outcomes, as increasing the frequency and types of ADRs and DDIs involving different drug classes, moreover, some studies show the most successful interventions to optimize prescribing. Conclusions: DDI and ADR among older adults continue to be a significant issue in the worldwide. The findings from the studies included in this integrative review, added to the previous reviews, can contribute to the improvement of advanced practices in geriatric nursing, to promote the safety of older patients in polypharmacy. However, more research is needed to elucidate gaps. PMID:27598380

  11. Clinical drug-drug interaction assessment of ivacaftor as a potential inhibitor of cytochrome P450 and P-glycoprotein.

    PubMed

    Robertson, Sarah M; Luo, Xia; Dubey, Neeraj; Li, Chonghua; Chavan, Ajit B; Gilmartin, Geoffrey S; Higgins, Mark; Mahnke, Lisa

    2015-01-01

    Ivacaftor is approved in the USA for the treatment of cystic fibrosis (CF) in patients with a G551D-CFTR mutation or one of eight other CFTR mutations. A series of in vitro experiments conducted early in the development of ivacaftor indicated ivacaftor and metabolites may have the potential to inhibit cytochrome P450 (CYP) 2C8, CYP2C9, CYP3A, and CYP2D6, as well as P-glycoprotein (P-gp). Based on these results, a series of clinical drug-drug interaction (DDI) studies were conducted to evaluate the effect of ivacaftor on sensitive substrates of CYP2C8 (rosiglitazone), CYP3A (midazolam), CYP2D6 (desipramine), and P-gp (digoxin). In addition, a DDI study was conducted to evaluate the effect of ivacaftor on a combined oral contraceptive, as this is considered an important comedication in CF patients. The results indicate ivacaftor is a weak inhibitor of CYP3A and P-gp, but has no effect on CYP2C8 or CYP2D6. Ivacaftor caused non-clinically significant increases in ethinyl estradiol and norethisterone exposure. Based on these results, caution and appropriate monitoring are recommended when concomitant substrates of CYP2C9, CYP3A and/or P-gp are used during treatment with ivacaftor, particularly drugs with a narrow therapeutic index, such as warfarin.

  12. Best practices for the use of itraconazole as a replacement for ketoconazole in drug-drug interaction studies.

    PubMed

    Liu, Lichuan; Bello, Akintunde; Dresser, Mark J; Heald, Donald; Komjathy, Steven Ferenc; O'Mara, Edward; Rogge, Mark; Stoch, S Aubrey; Robertson, Sarah M

    2016-02-01

    Ketoconazole has been widely used as a strong cytochrome P450 (CYP) 3A (CYP3A) inhibitor in drug-drug interaction (DDI) studies. However, the US Food and Drug Administration has recommended limiting the use of ketoconazole to cases in which no alternative therapies exist, and the European Medicines Agency has recommended the suspension of its marketing authorizations because of the potential for serious safety concerns. In this review, the Innovation and Quality in Pharmaceutical Development's Clinical Pharmacology Leadership Group (CPLG) provides a compelling rationale for the use of itraconazole as a replacement for ketoconazole in clinical DDI studies and provides recommendations on the best practices for the use of itraconazole in such studies. Various factors considered in the recommendations include the choice of itraconazole dosage form, administration in the fasted or fed state, the dose and duration of itraconazole administration, the timing of substrate and itraconazole coadministration, and measurement of itraconazole and metabolite plasma concentrations, among others. The CPLG's recommendations are based on careful review of available literature and internal industry experiences.

  13. Decreased tacrolimus plasma concentrations during HCV therapy: a drug-drug interaction or is there an alternative explanation?

    PubMed

    Smolders, E J; Pape, S; de Kanter, C T M M; van den Berg, A P; Drenth, J P H; Burger, D M

    2017-03-01

    Chronic hepatitis C virus (HCV) infection can cause severe liver cirrhosis, for which liver transplantation is the only therapy. To prevent organ rejection, transplanted patients are treated with immunosuppressive agents. We describe two transplanted patients treated with tacrolimus who were simultaneously treated with direct-acting antivirals (DAAs) for their chronic HCV infection. No pharmacokinetic drug-drug interactions (DDIs) were expected between tacrolimus and the selected DAAs. However, in both patients, tacrolimus plasma concentrations decreased during HCV treatment. We hypothesise that decreased plasma concentrations were not caused by a DDI but were an indirect result of the clearance of the HCV infection. During chronic HCV infection, pro-inflammatory cytokines may inhibit cytochrome P450 (CYP) enzymes, which are primarily responsible for tacrolimus metabolism. If this is true, then with clearance of the virus the activity of these enzymes will normalise and tacrolimus metabolism will increase. These changes were clinically relevant because the tacrolimus dosage needed to be adjusted. Therefore, physicians should be aware that CYP substrates with narrow therapeutic ranges might require dose adaption during HCV therapy with DAAs.

  14. Text mining for pharmacovigilance: Using machine learning for drug name recognition and drug-drug interaction extraction and classification.

    PubMed

    Ben Abacha, Asma; Chowdhury, Md Faisal Mahbub; Karanasiou, Aikaterini; Mrabet, Yassine; Lavelli, Alberto; Zweigenbaum, Pierre

    2015-12-01

    Pharmacovigilance (PV) is defined by the World Health Organization as the science and activities related to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem. An essential aspect in PV is to acquire knowledge about Drug-Drug Interactions (DDIs). The shared tasks on DDI-Extraction organized in 2011 and 2013 have pointed out the importance of this issue and provided benchmarks for: Drug Name Recognition, DDI extraction and DDI classification. In this paper, we present our text mining systems for these tasks and evaluate their results on the DDI-Extraction benchmarks. Our systems rely on machine learning techniques using both feature-based and kernel-based methods. The obtained results for drug name recognition are encouraging. For DDI-Extraction, our hybrid system combining a feature-based method and a kernel-based method was ranked second in the DDI-Extraction-2011 challenge, and our two-step system for DDI detection and classification was ranked first in the DDI-Extraction-2013 task at SemEval. We discuss our methods and results and give pointers to future work.

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

    PubMed

    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.

  16. A survey of attitudes, practices, and knowledge regarding drug-drug interactions among medical residents in Iran.

    PubMed

    Nabovati, Ehsan; Vakili-Arki, Hasan; Taherzadeh, Zhila; Saberi, Mohammad Reza; Abu-Hanna, Ameen; Eslami, Saeid

    2017-04-05

    Background When prescribing medications, physicians should recognize clinically relevant potential drug-drug interactions (DDIs). To improve medication safety, it is important to understand prescribers' knowledge and opinions pertaining to DDIs. Objective To determine the current DDI information sources used by medical residents, their knowledge of DDIs, their opinions about performance feedback on co-prescription of interacting drugs. Setting Academic hospitals of Mashhad University of Medical Sciences (MUMS) in Iran. Methods A questionnaire containing questions regarding demographic and practice characteristics, DDI information sources, ability to recognize DDIs, and opinions about performance feedback was distributed to medical residents of 22 specialties in eight academic hospitals in Iran. We analyzed their perception pertaining to DDIs, their performance on classifying drug pairs, and we used a linear regression model to assess the association of potential determinants on their DDI knowledge. Main Outcome Measure prescribers' knowledge and opinions pertaining to DDIs. Results The overall response rate and completion rate for 315 distributed questionnaires were 90% (n = 295) and 86% (n = 281), respectively. Among DDI information sources, books, software on mobile phone or tablet, and Internet were the most commonly-used references. Residents could correctly classify only 41% (5.7/14) of the drug pairs. The regression model showed no significant association between residents' characteristics and their DDI knowledge. An overwhelming majority of the respondents (n = 268, 95.4%) wished to receive performance feedback on co-prescription of interacting drugs in their prescriptions. They mostly selected information technology-based tools (i.e. short text message and email) as their preferred method of receiving feedback. Conclusion Our findings indicate that prescribers may have poor ability to prevent clinically relevant potential DDI occurrence, and they

  17. Drug-drug interactions between immunosuppressants and antidiabetic drugs in the treatment of post-transplant diabetes mellitus.

    PubMed

    Vanhove, Thomas; Remijsen, Quinten; Kuypers, Dirk; Gillard, Pieter

    2016-09-14

    Post-transplant diabetes mellitus is a frequent complication of solid organ transplantation that generally requires treatment with lifestyle interventions and antidiabetic medication. A number of demonstrated and potential pharmacokinetic drug-drug interactions (DDIs) exist between commonly used immunosuppressants and antidiabetic drugs, which are comprehensively summarized in this review. Cyclosporine (CsA) itself inhibits the cytochrome P450 (CYP) 3A4 enzyme and a variety of drug transporters. As a result, it increases exposure to repaglinide and sitagliptin, will likely increase the exposure to nateglinide, glyburide, saxagliptin, vildagliptin and alogliptin, and could theoretically increase the exposure to gliquidone and several sodium-glucose transporter (SGLT)-2 inhibitors. Currently available data, although limited, suggest that these increases are modest and, particularly with regard to gliptins and SGLT-2 inhibitors, unlikely to result in hypoglycemia. The interaction with repaglinide is more pronounced but does not preclude concomitant use if repaglinide dose is gradually titrated. Mycophenolate mofetil and azathioprine do not engage in DDIs with any antidiabetic drug. Although calcineurin inhibitors (CNIs) and mammalian target of rapamycin inhibitors (mTORi) are intrinsically prone to DDIs, their disposition is not influenced by metformin, pioglitazone, sulfonylureas (except possibly glyburide) or insulin. An effect of gliptins on the disposition of CNIs and mTORi is unlikely, but has not been definitively ruled out. Based on their disposition profiles, glyburide and canagliflozin could affect CNI and mTORi disposition although this requires further study. Finally, delayed gastric emptying as a result of glucagon-like peptide-1 agonists seems to have a limited, but not necessarily negligible effect on CNI disposition.

  18. Prediction of Drug-Drug Interactions Arising from CYP3A induction Using a Physiologically Based Dynamic Model

    PubMed Central

    Mukadam, Sophie; Gardner, Iain; Okialda, Krystle; Wong, Susan; Hatley, Oliver; Tay, Suzanne; Rowland-Yeo, Karen; Jamei, Masoud; Rostami-Hodjegan, Amin; Kenny, Jane R.

    2016-01-01

    Using physiologically based pharmacokinetic modeling, we predicted the magnitude of drug-drug interactions (DDIs) for studies with rifampicin and seven CYP3A4 probe substrates administered i.v. (10 studies) or orally (19 studies). The results showed a tendency to underpredict the DDI magnitude when the victim drug was administered orally. Possible sources of inaccuracy were investigated systematically to determine the most appropriate model refinement. When the maximal fold induction (Indmax) for rifampicin was increased (from 8 to 16) in both the liver and the gut, or when the Indmax was increased in the gut but not in liver, there was a decrease in bias and increased precision compared with the base model (Indmax = 8) [geometric mean fold error (GMFE) 2.12 vs. 1.48 and 1.77, respectively]. Induction parameters (mRNA and activity), determined for rifampicin, carbamazepine, phenytoin, and phenobarbital in hepatocytes from four donors, were then used to evaluate use of the refined rifampicin model for calibration. Calibration of mRNA and activity data for other inducers using the refined rifampicin model led to more accurate DDI predictions compared with the initial model (activity GMFE 1.49 vs. 1.68; mRNA GMFE 1.35 vs. 1.46), suggesting that robust in vivo reference values can be used to overcome interdonor and laboratory-to-laboratory variability. Use of uncalibrated data also performed well (GMFE 1.39 and 1.44 for activity and mRNA). As a result of experimental variability (i.e., in donors and protocols), it is prudent to fully characterize in vitro induction with prototypical inducers to give an understanding of how that particular system extrapolates to the in vivo situation when using an uncalibrated approach. PMID:27026679

  19. Information Technology-Based Interventions to Improve Drug-Drug Interaction Outcomes: A Systematic Review on Features and Effects.

    PubMed

    Nabovati, Ehsan; Vakili-Arki, Hasan; Taherzadeh, Zhila; Saberi, Mohammad Reza; Medlock, Stephanie; Abu-Hanna, Ameen; Eslami, Saeid

    2017-01-01

    The purpose of this systematic review was to identify features and effects of information technology (IT)-based interventions on outcomes related to drug-drug interactions (DDI outcomes). A literature search was conducted in Medline, EMBASE, and the Cochrane Library for published English-language studies. Studies were included if a main outcome was related to DDIs, the intervention involved an IT-based system, and the study design was experimental or observational with controls. Study characteristics, including features and effects of IT-based interventions, were extracted. Nineteen studies comprising five randomized controlled trials (RCT), five non-randomized controlled trials (NRCT) and nine observational studies with controls (OWC) were included. Sixty-four percent of prescriber-directed interventions, and all non-prescriber interventions, were effective. Each of the following characteristics corresponded to groups of studies of which a majority were effective: automatic provision of recommendations within the providers' workflow, intervention at the time of decision-making, integration into other systems, and requiring the reason for not following the recommendations. Only two studies measured clinical outcomes: an RCT that showed no significant improvement and an OWC that showed improvement, but did not statistically assess the effect. Most studies that measured surrogate outcomes (e.g. potential DDIs) and other outcomes (e.g. adherence to alerts) showed improvements. IT-based interventions improve surrogate clinical outcomes and adherence to DDI alerts. However, there is lack of robust evidence about their effectiveness on clinical outcomes. It is recommended that researchers consider the identified features of effective interventions in the design of interventions and evaluate the effectiveness on DDI outcomes, particularly clinical outcomes.

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

    PubMed

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

    2013-01-01

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

  1. Prediction of the Transporter-Mediated Drug-Drug Interaction Potential of Dabrafenib and Its Major Circulating Metabolites.

    PubMed

    Ellens, Harma; Johnson, Marta; Lawrence, Sarah K; Watson, Cory A; Chen, Liangfu; Richards-Peterson, Lauren E

    2017-03-20

    The BRAF inhibitor dabrafenib was recently approved for the treatment of certain BRAF V600 mutation-positive tumors, either alone or in combination therapy with the MEK inhibitor trametinib. This article presents the dabrafenib transporter-mediated drug-drug interaction risk assessment, which is currently an important part of drug development, regulatory submission and drug registration. Dabrafenib and its major circulating metabolites (hydroxy-, carboxy- and desmethyl-dabrafenib) were investigated as inhibitors of the clinically relevant transporters Pgp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1 and OAT3. The DDI guidance risk assessment decision criteria for inhibition of BCRP, OATP1B1 and OAT3 were slightly exceeded and therefore a minor DDI effect resulting from inhibition of these transporters remained possible. Biliary secretion is the major excretion pathway of dabrafenib related material (71% of orally administered radiolabeled dose recovered in feces), while urinary excretion was observed as well (22.7% of the dose). In vitro uptake into human hepatocytes of the dabrafenib metabolites, but not of dabrafenib parent compound, was mediated, at least in part, by hepatic uptake transporters. The transporters responsible for uptake of the pharmacologically active hydroxy- and desmethyl dabrafenib could not be identified, whereas carboxy-dabrafenib was a substrate of several OATPs. Dabrafenib, hydroxy- and desmethyl dabrafenib were substrates of P-gp and BCRP, while carboxy-dabrafenib was not. While a small increase in exposure to carboxy-dabrafenib upon inhibition of OATPs and an increase in exposure to desmethyl-dabrafenib upon inhibition of P-gp or BCRP cannot be excluded, the clinical significance of such increases is likely low.

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

    PubMed

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

    2009-11-01

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

  3. The inhibition of human multidrug and toxin extrusion 1 is involved in the drug-drug interaction caused by cimetidine.

    PubMed

    Matsushima, Soichiro; Maeda, Kazuya; Inoue, Katsuhisa; Ohta, Kin-ya; Yuasa, Hiroaki; Kondo, Tsunenori; Nakayama, Hideki; Horita, Shigeru; Kusuhara, Hiroyuki; Sugiyama, Yuichi

    2009-03-01

    Cimetidine is known to cause drug-drug interactions (DDIs) with organic cations in the kidney, and a previous clinical study showed that coadministration of cimetidine or probenecid with fexofenadine (FEX) decreased its renal clearance. FEX was taken up into human kidney by human organic anion transporter (hOAT) 3 (SLC22A8), but the mechanism of its luminal efflux has not been clarified. The present study examined the molecular mechanism of these DDIs. Saturable uptake of FEX was observed in human kidney slices, with K(m) and V(max) values of 157+/-7 microM and 418+/-16 nmol/15 min/g kidney, respectively. Cimetidine only slightly inhibited its uptake even at 100 microM, far greater than its clinically relevant concentration, whereas 10 microM probenecid markedly inhibited its uptake. As candidate transporters for the luminal efflux of FEX, we focused on human multidrug and toxin extrusions MATE1 (SLC47A1) and MATE2-K (SLC47A2). Saturable uptake of FEX could be observed in human embryonic kidney 293 cells expressing human MATE1 (hMATE1), whereas hMATE2-K-specific uptake of FEX was too small to conduct its further kinetic analysis. The hMATE1-mediated uptake clearance of FEX was inhibited by cimetidine in a concentration-dependent manner, and it was decreased to 60% of the control value in the presence of 3 microM cimetidine. Taken together, our results suggest that the DDI of FEX with probenecid can be explained by the inhibition of renal uptake mediated by hOAT3, whereas the DDI with cimetidine is mainly caused by the inhibition of hMATE1-mediated efflux of FEX rather than the inhibition of its renal uptake process.

  4. Incidence of Potential Drug-Drug Interactions in a Limited and Stereotyped Prescription Setting - Comparison of Two Free Online Pharmacopoeias

    PubMed Central

    Kannan, Bhaskar; Nagella, Amrutha Bindu; Sathia Prabhu, A; Sasidharan, Gopalakrishnan M; Ramesh, A S

    2016-01-01

    Background: Drug-drug interactions (DDIs) are very common adverse events in health care delivery settings. The use of electronic pharmacopeias can potentially reduce the incidence of DDIs, but they are often thought to be cumbersome to use. This study is aimed at studying the incidence of potential DDIs in a surgical department, where a limited number of drugs are used in stereotyped combinations. We also compared two popular drug compendia in detecting potential DDIs. Methods: The prescriptions of selected patients were entered into Epocrates® and Medscape® for Android smartphones. Potential DDIs were generated and their categories were noted. The warnings generated by Epocrates® were compared with those generated by Medscape® and an agreement index was calculated. Results: Three hundred and thirty-one patients were included for analysis who had received a total of 2,878 drug orders. The incidence of potential DDIs was very high - 89% of all prescriptions. Phenytoin was the drug most commonly implicated, followed by furosemide. Of the DDIs detected, 0.14% were potentially serious and the drug combinations were contraindicated. There was a significant discrepancy between the categories of potential DDIs detected by Epocrates® and Medscape®. No clinically significant DDI was detected in any patient in this cohort. Conclusions: Despite routinely using only a limited number of drugs in stereotyped combinations, prescriptions in surgical departments may not be immune from a significant incidence of DDIs. The use of free apps could reduce the incidence of DDIs, enhance patient safety, and also aid in educating trainees. PMID:28018756

  5. Surveillance of Physicians Causing Potential Drug-Drug Interactions in Ambulatory Care: A Pilot Study in Switzerland

    PubMed Central

    Bucher, Heiner C.; Achermann, Rita; Stohler, Nadja; Meier, Christoph R.

    2016-01-01

    Objectives We analysed potential drug-drug interactions (DDI) in ambulatory care in Switzerland based on claims data from three large health insurers in 2010 to identify physicians with peculiar prescription behaviour differing from peers of the same specialty. Methods We analysed contraindicated or potentially contraindicated DDI from the national drug formulary and calculated for each physician the ratios of the number of patients with a potential DDI divided by the number of patients at risk and used a zero inflated binomial distribution to correct for the inflated number of observations with no DDI. We then calculated the probability that the number of caused potential DDI of physicians was unlikely (p-value < 0.05 and ≥0.01) and very unlikely (p-value <0.01) to be due to chance. Results Of 1'607'233 females and 1'525'307 males 1.3% and 1.2% were exposed to at least one potential DDI during 12 months. When analysing the 40 most common DDI, 598 and 416 of 18,297 physicians (3.3% and 2.3%) were causing potential DDI in a frequency unlikely (p<0.05 and p≥0.01) and very unlikely (p<0.01) to be explained by chance. Patients cared by general practitioners and cardiologists had the lowest probability (0.20 and 0.26) for not being exposed to DDI. Conclusions Contraindicated or potentially contraindicated DDI are frequent in ambulatory care in Switzerland, with a small proportion of physicians causing potential DDI in a frequency that is very unlikely to be explained by chance when compared to peers of the same specialty. PMID:26808430

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

    PubMed

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

    2015-06-01

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

  7. Integrated in vitro analysis for the in vivo prediction of cytochrome P450-mediated drug-drug interactions.

    PubMed

    McGinnity, Dermot F; Waters, Nigel J; Tucker, James; Riley, Robert J

    2008-06-01

    Unbound IC(50) (IC(50,u)) values of 15 drugs were determined in eight recombinantly expressed human cytochromes P450 (P450s) and human hepatocytes, and the data were used to simulate clinical area under the plasma concentration-time curve changes (deltaAUC) on coadministration with prototypic CYP2D6 substrates. Significant differences in IC(50,u) values between enzyme sources were observed for quinidine (0.02 microM in recombinant CYP2D6 versus 0.5 microM in hepatocytes) and propafenone (0.02 versus 4.1 microM). The relative contribution of individual P450s toward the oxidative metabolism of clinical probes desipramine, imipramine, tolterodine, propranolol, and metoprolol was estimated via determinations of intrinsic clearance using recombinant P450s (rP450s). Simulated deltaAUC were compared with those observed in vivo via the ratios of unbound inhibitor concentration at the entrance to the liver to inhibition constants determined against rP450s ([I](in,u)/K(i)) and incorporating parallel substrate elimination pathways. For this dataset, there were 20% false negatives (observed deltaAUC >or= 2, predicted deltaAUC < 2), 77% correct predictions, and 3% false positives. Thus, the [I](in,u)/K(i) approach appears relatively successful at estimating the degree of clinical interactions and can be incorporated into drug discovery strategies. Using a Simcyp ADME (absorption, metabolism, distribution, elimination) simulator (Simcyp Ltd., Sheffield, UK), there were 3% false negatives, 94% correct simulations, and 3% false positives. False-negative predictions were rationalized as a result of mechanism-based inhibition, production of inhibitory metabolites, and/or hepatic uptake. Integrating inhibition and reaction phenotyping data from automated rP450 screens have shown applicability to predict the occurrence and degree of in vivo drug-drug interactions, and such data may identify the clinical consequences for candidate drugs as both "perpetrators" and "victims" of P450

  8. Semi-mechanistic physiologically-based pharmacokinetic modeling of clinical glibenclamide pharmacokinetics and drug-drug-interactions.

    PubMed

    Greupink, Rick; Schreurs, Marieke; Benne, Marina S; Huisman, Maarten T; Russel, Frans G M

    2013-08-16

    We studied if the clinical pharmacokinetics and drug-drug interactions (DDIs) of the sulfonylurea-derivative glibenclamide can be simulated via a physiologically-based pharmacokinetic modeling approach. To this end, a glibenclamide PBPK-model was build in Simcyp using in vitro physicochemical and biotransformation data of the drug, and was subsequently optimized using plasma disappearance data observed after i.v. administration. The model was validated against data observed after glibenclamide oral dosing, including DDIs. We found that glibenclamide pharmacokinetics could be adequately modeled if next to CYP metabolism an active hepatic uptake process was assumed. This hepatic uptake process was subsequently included in the model in a non-mechanistic manner. After an oral dose of 0.875 mg predicted Cmax and AUC were 39.7 (95% CI:37.0-42.7)ng/mL and 108 (95% CI: 96.9-120)ng/mLh, respectively, which is in line with observed values of 43.6 (95% CI: 37.7-49.5)ng/mL and 133 (95% CI: 107-159)ng/mLh. For a 1.75 mg oral dose, the predicted and observed values were 82.5 (95% CI:76.6-88.9)ng/mL vs 91.1 (95% CI: 67.9-115.9) for Cmax and 224 (95% CI: 202-248) vs 324 (95% CI: 197-451)ng/mLh for AUC, respectively. The model correctly predicted a decrease in exposure after rifampicin pre-treatment. An increase in glibenclamide exposure after clarithromycin co-treatment was predicted, but the magnitude of the effect was underestimated because part of this DDI is the result of an interaction at the transporter level. Finally, the effects of glibenclamide and fluconazol co-administration were simulated. Our simulations indicated that co-administration of this potent CYP450 inhibitor will profoundly increase glibenclamide exposure, which is in line with clinical observations linking the glibenclamide-fluconazol combination to an increased risk of hypoglycemia. In conclusion, glibenclamide pharmacokinetics and its CYP-mediated DDIs can be simulated via PBPK-modeling. In addition, our

  9. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios.

    PubMed

    Williams, J Andrew; Hyland, Ruth; Jones, Barry C; Smith, Dennis A; Hurst, Susan; Goosen, Theunis C; Peterkin, Vincent; Koup, Jeffrey R; Ball, Simon E

    2004-11-01

    Glucuronidation is a listed clearance mechanism for 1 in 10 of the top 200 prescribed drugs. The objective of this article is to encourage those studying ligand interactions with UDP-glucuronosyltransferases (UGTs) to adequately consider the potential consequences of in vitro UGT inhibition in humans. Spurred on by interest in developing potent and selective inhibitors for improved confidence around UGT reaction phenotyping, and the increased availability of recombinant forms of human UGTs, several recent studies have reported in vitro inhibition of UGT enzymes. In some cases, the observed potency of UGT inhibitors in vitro has been interpreted as having potential relevance in humans via pharmacokinetic drug-drug interactions. Although there are reported examples of clinically relevant drug-drug interactions for UGT substrates, exposure increases of the aglycone are rarely greater than 100% in the presence of an inhibitor relative to its absence (i.e., AUCi/AUC < or = 2). This small magnitude in change is in contrast to drugs primarily cleared by cytochrome P450 enzymes, where exposures have been reported to increase as much as 35-fold on coadministration with an inhibitor (e.g., ketoconazole inhibition of CYP3A4-catalyzed terfenadine metabolism). In this article the evidence for purported clinical relevance of potent in vitro inhibition of UGT enzymes will be assessed, taking the following into account: in vitro data on the enzymology of glucuronide formation from aglycone, pharmacokinetic principles based on empirical data for inhibition of metabolism, and clinical data on the pharmacokinetic drug-drug interactions of drugs primarily cleared by glucuronidation.

  10. Evaluation of the safety, pharmacokinetics, pharmacodynamics, and drug-drug interaction potential of a selective Lp-PLA2 inhibitor (GSK2647544) in healthy volunteers

    PubMed Central

    Wu, Kai; Xu, Jianfeng; Fong, Regan; Yao, Xiaozhou; Xu, Yanmei; Guiney, William; Gray, Frank; Lockhart, Andrew

    2016-01-01

    Abstract. Objective: To evaluate in healthy volunteers the safety, pharmacokinetics (PK), pharmacodynamics (PD), and drug-drug interaction (DDI) potential of GSK2647544, (a selective lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor). Methods: Study 1 was a single-blind, randomized, placebo-controlled, crossover study with healthy male volunteers randomized to receive single escalating oral doses (0.5 – 750 mg) of GSK2647544. Study 2 was a single-blind, randomized, placebo-controlled study with healthy volunteers randomized to receive repeat doses (80 mg) of GSK2647544. The drug-drug interaction of GSK2647544 with simvastatin was also evaluated in study 2. Results: Across both studies GSK2647544 doses were generally well tolerated with no GSK2647544-related clinically significant findings. GSK2647544 was readily absorbed and its plasma concentration declined bi-exponentially with a terminal half-life ranging from 8 to 16 hours. Plasma exposure of GSK2647544 increased approximately dose-proportionally. There was GSK2647544 dose-dependent inhibition of plasma Lp-PLA2 activity, with a trough inhibition (12 hours after dose) of 85.6% after 7-day twice daily dosing. The administration of simvastatin concomitantly with GSK2647544 increased the overall exposure (area under the plasma concentration-time curve and maximum plasma concentration) of simvastatin and simvastatin acid by 3.6- to 4.3-fold and 1.5- to 3.1-fold, respectively. Conclusions: GSK2647544 was generally well tolerated and had a reasonable PK-PD profile. The clinically significant drug-drug interaction led to an early termination of study 2. PMID:27719741

  11. Evaluation of Drug-Drug Interaction Potential Between Sacubitril/Valsartan (LCZ696) and Statins Using a Physiologically Based Pharmacokinetic Model.

    PubMed

    Lin, Wen; Ji, Tao; Einolf, Heidi; Ayalasomayajula, Surya; Lin, Tsu-Han; Hanna, Imad; Heimbach, Tycho; Breen, Christopher; Jarugula, Venkateswar; He, Handan

    2017-01-13

    Sacubitril/valsartan (LCZ696) has been approved for the treatment of heart failure. Sacubitril is an in vitro inhibitor of organic anion-transporting polypeptides (OATPs). In clinical studies, LCZ696 increased atorvastatin Cmax by 1.7-fold and area under the plasma concentration-time curve by 1.3-fold, but had little or no effect on simvastatin or simvastatin acid exposure. A physiologically based pharmacokinetics modeling approach was applied to explore the underlying mechanisms behind the statin-specific LCZ696 drug interaction observations. The model incorporated OATP-mediated clearance (CLint,T) for simvastatin and simvastatin acid to successfully describe the pharmacokinetic profiles of either analyte in the absence or presence of LCZ696. Moreover, the model successfully described the clinically observed drug effect with atorvastatin. The simulations clarified the critical parameters responsible for the observation of a low, yet clinically relevant, drug-drug interaction DDI between sacubitril and atorvastatin and the lack of effect with simvastatin acid. Atorvastatin is administered in its active form and rapidly achieves Cmax that coincide with the low Cmax of sacubitril. In contrast, simvastatin requires a hydrolysis step to the acid form and therefore is not present at the site of interactions at sacubitril concentrations that are inhibitory. Similar models were used to evaluate the drug-drug interaction risk for additional OATP-transported statins which predicted to maximally result in a 1.5-fold exposure increase.

  12. Differential drug-drug interactions of the synthetic Cannabinoids JWH-018 and JWH-073: implications for drug abuse liability and pain therapy.

    PubMed

    Brents, Lisa K; Zimmerman, Sarah M; Saffell, Amanda R; Prather, Paul L; Fantegrossi, William E

    2013-09-01

    Marijuana substitutes often contain blends of multiple psychoactive synthetic cannabinoids (SCBs), including the prevalent SCBs (1-pentyl-1H-indole-3-yl)-1-naphthalenyl-methanone (JWH-018) and (1-butyl-1H-indole-3-yl)-1-naphthalenyl-methanone (JWH-073). Because SCBs are frequently used in combinations, we hypothesized that coadministering multiple SCBs induces synergistic drug-drug interactions. Drug-drug interactions between JWH-018 and JWH-073 were investigated in vivo for Δ(9)-tetrahydrocannabinol (Δ(9)-THC)-like discriminative stimulus effects, analgesia, task disruption, and hypothermia. Combinations (JWH-018:JWH-073) of these drugs were administered to mice in assays of Δ(9)-THC discrimination, tail-immersion, and food-maintained responding, and rectal temperatures were measured. Synergism occurred in the Δ(9)-THC discrimination assay for two constant dose ratio combinations (1:3 and 1:1). A 1:1 and 2:3 dose ratio induced additivity and synergy, respectively, in the tail-immersion assay. Both 1:1 and 2:3 dose ratios were additive for hypothermia, whereas a 1:3 dose ratio induced subadditive suppression of food-maintained responding. In vitro drug-drug interactions were assessed using competition receptor-binding assays employing mouse brain homogenates and cannabinoid 1 receptor (CB1R)-mediated inhibition of adenylyl cyclase activity in Neuro2A wild-type cells. Interestingly, synergy occurred in the competition receptor-binding assay for two dose ratios (1:5 and 1:10), but not in the adenylyl cyclase activity assay (1:5). Altogether, these data indicate that drug-drug interactions between JWH-018 and JWH-073 are effect- and ratio-dependent and may increase the relative potency of marijuana substitutes for subjective Δ(9)-THC-like effects. Combinations may improve the therapeutic profile of cannabinoids, considering that analgesia but not hypothermia or task disruption was potentiated. Importantly, synergy in the competition receptor-binding assay

  13. Clinical drug-drug interactions of bosentan, a potent endothelial receptor antagonist, with various drugs: Physiological role of enzymes and transporters.

    PubMed

    Srinivas, Nuggehally R

    2016-07-01

    Bosentan, an endothelin-1 (ET) receptor antagonist is an important drug for the effective management of patients with pulmonary arterial hypertension. Bosentan has a rather complicated pharmacokinetics in humans involving multiple physiological components that have a profound influence on its drug disposition. Bosentan is mainly metabolized by cytochrome P450 (CYP) 3A4 and 2C9 enzymes with the involvement of multiple transporters that control its hepatic uptake and biliary excretion. The involvement of phase 2 metabolism of bosentan is a key to have an enhanced biliary excretion of the drug-related products. While bosentan exhibits high protein binding restricting the drug from extensive distribution and significant urinary excretion, bosentan induces its own metabolism by an increased expression of CYP3A4 on repeated dosing. Due to the above properties, bosentan has the potential to display drug-drug interaction with the co-administered drugs, either being a perpetrator or a victim. The intent of this review is manifold: a) to summarize the physiological role of CYP enzymes and hepatic-biliary transporters; b) to discuss the mechanism(s) involved in the purported liver injury caused by bosentan; c) to tabulate the numerous clinical drug-drug interaction studies involving the physiological interplay with CYP and/or transporters; d) to provide some perspectives on dosing strategy of bosentan.

  14. Drug-drug interaction and doping, part 1: an in vitro study on the effect of non-prohibited drugs on the phase I metabolic profile of toremifene.

    PubMed

    Mazzarino, Monica; de la Torre, Xavier; Fiacco, Ilaria; Palermo, Amelia; Botrè, Francesco

    2014-05-01

    The present study was designed to provide preliminary information on the potential impact of metabolic drug-drug interaction on the effectiveness of doping control strategies currently followed by the anti-doping laboratories to detect the intake of banned agents. In vitro assays based on the use of human liver microsomes and recombinant CYP isoforms were designed and performed to characterize the phase I metabolic profile of the prohibited agent toremifene, selected as a prototype drug of the class of selective oestrogen receptor modulators, both in the absence and in the presence of medicaments (fluconazole, ketoconazole, itraconazole, miconazole, cimetidine, ranitidine, fluoxetine, paroxetine, nefazodone) not included in the World Anti-Doping Agency list of prohibited substances and methods and frequently administered to athletes. The results show that the in vitro model developed in this study was adequate to simulate the in vivo metabolism of toremifene, confirming the results obtained in previous studies. Furthermore, our data also show that ketoconazole, itraconazole, miconazole and nefazodone cause a marked modification in the production of the metabolic products (i.e. hydroxylated and carboxylated metabolites) normally selected by the anti-doping laboratories as target analytes to detect toremifene intake; moderate variations were registered in the presence of fluconazole, paroxetine and fluoxetine; while no significant modifications were measured in the presence of ranitidine and cimetidine. This evidence imposes that the potential effect of drug-drug interactions is duly taken into account in anti-doping analysis, also for a broader significance of the analytical results.

  15. Breast cancer resistance protein (ABCG2) in clinical pharmacokinetics and drug interactions: practical recommendations for clinical victim and perpetrator drug-drug interaction study design.

    PubMed

    Lee, Caroline A; O'Connor, Meeghan A; Ritchie, Tasha K; Galetin, Aleksandra; Cook, Jack A; Ragueneau-Majlessi, Isabelle; Ellens, Harma; Feng, Bo; Taub, Mitchell E; Paine, Mary F; Polli, Joseph W; Ware, Joseph A; Zamek-Gliszczynski, Maciej J

    2015-04-01

    Breast cancer resistance protein (BCRP; ABCG2) limits intestinal absorption of low-permeability substrate drugs and mediates biliary excretion of drugs and metabolites. Based on clinical evidence of BCRP-mediated drug-drug interactions (DDIs) and the c.421C>A functional polymorphism affecting drug efficacy and safety, both the US Food and Drug Administration and European Medicines Agency recommend preclinical evaluation and, when appropriate, clinical assessment of BCRP-mediated DDIs. Although many BCRP substrates and inhibitors have been identified in vitro, clinical translation has been confounded by overlap with other transporters and metabolic enzymes. Regulatory recommendations for BCRP-mediated clinical DDI studies are challenging, as consensus is lacking on the choice of the most robust and specific human BCRP substrates and inhibitors and optimal study design. This review proposes a path forward based on a comprehensive analysis of available data. Oral sulfasalazine (1000 mg, immediate-release tablet) is the best available clinical substrate for intestinal BCRP, oral rosuvastatin (20 mg) for both intestinal and hepatic BCRP, and intravenous rosuvastatin (4 mg) for hepatic BCRP. Oral curcumin (2000 mg) and lapatinib (250 mg) are the best available clinical BCRP inhibitors. To interrogate the worst-case clinical BCRP DDI scenario, study subjects harboring the BCRP c.421C/C reference genotype are recommended. In addition, if sulfasalazine is selected as the substrate, subjects having the rapid acetylator phenotype are recommended. In the case of rosuvastatin, subjects with the organic anion-transporting polypeptide 1B1 c.521T/T genotype are recommended, together with monitoring of rosuvastatin's cholesterol-lowering effect at baseline and DDI phase. A proof-of-concept clinical study is being planned by a collaborative consortium to evaluate the proposed BCRP DDI study design.

  16. Evaluation of Mutual Drug-Drug Interaction within Geneva Cocktail for Cytochrome P450 Phenotyping using Innovative Dried Blood Sampling Method.

    PubMed

    Bosilkovska, Marija; Samer, Caroline; Déglon, Julien; Thomas, Aurélien; Walder, Bernhard; Desmeules, Jules; Daali, Youssef

    2016-09-01

    Cytochrome P450 (CYP) activity can be assessed using a 'cocktail' phenotyping approach. Recently, we have developed a cocktail (Geneva cocktail) which combines the use of low-dose probes with a low-invasiveness dried blood spots (DBS) sampling technique and a single analytical method for the phenotyping of six major CYP isoforms. We have previously demonstrated that modulation of CYP activity after pre-treatment with CYP inhibitors/inducer could be reliably predicted using Geneva cocktail. To further validate this cocktail, in this study, we have verified whether probe drugs contained in the latter cause mutual drug-drug interactions. In a randomized, four-way, Latin-square crossover study, 30 healthy volunteers received low-dose caffeine, flurbiprofen, omeprazole, dextromethorphan and midazolam (a previously validated combination with no mutual drug-drug interactions); fexofenadine alone; bupropion alone; or all seven drugs simultaneously (Geneva cocktail). Pharmacokinetic profiles of the probe drugs and their metabolites were determined in DBS samples using both conventional micropipette sampling and new microfluidic device allowing for self-sampling. The 90% confidence intervals for the geometric mean ratios of AUC metabolite/AUC probe for CYP probes administered alone or within Geneva cocktail fell within the 0.8-1.25 bioequivalence range indicating the absence of pharmacokinetic interaction. The same result was observed for the chosen phenotyping indices, that is metabolic ratios at 2 hr (CYP1A2, CYP3A) or 3 hr (CYP2B6, CYP2C9, CYP2C19, CYP2D6) post-cocktail administration. DBS sampling could successfully be performed using a new microfluidic device. In conclusion, Geneva cocktail combined with an innovative DBS sampling device can be used routinely as a test for simultaneous CYP phenotyping.

  17. A combined model for predicting CYP3A4 clinical net drug-drug interaction based on CYP3A4 inhibition, inactivation, and induction determined in vitro.

    PubMed

    Fahmi, Odette A; Maurer, Tristan S; Kish, Mary; Cardenas, Edwin; Boldt, Sherri; Nettleton, David

    2008-08-01

    Although approaches to the prediction of drug-drug interactions (DDIs) arising via time-dependent inactivation have recently been developed, such approaches do not account for simple competitive inhibition or induction. Accordingly, these approaches do not provide accurate predictions of DDIs arising from simple competitive inhibition (e.g., ketoconazole) or induction of cytochromes P450 (e.g., phenytoin). In addition, methods that focus upon a single interaction mechanism are likely to yield misleading predictions in the face of mixed mechanisms (e.g., ritonavir). As such, we have developed a more comprehensive mathematical model that accounts for the simultaneous influences of competitive inhibition, time-dependent inactivation, and induction of CYP3A in both the liver and intestine to provide a net drug-drug interaction prediction in terms of area under the concentration-time curve ratio. This model provides a framework by which readily obtained in vitro values for competitive inhibition, time-dependent inactivation and induction for the precipitant compound as well as literature values for f(m) and F(G) for the object drug can be used to provide quantitative predictions of DDIs. Using this model, DDIs arising via inactivation (e.g., erythromycin) continue to be well predicted, whereas those arising via competitive inhibition (e.g., ketoconazole), induction (e.g., phenytoin), and mixed mechanisms (e.g., ritonavir) are also predicted within the ranges reported in the clinic. This comprehensive model quantitatively predicts clinical observations with reasonable accuracy and can be a valuable tool to evaluate candidate drugs and rationalize clinical DDIs.

  18. In Vitro and Clinical Evaluations of the Drug-Drug Interaction Potential of a Metabotropic Glutamate 2/3 Receptor Agonist Prodrug with Intestinal Peptide Transporter 1

    PubMed Central

    Long, Amanda J.; Annes, William F.; Witcher, Jennifer W.; Knadler, Mary Pat; Ayan-Oshodi, Mosun A.; Mitchell, Malcolm I.; Leese, Phillip; Hillgren, Kathleen M.

    2017-01-01

    Despite peptide transporter 1 (PEPT1) being responsible for the bioavailability for a variety of drugs, there has been little study of its potential involvement in drug-drug interactions. Pomaglumetad methionil, a metabotropic glutamate 2/3 receptor agonist prodrug, utilizes PEPT1 to enhance absorption and bioavailability. In vitro studies were conducted to guide the decision to conduct a clinical drug interaction study and to inform the clinical study design. In vitro investigations determined the prodrug (LY2140023 monohydrate) is a substrate of PEPT1 with Km value of approximately 30 µM, whereas the active moiety (LY404039) is not a PEPT1 substrate. In addition, among the eight known PEPT1 substrates evaluated in vitro, valacyclovir was the most potent inhibitor (IC50 = 0.46 mM) of PEPT1-mediated uptake of the prodrug. Therefore, a clinical drug interaction study was conducted to evaluate the potential interaction between the prodrug and valacyclovir in healthy subjects. No effect of coadministration was observed on the pharmacokinetics of the prodrug, valacyclovir, or either of their active moieties. Although in vitro studies showed potential for the prodrug and valacyclovir interaction via PEPT1, an in vivo study showed no interaction between these two drugs. PEPT1 does not appear to easily saturate because of its high capacity and expression in the intestine. Thus, a clinical interaction at PEPT1 is unlikely even with a compound with high affinity for the transporter. PMID:27895114

  19. Low Potential of Basimglurant to Be Involved in Drug-Drug Interactions: Influence of Non-Michaelis-Menten P450 Kinetics on Fraction Metabolized.

    PubMed

    Fowler, Stephen; Guerini, Elena; Qiu, NaHong; Cleary, Yumi; Parrott, Neil; Greig, Gerard; Mallalieu, Navita L

    2017-01-01

    Basimglurant, a novel mGlu5-negative allosteric modulator under development for the treatment of major depressive disorder, is cleared via cytochrome P450 (P450)-mediated oxidative metabolism. Initial enzyme phenotyping studies indicated that CYP3A4/5 dominates basimglurant metabolism and highlights a risk for drug-drug interactions when it is comedicated with strong CYP3A4/5 inhibitors or inactivators; however, a clinical drug-drug interaction (DDI) study using the potent and selective CYP3A4/5 inhibitor ketoconazole resulted in an area under the curve (AUC) AUCi/AUC ratio of only 1.24. A further study using the CYP3A4 inducer carbamazepine resulted in an AUCi/AUC ratio of 0.69. More detailed in vitro enzyme phenotyping and kinetics studies showed that, at the low concentrations attained clinically, basimglurant metabolic clearance is catalyzed mainly by CYP1A2. The relative contributions of the enzymes were estimated as 70:30 CYP1A2:CYP3A4/5. Using this information, a clinical study using the CYP1A2 inhibitor fluvoxamine was performed, resulting in an AUCi/AUC ratio of 1.60, confirming the role of CYP1A2 and indicating a balanced DDI risk profile. Basimglurant metabolism kinetics show enzyme dependency: CYP1A2-mediated metabolism follows Michaelis-Menten kinetics, whereas CYP3A4 and CYP3A5 follow sigmoidal kinetics [with similar constant (KM) and S50 values]. The interplay of the different enzyme kinetics leads to changing fractional enzyme contributions to metabolism with substrate concentration, even though none of the metabolic enzymes is saturated. This example demonstrates the relevance of non-Michaelis-Menten P450 enzyme kinetics and highlights the need for a thorough understanding of metabolism enzymology to make accurate predictions for human metabolism in vivo.

  20. Therapeutic protein drug-drug interactions: navigating the knowledge gaps-highlights from the 2012 AAPS NBC Roundtable and IQ Consortium/FDA workshop.

    PubMed

    Kenny, Jane R; Liu, Maggie M; Chow, Andrew T; Earp, Justin C; Evers, Raymond; Slatter, J Greg; Wang, Diane D; Zhang, Lei; Zhou, Honghui

    2013-10-01

    The investigation of therapeutic protein drug-drug interactions has proven to be challenging. In May 2012, a roundtable was held at the American Association of Pharmaceutical Scientists National Biotechnology Conference to discuss the challenges of preclinical assessment and in vitro to in vivo extrapolation of these interactions. Several weeks later, a 2-day workshop co-sponsored by the U.S. Food and Drug Administration and the International Consortium for Innovation and Quality in Pharmaceutical Development was held to facilitate better understanding of the current science, investigative approaches and knowledge gaps in this field. Both meetings focused primarily on drug interactions involving therapeutic proteins that are pro-inflammatory cytokines or cytokine modulators. In this meeting synopsis, we provide highlights from both meetings and summarize observations and recommendations that were developed to reflect the current state of the art thinking, including a four-step risk assessment that could be used to determine the need (or not) for a dedicated clinical pharmacokinetic interaction study.

  1. Evaluation of drug-drug interaction between henagliflozin, a novel sodium-glucose co-transporter 2 inhibitor, and metformin in healthy Chinese males.

    PubMed

    Wang, Liupeng; Wu, Chunyong; Shen, Lu; Liu, Haiyan; Chen, Ying; Liu, Fang; Wang, Youqun; Yang, Jin

    2016-08-01

    1. Henagliflozin is a novel sodium-glucose transporter 2 inhibitor and presents a complementary therapy to metformin for patients with T2DM due to its insulin-independent mechanism of action. This study evaluated the potential pharmacokinetic drug-drug interaction between henagliflozin and metformin in healthy Chinese male subjects. 2. In open-label, single-center, single-arm, two-period, three-treatment self-control study, 12 subjects received 25 mg henagliflozin, 1000 mg metformin or the combination. Lack of PK interaction was defined as the ratio of geometric means and 90% confidence interval (CI) for combination: monotherapy being within the range of 0.80-1.25. 3. Co-administration of henagliflozin with metformin had no effect on henagliflozin area under the plasma concentration-time curve (AUC0-24) (GRM: 1.08; CI: 1.05, 1.10) and peak plasma concentration (Cmax) (GRM: 0.99; CI: 0.92, 1.07). Reciprocally, co-administration of metformin with henagliflozin had no clinically significant on metformin AUC0-24 (GRM: 1.09, CI: 1.02, 1.16) although there was an 11% increase in metformin Cmax (GRM 1.12; CI 1.02, 1.23). All monotherapies and combination therapy were well tolerated. 4. Henagliflozin can be co-administered with metformin without dose adjustment of either drug.

  2. Strategy for the Prediction of Steady-State Exposure of Digoxin to Determine Drug-Drug Interaction Potential of Digoxin With Other Drugs in Digitalization Therapy.

    PubMed

    Srinivas, Nuggehally R

    2016-01-20

    Digoxin, a narrow therapeutic index drug, is widely used in congestive heart failure. However, the digitalization therapy involves dose titration and can exhibit drug-drug interaction. Ctrough versus area under the plasma concentration versus time curve in a dosing interval of 24 hours (AUC0-24h) and Cmax versus AUC0-24h for digoxin were established by linear regression. The predictions of digoxin AUC0-24h values were performed using published Ctrough or Cmax with appropriate regression lines. The fold difference, defined as the quotient of the observed/predicted AUC0-24h values, was evaluated. The mean square error and root mean square error, correlation coefficient (r), and goodness of the fold prediction were used to evaluate the models. Both Ctrough versus AUC0-24h (r = 0.9215) and Cmax versus AUC0-24h models for digoxin (r = 0.7781) showed strong correlations. Approximately 93.8% of the predicted digoxin AUC0-24h values were within 0.76-fold to 1.25-fold difference for Ctrough model. In sharp contrast, the Cmax model showed larger variability with only 51.6% of AUC0-24h predictions within 0.76-1.25-fold difference. The r value for observed versus predicted AUC0-24h for Ctrough (r = 0.9551; n = 177; P < 0.001) was superior to the Cmax (r = 0.6134; n = 275; P < 0.001) model. The mean square error and root mean square error (%) for the Ctrough model were 11.95% and 16.2% as compared to 67.17% and 42.3% obtained for the Cmax model. Simple linear regression models for Ctrough/Cmax versus AUC0-24h were derived for digoxin. On the basis of statistical evaluation, Ctrough was superior to Cmax model for the prediction of digoxin AUC0-24h and can be potentially used in a prospective setting for predicting drug-drug interaction or lack of it.

  3. Drug disposition and drug-drug interaction data in 2013 FDA new drug applications: a systematic review.

    PubMed

    Yu, Jingjing; Ritchie, Tasha K; Mulgaonkar, Aditi; Ragueneau-Majlessi, Isabelle

    2014-12-01

    The aim of the present work was to perform a systematic review of drug metabolism, transport, pharmacokinetics, and DDI data available in the NDAs approved by the FDA in 2013, using the University of Washington Drug Interaction Database, and to highlight significant findings. Among 27 NMEs approved, 22 (81%) were well characterized with regard to drug metabolism, transport, or organ impairment, in accordance with the FDA drug interaction guidance (2012) and were fully analyzed in this review. In vitro, a majority of the NMEs were found to be substrates or inhibitors/inducers of at least one drug metabolizing enzyme or transporter. However, in vivo, only half (n = 11) showed clinically relevant drug interactions, with most related to the NMEs as victim drugs and CYP3A being the most affected enzyme. As perpetrators, the overall effects for NMEs were much less pronounced, compared with when they served as victims. In addition, the pharmacokinetic evaluation in patients with hepatic or renal impairment provided useful information for further understanding of the drugs' disposition.

  4. Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): interindividual differences due to polymorphisms and drug-drug interactions.

    PubMed

    Rietjens, Saskia J; Hondebrink, Laura; Westerink, Remco H S; Meulenbelt, Jan

    2012-11-01

    Clinical outcome following 3,4-methylenedioxymethamphetamine (MDMA) intake ranges from mild entactogenic effects to a life-threatening intoxication. Despite ongoing research, the clinically most relevant mechanisms causing acute MDMA-induced adverse effects remain largely unclear. This complicates the triage and treatment of MDMA users needing medical care. The user's genetic profile and interactions resulting from polydrug use are key factors that modulate the individual response to MDMA and influence MDMA pharmacokinetics and dynamics, and thus clinical outcome. Polymorphisms in CYP2D6, resulting in poor metabolism status, as well as co-exposure of MDMA with specific substances (e.g. selective serotonin reuptake inhibitors (SSRIs)) can increase MDMA plasma levels, but can also decrease the formation of toxic metabolites and subsequent cellular damage. While pre-exposure to e.g. SSRIs can increase MDMA plasma levels, clinical effects (e.g. blood pressure, heart rate, body temperature) can be reduced, possibly due to a pharmacodynamic interaction at the serotonin reuptake transporter (SERT). Pretreatment with inhibitors of the dopamine or norepinephrine reuptake transporter (DAT or NET), 5-HT(2A) or α-β adrenergic receptor antagonists or antipsychotics prior to MDMA exposure can also decrease one or more MDMA-induced physiological and/or subjective effects. Carvedilol, ketanserin and haloperidol can reduce multiple MDMA-induced clinical and neurotoxic effects. Thus besides supportive care, i.e. sedation using benzodiazepines, intravenous hydration, aggressive cooling and correction of electrolytes, it is worthwhile to investigate the usefulness of carvedilol, ketanserin and haloperidol in the treatment of MDMA-intoxicated patients.

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

    PubMed

    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 <50 µM), and exhibited time-dependent inhibition of microsomal CYP1A2 with the inactivation efficiency (kinact/KI) of 0.68 and 0.51 minute(-1)·mM(-1), respectively. ISOX did not inhibit or inactivate any tested microsomal P450. In conclusion, hCE1b and hCE2 play a key role in the bioactivation of UTL-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.

  6. Cobicistat versus ritonavir boosting and differences in the drug-drug interaction profiles with co-medications.

    PubMed

    Marzolini, Catia; Gibbons, Sara; Khoo, Saye; Back, David

    2016-07-01

    Nearly all HIV PIs and the integrase inhibitor elvitegravir require a pharmacokinetic enhancer in order to achieve therapeutic plasma concentrations at the desired dose and frequency. Whereas ritonavir has been the only available pharmacokinetic enhancer for more than a decade, cobicistat has recently emerged as an alternative boosting agent. Cobicistat and ritonavir are equally strong inhibitors of cytochrome P450 (CYP) 3A4 and consequently were shown to be equivalent pharmacokinetic enhancers for elvitegravir and for the PIs atazanavir and darunavir. Since cobicistat is a more selective CYP inhibitor than ritonavir and is devoid of enzyme-inducing properties, differences are expected in their interaction profiles with some co-medications. Drugs whose exposure might be altered by ritonavir but unaltered by cobicistat are drugs primarily metabolized by CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP2C19 or drugs undergoing mainly glucuronidation. Thus, co-medications should be systematically reviewed when switching the pharmacokinetic enhancer to anticipate potential dosage adjustments.

  7. Prediction of pharmacokinetics and drug-drug interaction potential using physiologically based pharmacokinetic (PBPK) modeling approach: A case study of caffeine and ciprofloxacin

    PubMed Central

    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

  8. Quantitative Prediction of Human Renal Clearance and Drug-Drug Interactions of Organic Anion Transporter Substrates Using In Vitro Transport Data: A Relative Activity Factor Approach.

    PubMed

    Mathialagan, Sumathy; Piotrowski, Mary A; Tess, David A; Feng, Bo; Litchfield, John; Varma, Manthena V

    2017-04-01

    Organic anion transporters (OATs) are important in the renal secretion, and thus, the clearance, of many drugs; and their functional change can result in pharmacokinetic variability. In this study, we applied transport rates measured in vitro using OAT-transfected human embryonic kidney cells to predict human renal secretory and total renal clearance of 31 diverse drugs. Selective substrates to OAT1 (tenofovir), OAT2 (acyclovir and ganciclovir), and OAT3 (benzylpenicillin, oseltamivir acid) were used to obtain relative activity factors (RAFs) for these individual transporters by relating in vitro transport clearance (after physiologic scaling) to in vivo secretory clearance. Using the estimated RAFs (0.64, 7.3, and 4.1, respectively, for OAT1, OAT2, and OAT3, respectively) and the in vitro active clearances, renal secretory clearance and total renal clearance were predicted with average fold errors (AFEs) of 1.89 and 1.40, respectively. The results show that OAT3-mediated transport play a predominant role in renal secretion for 22 of the 31 drugs evaluated. This mechanistic static approach was further applied to quantitatively predict renal drug-drug interactions (AFE ∼1.6) of the substrate drugs with probenecid, a clinical probe OAT inhibitor. In conclusion, the proposed in vitro-in vivo extrapolation approach is the first comprehensive attempt toward mechanistic modeling of renal secretory clearance based on routinely employed in vitro cell models.

  9. Prediction of drug-drug interactions with carbamazepine-10,11-epoxide using a new in vitro assay for epoxide hydrolase inhibition.

    PubMed

    Rosa, Maria; Bonnaillie, Pierre; Chanteux, Hugues

    2016-12-01

    1. Carbamazepine is an antiepileptic drug which is metabolized by CYP3A4 into carbamazepine-10,11-epoxide. This metabolite is then detoxified by epoxide hydrolase. As carbamazepine-10,11-epoxide has been associated with neurotoxicity, it is critical to identify whether a new antiepileptic drug has the potential to inhibit epoxide hydrolase and therefore increase carbamazepine-10,11-epoxide plasma levels. 2. In this study, an in vitro assay was developed to evaluate epoxide hydrolase activity by using carbamazepine-10,11-epoxide as probe substrate. The ability of this assay to predict drug-drug interactions (DDI) at the epoxide hydrolase level was also investigated. 3. To this aim, known inhibitors of epoxide hydrolase for which in vivo data are available were used. Firstly, carbamazepine-10,11-epoxide hydrolase activity was determined in liver microsomes, cytosol and hepatocytes. Thereafter, the IC50 of epoxide hydrolase inhibitors (progabide, valproic acid, valpromide and valnoctamide) was determined in liver microsomes and hepatocytes. Finally, prediction of AUC increase was performed using the in vitro data generated. 4. Interestingly, epoxide hydrolase activity was found to be much higher in human hepatocytes compared to liver microsomes/cytosol. Even though assessed on a limited number of compounds, this study demonstrated that the use of hepatocytes seems to be a more relevant model to assess and predict DDI at the epoxide hydrolase level.

  10. Underlying mechanism of drug-drug interaction between pioglitazone and gemfibrozil: Gemfibrozil acyl-glucuronide is a mechanism-based inhibitor of CYP2C8.

    PubMed

    Takagi, Motoi; Sakamoto, Masaya; Itoh, Tomoo; Fujiwara, Ryoichi

    2015-08-01

    While co-administered gemfibrozil can increase the area under the concentration/time curve (AUC) of pioglitazone more than 3-fold, the underlying mechanism of the drug-drug interaction between gemfibrozil and pioglitazone has not been fully understood. In the present study, gemfibrozil preincubation time-dependently inhibited the metabolism of pioglitazone in the cytochrome P450 (CYP)- and UDP-glucuronosyltransferase (UGT)-activated human liver microsomes. We estimated the kinact and K'app values, which are the maximum inactivation rate constant and the apparent dissociation constant, of gemfibrozil to be 0.071 min(-1) and 57.3 μM, respectively. In this study, the kobs, in vivo value was defined as a parameter that indicates the potency of the mechanism-based inhibitory effect at the blood drug concentration in vivo. The kobs, in vivo values of potent mechanism-based inhibitors, clarithromycin and erythromycin, were estimated to be 0.0096 min(-1) and 0.0051 min(-1), respectively. The kobs, in vivo value of gemfibrozil was 0.0060 min(-1), which was comparable to those of clarithromycin and erythromycin, suggesting that gemfibrozil could be a mechanism-based inhibitor as potent as clarithromycin and erythromycin in vivo.

  11. Establishment of in vitro P-glycoprotein inhibition assay and its exclusion criteria to assess the risk of drug-drug interaction at the drug discovery stage.

    PubMed

    Sugimoto, Hiroshi; Matsumoto, Shin-ichi; Tachibana, Miho; Niwa, Shin-ichi; Hirabayashi, Hideki; Amano, Nobuyuki; Moriwaki, Toshiya

    2011-09-01

    The decision tree to determine whether the P-glycoprotein (P-gp)/multidrug resistance protein 1 (MDR1)-mediated drug-drug interaction (DDI) study is recommended has been proposed by the International Transporter Consortium. We, therefore, designed an in vitro P-gp inhibition assay and determined the appropriate risk criteria for P-gp-mediated DDI at the drug discovery stage. Effects of P-gp inhibitors on digoxin transport across a monolayer of MDR1-expressing cells were examined. The IC(50) (half-maximal inhibitory concentration) values generated from the efflux ratio (ER) were smaller than those generated from basolateral-to-apical directional apparent permeability. The difference in IC(50) values was kinetically described in a compartment model analysis. This analysis indicated that ER is a highly sensitive parameter that can be used for the degree of P-gp inhibition. Considering IC(50) values and the increase in digoxin exposure in clinical DDI studies, the risk criteria of [I(2)]/IC(50) = 30 ([I(2)], theoretically maximal gastrointestinal concentration) was the optimal cutoff value to predict a clinically relevant DDI. We also investigated whether the IC(50) value itself is applicable to assess the DDI risk. In conclusion, compounds with IC(50) values less than 2 μM exhibit high risk for P-gp-mediated DDIs. However, compounds with IC(50) values greater than or equal to 2 μM are inconclusive because clinical doses should be considered for the precise DDI risk assessment.

  12. Drug-drug Interaction between Losartan and Paclitaxel in Human Liver Microsomes with Different CYP2C8 Genotypes.

    PubMed

    Mukai, Yuji; Senda, Asuna; Toda, Takaki; Hayakawa, Toru; Eliasson, Erik; Rane, Anders; Inotsume, Nobuo

    2015-06-01

    The cytochrome P450 (CYP) 2C8*3 allele is associated with reduced metabolic activity of paclitaxel. This study was aimed to investigate the inhibitory effect of losartan on paclitaxel metabolism in human liver microsomes (HLMs) and to determine the impact of the CYP2C8*3 polymorphism. HLMs that contained the CYP2C8*1 homozygote (HL60) or CYP2C8*3 heterozygote (HL54) genotype were used for the inhibition study. Losartan, at a concentration of 50 μmol/L, significantly inhibited paclitaxel metabolism by 29% and 57% in the HL60 (p < 0.001) and HL54 (p < 0.01), respectively. When using HL60, losartan and the CYP3A4-selective inhibitors, erythromycin and ketoconazole, caused a greater inhibition of the paclitaxel metabolism than quercetin, a CYP2C8-selective inhibitor. This demonstrated that the paclitaxel metabolism was mainly catalysed by CYP3A4 in HL60. There were no significant differences found for the inhibitory effects caused by the four inhibitors of the paclitaxel metabolism in HL54, indicating that both CYP2C8 and CYP3A4 play important roles in paclitaxel metabolism in HL54. These findings suggest that 50 μmol/L of losartan inhibits both CYP2C8 and CYP3A4 in HLMs. In summary, losartan inhibited paclitaxel metabolism, with concentrations over 50 μmol/L in HLMs. The CYP2C8*3 allele carriers are likely susceptible to the interactions of losartan and CYP3A4 inhibitors to paclitaxel metabolism.

  13. The use of HepaRG and human hepatocyte data in predicting CYP induction drug-drug interactions via static equation and dynamic mechanistic modelling approaches.

    PubMed

    Grime, Ken; Ferguson, Douglas D; Riley, Robert J

    2010-12-01

    The method of predicting CYP induction drug-drug interactions (DDIs) from a relative induction score (RIS) calibration has been developed to provide a novel model facilitating predictions for any CYP-inducer substrate combination by inclusion of parameters such as the fraction of hepatic clearance mediated by a specific CYP and fraction of the dose escaping intestinal extraction. In vitro HepaRG CYP3A4 induction data were used as a basis for the approach and a large number of DDIs were well predicted. Primary human hepatocyte data were also used to make predictions, using the HepaRG calibration as a foundation. Similar predictive accuracy suggests that HepaRG and primary hepatocyte data can be used inter-changeably within the same laboratory. A comparison of this 'indirect' calibration method with a direct in vitro-in vivo scaling approach was made and investigations undertaken to define the most appropriate in vivo inducer concentration to use. Additionally, a reasonably effective prediction model based on F(2) (the concentration of inducer taken to increase the CYP mRNA 2-fold above background) was established. An accurate prediction for the CYP1A2-dependent omeprazole-caffeine interaction was also made, demonstrating that the methods are useful for the evaluation of DDIs from induction involving mechanisms other than PXR activation. Finally, a dynamic mechanistic model accounting for the simultaneous influence of CYP induction and reversible and irreversible CYP inhibition in both the liver and intestine was written to provide a prediction of the overall DDI when several interactions occur concurrently. The rationale for using the various models described, alongside commercially available prediction tools, at various stages of the drug discovery process is described.

  14. Predictions of cytochrome P450-mediated drug-drug interactions using cryopreserved human hepatocytes: comparison of plasma and protein-free media incubation conditions.

    PubMed

    Mao, Jialin; Mohutsky, Michael A; Harrelson, John P; Wrighton, Steven A; Hall, Stephen D

    2012-04-01

    Cryopreserved human hepatocytes suspended in human plasma (HHSHP) have previously provided accurate CYP3A drug-drug interaction (DDI) predictions from a single IC(50) that captures both reversible and time-dependent inhibition. The goal of this study was to compare the accuracy of DDI predictions by a protein-free human hepatocyte system combined with the fraction unbound in plasma for inhibitor(s) with those obtained with protein-containing incubations. Seventeen CYP3A, CYP2C9, or CYP2D6 inhibitors were incubated with hepatocytes in human plasma or hepatocyte maintenance medium (HMM) for 20 min over a range of concentrations after which midazolam 1'-hydroxylation, diclofenac 4'-hydroxylation or (R)-bufuralol 1'-hydroxylation were used to quantify the corresponding cytochrome P450 (P450) catalytic activities. Two methods were used to predict the human exposure ratio of the victim drug in the presence and absence of inhibitor. The HMM K(i, app) values were combined with the free average systemic plasma concentration ("free [I] with HMM K(i, app)") and the plasma K(i, app) values were combined with the total average systemic plasma concentration ("total [I] with plasma K(i, app)"). Of 63 clinical DDI studies, the total [I] with plasma K(i, app) method predicted 89% of cases within 2-fold of the reported interaction whereas the free [I] with HMM K(i, app) method predicted only 59%. There was a general underprediction by the free [I] with HMM K(i, app) method, which is consistent with an underestimation of in vitro inhibition potency in this system. In conclusion, the HHSHP system proved to be a simple, accurate predictor of DDIs for three major P450s and superior to the protein-free approach.

  15. Contribution of metabolites to P450 inhibition-based drug-drug interactions: scholarship from the drug metabolism leadership group of the innovation and quality consortium metabolite group.

    PubMed

    Yu, Hongbin; Balani, Suresh K; Chen, Weichao; Cui, Donghui; He, Ling; Humphreys, W Griffith; Mao, Jialin; Lai, W George; Lee, Anthony J; Lim, Heng-Keang; MacLauchlin, Christopher; Prakash, Chandra; Surapaneni, Sekhar; Tse, Susanna; Upthagrove, Alana; Walsky, Robert L; Wen, Bo; Zeng, Zhaopie

    2015-04-01

    Recent European Medicines Agency (final) and US Food and Drug Administration (draft) drug interaction guidances proposed that human circulating metabolites should be investigated in vitro for their drug-drug interaction (DDI) potential if present at ≥ 25% of the parent area under the time-concentration curve (AUC) (US Food and Drug Administration) or ≥ 25% of the parent and ≥ 10% of the total drug-related AUC (European Medicines Agency). To examine the application of these regulatory recommendations, a group of scientists, representing 18 pharmaceutical companies of the Drug Metabolism Leadership Group of the Innovation and Quality Consortium, conducted a scholarship to assess the risk of contributions by metabolites to cytochrome P450 (P450) inhibition-based DDIs. The group assessed the risk of having a metabolite as the sole contributor to DDI based on literature data and analysis of the 137 most frequently prescribed drugs, defined structural alerts associated with P450 inhibition/inactivation by metabolites, and analyzed current approaches to trigger in vitro DDI studies for metabolites. The group concluded that the risk of P450 inhibition caused by a metabolite alone is low. Only metabolites from 5 of 137 drugs were likely the sole contributor to the in vivo P450 inhibition-based DDIs. Two recommendations were provided when assessing the need to conduct in vitro P450 inhibition studies for metabolites: 1) consider structural alerts that suggest P450 inhibition potential, and 2) use multiple approaches (e.g., a metabolite cut-off value of 100% of the parent AUC and the R(met) strategy) to predict P450 inhibition-based DDIs caused by metabolites in the clinic.

  16. Application of permeability-limited physiologically-based pharmacokinetic models: part II - prediction of P-glycoprotein mediated drug-drug interactions with digoxin.

    PubMed

    Neuhoff, Sibylle; Yeo, Karen Rowland; Barter, Zoe; Jamei, Masoud; Turner, David B; Rostami-Hodjegan, Amin

    2013-09-01

    Digoxin is the recommended substrate for assessment of P-glycoprotein (P-gp)-mediated drug-drug interactions (DDIs) in vivo. The overall aim of our study was to investigate the inhibitory potential of both verapamil and norverapamil on the P-gp-mediated efflux of digoxin in both gut and liver. Therefore, a physiologically-based pharmacokinetic (PBPK) model for verapamil and its primary metabolite was developed and validated through the recovery of observed clinical plasma concentration data for both moieties and the reported interaction with midazolam, albeit a cytochrome P450 3A4-mediated DDI. The validated inhibitor model was then used in conjunction with the model developed previously for digoxin. The range of values obtained for the 10 trials indicated that increases in area under the plasma concentration-time curve (AUC) profiles and maximum plasma concentration observed (Cmax ) values of digoxin following administration of verapamil were more comparable with in vivo observations, when P-gp inhibition by the metabolite, norverapamil, was considered as well. The predicted decrease in AUC and Cmax values of digoxin following administration of rifampicin because of P-gp induction was 1.57- (range: 1.42-1.77) and 1.62-fold (range: 1.53-1.70), which were reasonably consistent with observed values of 1.4- and 2.2-fold, respectively. This study demonstrates the application of permeability-limited models of absorption and distribution within a PBPK framework together with relevant in vitro data on transporters to assess the clinical impact of modulated P-gp-mediated efflux by drugs in development.

  17. A Physiologically-Based Pharmacokinetic Modeling Approach To Predict Drug-Drug Interactions of Sonidegib (LDE225) with Perpetrators of CYP3A in Cancer Patients.

    PubMed

    Einolf, Heidi J; Zhou, Jocelyn; Won, Christina; Wang, Lai; Rebello, Sam

    2017-04-01

    Sonidegib (Odomzo) is an orally available Smoothened inhibitor for the treatment of advanced basal cell carcinoma. Sonidegib was found to be metabolized primarily by cytochrome P450 (CYP)3A in vitro. The effect of multiple doses of the strong CYP3A perpetrators, ketoconazole (KTZ) and rifampin (RIF), on sonidegib pharmacokinetics (PK) after a single 800 mg dose in healthy subjects was therefore assessed. These data were used to verify a physiologically-based pharmacokinetic (PBPK) model developed to 1) bridge the clinical drug-drug interaction (DDI) study of sonidegib with KTZ and RIF in healthy subjects to the marketed dose (200 mg) in patients 2) predict acute (14 days) versus long-term dosing of the perpetrators with sonidegib at steady state and 3) predict the effect of moderate CYP3A perpetrators on sonidegib exposure in patients. Treatment of healthy subjects with KTZ resulted in an increased sonidegib exposure of 2.25- and 1.49-fold (area under the curve0-240h and maximal concentration respectively), and RIF decreased exposure by 72% and 54%, respectively. The model simulated the single- and/or multiple-dose PK of sonidegib (healthy subjects and patients) within ∼50% of observed values. The effect of KTZ and RIF on sonidegib in healthy subjects was also simulated well, and the predicted DDI in patients was slightly less and independent of sonidegib dose. At steady state, sonidegib was predicted to have a higher DDI magnitude with strong or moderate CYP3A perpetrators compared with a single dose. Different dosing regimens of sondigeb with the perpetrators were also simulated and provided guidance to the current dosing recommendations incorporated in the product label.

  18. VX-509 (Decernotinib)-Mediated CYP3A Time-Dependent Inhibition: An Aldehyde Oxidase Metabolite as a Perpetrator of Drug-Drug Interactions.

    PubMed

    Zetterberg, Craig; Maltais, Francois; Laitinen, Leena; Liao, Shengkai; Tsao, Hong; Chakilam, Ananthsrinivas; Hariparsad, Niresh

    2016-08-01

    (R)-2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (VX-509, decernotinib) is an oral Janus kinase 3 inhibitor that has been studied in patients with rheumatoid arthritis. Patients with rheumatoid arthritis often receive multiple medications, such as statins and steroids, to manage the signs and symptoms of comorbidities, which increases the chances of drug-drug interactions (DDIs). Mechanism-based inhibition is a subset of time-dependent inhibition (TDI) and occurs when a molecule forms a reactive metabolite which irreversibly binds and inactivates drug-metabolizing enzymes, potentially increasing the systemic load to toxic concentrations. Traditionally, perpetrating compounds are screened using human liver microsomes (HLMs); however, this system may be inadequate when the precipitant is activated by a non-cytochrome P450 (P450)-mediated pathway. Even though studies assessing competitive inhibition and TDI using HLM suggested a low risk for CYP3A4-mediated DDI in the clinic, VX-509 increased the area under the curve of midazolam, atorvastatin, and methyl-prednisolone by approximately 12.0-, 2.7-, and 4.3-fold, respectively. Metabolite identification studies using human liver cytosol indicated that VX-509 is converted to an oxidative metabolite, which is the perpetrator of the DDIs observed in the clinic. As opposed to HLM, hepatocytes contain the full complement of drug-metabolizing enzymes and transporters and can be used to assess TDI arising from non-P450-mediated metabolic pathways. In the current study, we highlight the role of aldehyde oxidase in the formation of the hydroxyl-metabolite of VX-509, which is involved in clinically significant TDI-based DDIs and represents an additional example in which a system-dependent prediction of TDI would be evident.

  19. Drug-drug interactions with sodium-glucose cotransporters type 2 (SGLT2) inhibitors, new oral glucose-lowering agents for the management of type 2 diabetes mellitus.

    PubMed

    Scheen, André J

    2014-04-01

    Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) reduce hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion. They are proposed as a novel approach for the management of type 2 diabetes mellitus. They have proven their efficacy in reducing glycated haemoglobin, without inducing hypoglycaemia, as monotherapy or in combination with various other glucose-lowering agents, with the add-on value of promoting some weight loss and lowering arterial blood pressure. As they may be used concomitantly with many other drugs, we review the potential drug-drug interactions (DDIs) regarding the three leaders in the class (dapagliglozin, canagliflozin and empagliflozin). Most of the available studies were performed in healthy volunteers and have assessed the pharmacokinetic interferences with a single administration of the SGLT2 inhibitor. The exposure [assessed by peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC)] to each SGLT2 inhibitor tested was not significantly influenced by the concomitant administration of other glucose-lowering agents or cardiovascular agents commonly used in patients with type 2 diabetes. Reciprocally, these medications did not influence the pharmacokinetic parameters of dapagliflozin, canagliflozin or empagliflozin. Some modest changes were not considered as clinically relevant. However, drugs that could specifically interfere with the metabolic pathways of SGLT2 inhibitors [rifampicin, inhibitors or inducers of uridine diphosphate-glucuronosyltransferase (UGT)] may result in significant changes in the exposure of SGLT2 inhibitors, as shown for dapagliflozin and canagliflozin. Potential DDIs in patients with type 2 diabetes receiving chronic treatment with an SGLT2 inhibitor deserve further attention, especially in individuals treated with several medications or in more fragile patients with hepatic and/or renal impairment.

  20. Development of an evidence evaluation and synthesis system for drug-drug interactions, and its application to a systematic review of HIV and malaria co-infection

    PubMed Central

    Seden, Kay; Gibbons, Sara; Marzolini, Catia; Schapiro, Jonathan M.; Burger, David M.; Back, David J.; Khoo, Saye H.

    2017-01-01

    Background In all settings, there are challenges associated with safely treating patients with multimorbidity and polypharmacy. The need to characterise, understand and limit harms resulting from medication use is therefore increasingly important. Drug-drug interactions (DDIs) are prevalent in patients taking antiretrovirals (ARVs) and if unmanaged, may pose considerable risk to treatment outcome. One of the biggest challenges in preventing DDIs is the substantial gap between theory and clinical practice. There are no robust methods published for formally assessing quality of evidence relating to DDIs, despite the diverse sources of information. We defined a transparent, structured process for developing evidence quality summaries in order to guide therapeutic decision making. This was applied to a systematic review of DDI data with considerable public health significance: HIV and malaria. Methods and findings This was a systematic review of DDI data between antiretrovirals and drugs used in prophylaxis and treatment of malaria. The data comprised all original research in humans that evaluated pharmacokinetic data and/or related adverse events when antiretroviral agents were combined with antimalarial agents, including healthy volunteers, patients with HIV and/or malaria, observational studies, and case reports. The data synthesis included 36 articles and conference presentations published via PubMed and conference websites/abstract books between 1987-August 2016. There is significant risk of DDIs between HIV protease inhibitors, or NNRTIs and artemesinin-containing antimalarial regimens. For many antiretrovirals, DDI studies with antimalarials were lacking, and the majority were of moderate to very low quality. Quality of evidence and strength of recommendation categories were defined and developed specifically for recommendations concerning DDIs. Conclusions There is significant potential for DDIs between antiretrovirals and antimalarials. The application of

  1. Metabolite Identification, Reaction Phenotyping and Retrospective Drug-Drug Interaction Predictions of 17-deacetylnorgestimate, the Active Component of the Oral Contraceptive Norgestimate.

    PubMed

    Ahire, Deepak; Sinha, Sarmistha; Brock, Barry; Iyer, Ramaswamy; Mandlekar, Sandhya; Subramanian, Murali

    2017-03-10

    Ortho-Tri-Cyclen® (OTC), a two drug cocktail comprising of ethinylestradiol (EE) and norgestimate (13-ethyl-17-acetoxy-18, 19-dinor-17α-pregn-4-en-20yn-3 oxime), is commonly prescribed to avert unwanted pregnancies in women of reproductive age. In vivo, norgestimate undergoes extensive and rapid deacetylation to produce 17-deacetylnorgestimate (NGMN), an active circulating metabolite that likely contributes significantly to norgestimate efficacy. Despite being of primary significance, the metabolism and reaction phenotyping of NGMN have not been previously reported. Hence, detailed biotransformation and reaction phenotyping studies of NGMN with recombinant cytochrome P450s (rCYPs), recombinant uridine 5'-diphospho-glucuronosyltransferases (rUGTs) and human liver microsomes (HLM) in the presence and absence of selective cytochrome P450 (CYP) inhibitors were conducted. It was found that cytochrome P450 3A4 (CYP3A4) plays a key role in NGNM metabolism with a fraction metabolized (fm) of 0.57. CYP2B6 and to an even lesser extent CYP2C9 were also observed to catalyze NGMN metabolism. Using this CYP3A4 fm, the predicted area under the plasma concentration vs. time curve (AUC) change in NGMN using a basic/mechanistic static model was found to be within 1.3-fold of reported NGMN AUC changes for four modulators of CYP3A4. In addition to NGMN, we have also elucidated the biotransformation of norgestrel (NG), a downstream norgestimate and NGMN metabolite, and found that CYP3A4 and UGT1A1 have a major contribution to the elimination of NG with a combined fm of 1. The data presented in this manuscript will lead to a better understanding and management of NGMN based drug-drug interactions (DDIs) when norgestimate is co-administered with CYP3A4 modulators.

  2. Use of immortalized human hepatocytes to predict the magnitude of clinical drug-drug interactions caused by CYP3A4 induction.

    PubMed

    Ripp, Sharon L; Mills, Jessica B; Fahmi, Odette A; Trevena, Kristen A; Liras, Jennifer L; Maurer, Tristan S; de Morais, Sonia M

    2006-10-01

    Cytochrome P4503A4 (CYP3A4) is the principal drug-metabolizing enzyme in human liver. Drug-drug interactions (DDIs) caused by induction of CYP3A4 can result in decreased exposure to coadministered drugs, with potential loss of efficacy. Immortalized hepatocytes (Fa2N-4 cells) have been proposed as a tool to identify CYP3A4 inducers. The purpose of the current studies was to characterize the effect of known inducers on CYP3A4 in Fa2N-4 cells, and to determine whether these in vitro data could reliably project the magnitude of DDIs caused by induction. Twenty-four compounds were chosen for these studies, based on previously published data using primary human hepatocytes. Eighteen compounds had been shown to be positive for induction, and six compounds had been shown to be negative for induction. In Fa2N-4 cells, all 18 positive controls produced greater than 2-fold maximal CYP3A4 induction, and all 6 negative controls produced less than 1.5-fold maximal CYP3A4 induction. Subsequent studies were conducted to determine the relationship between in vitro induction data and in vivo induction response. The approach was to relate in vitro induction data (E(max) and EC(50) values) with efficacious free plasma concentrations to calculate a relative induction score. This score was then correlated with decreases in area under the plasma concentration versus time curve values for coadministered CYP3A4 object drugs (midazolam or ethinylestradiol) from previously published clinical DDI studies. Excellent correlations (r(2) values >0.92) were obtained, suggesting that Fa2N-4 cells can be used for identification of inducers as well as prediction of the magnitude of clinical DDIs.

  3. Evaluation of CYP2B6 Induction and Prediction of Clinical Drug-Drug Interactions: Considerations from the IQ Consortium Induction Working Group-An Industry Perspective.

    PubMed

    Fahmi, Odette A; Shebley, Mohamad; Palamanda, Jairam; Sinz, Michael W; Ramsden, Diane; Einolf, Heidi J; Chen, Liangfu; Wang, Hongbing

    2016-10-01

    Drug-drug interactions (DDIs) due to CYP2B6 induction have recently gained prominence and clinical induction risk assessment is recommended by regulatory agencies. This work aimed to evaluate the potency of CYP2B6 versus CYP3A4 induction in vitro and from clinical studies and to assess the predictability of efavirenz versus bupropion as clinical probe substrates of CYP2B6 induction. The analysis indicates that the magnitude of CYP3A4 induction was higher than CYP2B6 both in vitro and in vivo. The magnitude of DDIs caused by induction could not be predicted for bupropion with static or dynamic models. On the other hand, the relative induction score, net effect, and physiologically based pharmacokinetics SimCYP models using efavirenz resulted in improved DDI predictions. Although bupropion and efavirenz have been used and are recommended by regulatory agencies as clinical CYP2B6 probe substrates for DDI studies, CYP3A4 contributes to the metabolism of both probes and is induced by all reference CYP2B6 inducers. Therefore, caution must be taken when interpreting clinical induction results because of the lack of selectivity of these probes. Although in vitro-in vivo extrapolation for efavirenz performed better than bupropion, interpretation of the clinical change in exposure is confounded by the coinduction of CYP2B6 and CYP3A4, as well as the increased contribution of CYP3A4 to efavirenz metabolism under induced conditions. Current methods and probe substrates preclude accurate prediction of CYP2B6 induction. Identification of a sensitive and selective clinical substrate for CYP2B6 (fraction metabolized > 0.9) is needed to improve in vitro-in vivo extrapolation for characterizing the potential for CYP2B6-mediated DDIs. Alternative strategies and a framework for evaluating the CYP2B6 induction risk are proposed.

  4. Prediction of time-dependent CYP3A4 drug-drug interactions by physiologically based pharmacokinetic modelling: impact of inactivation parameters and enzyme turnover.

    PubMed

    Rowland Yeo, K; Walsky, R L; Jamei, M; Rostami-Hodjegan, A; Tucker, G T

    2011-06-14

    Predicting the magnitude of time-dependent metabolic drug-drug (mDDIs) interactions involving cytochrome P-450 3A4 (CYP3A4) from in vitro data requires accurate knowledge of the inactivation parameters of the inhibitor (K(I), k(inact)) and of the turnover of the enzyme (k(deg)) in both the gut and the liver. We have predicted the magnitude of mDDIs observed in 29 in vivo studies involving six CYP3A4 probe substrates and five mechanism based inhibitors of CYP3A4 of variable potency (azithromycin, clarithromycin, diltiazem, erythromycin and verapamil). Inactivation parameters determined anew in a single laboratory under standardised conditions together with data from substrate and inhibitor files within the Simcyp Simulator (Version 9.3) were used to determine a value of the hepatic k(deg) (0.0193 or 0.0077h(-1)) most appropriate for the prediction of mDDIs involving time-dependent inhibition of CYP3A4. The higher value resulted in decreased bias (geometric mean fold error - 1.05 versus 1.30) and increased precision (root mean squared error - 1.29 versus 2.30) of predictions of mean ratios of AUC in the absence and presence of inhibitor. Depending on the k(deg) value used (0.0193 versus 0.0077h(-1)), predicted mean ratios of AUC were within 2-fold of the observed values for all (100%) and 27 (93%) of the 29 studies, respectively and within 1.5-fold for 24 (83%) and 17 (59%) of the 29 studies, respectively. Comprehensive PBPK models were applied for accurate assessment of the potential for mDDIs involving time-dependent inhibition of CYP3A4 using a hepatic k(deg) value of 0.0193h(-1) in conjunction with inactivation parameters determined by the conventional experimental approach.

  5. In Vitro Dissolution of Fluconazole and Dipyridamole in Gastrointestinal Simulator (GIS), Predicting in Vivo Dissolution and Drug-Drug Interaction Caused by Acid-Reducing Agents.

    PubMed

    Matsui, Kazuki; Tsume, Yasuhiro; Amidon, Gregory E; Amidon, Gordon L

    2015-07-06

    Weakly basic drugs typically exhibit pH-dependent solubility in the physiological pH range, displaying supersaturation or precipitation along the gastrointestinal tract. Additionally, their oral bioavailabilities may be affected by coadministration of acid-reducing agents that elevate gastric pH. The purpose of this study was to assess the feasibility of a multicompartmental in vitro dissolution apparatus, Gastrointestinal Simulator (GIS), in predicting in vivo dissolution of certain oral medications. In vitro dissolution studies of fluconazole, a BCS class I, and dipyridamole, a BCS class II weak bases (class IIb), were performed in the GIS as well as United States Pharmacopeia (USP) apparatus II and compared with the results of clinical drug-drug interaction (DDI) studies. In both USP apparatus II and GIS, fluconazole completely dissolved within 60 min regardless of pH, reflecting no DDI between fluconazole and acid-reducing agents in a clinical study. On the other hand, seven-fold and 15-fold higher concentrations of dipyridamole than saturation solubility were observed in the intestinal compartments in GIS with gastric pH 2.0. Precipitation of dipyridamole was also observed in the GIS, and the percentage of dipyridamole in solution was 45.2 ± 7.0%. In GIS with gastric pH 6.0, mimicking the coadministration of acid-reducing agents, the concentration of dipyridamole was equal to its saturation solubility, and the percentage of drug in solution was 9.3 ± 2.7%. These results are consistent with the clinical DDI study of dipyridamole with famotidine, which significantly reduced the Cmax and area under the curve. An In situ mouse infusion study combined with GIS revealed that high concentration of dipyridamole in the GIS enhanced oral drug absorption, which confirmed the supersaturation of dipyridamole. In conclusion, GIS was shown to be a useful apparatus to predict in vivo dissolution for BCS class IIb drugs.

  6. Using a Simulated Infobutton Linked to an Evidence-Based Resource to Research Drug-Drug Interactions: A Pilot Study with Third-Year Dental Students.

    PubMed

    Dragan, Irina F; Newman, Michael; Stark, Paul; Steffensen, Bjorn; Karimbux, Nadeem

    2015-11-01

    Many health professions students and clinicians are using evidence-based databases that allow for quicker and more accurate clinical decisions. The aims of this pilot study were to compare third-year dental students' speed and accuracy in researching questions about drug-drug interactions (DDI) when using two different methods: a simulated infobutton linked to the evidence-based clinical decision support resource UpToDate versus traditional Internet resources accessed through a computer or smart device. Students researched two simulated cases during two sessions. In the first session, half the students used the infobutton, while the other half used traditional electronic tools only. In the second session, ten days later, a cross-over took place. The sessions were timed, and after researching the case, students answered three questions on the use of antibiotics, analgesics, and local anesthetics. Of the 50 students who volunteered for the study, two were excluded, and 44 participated in both sessions and the exam. The results showed that the students took a similar amount of time to identify DDI whether they used the infobutton (mean=286.5 seconds) or traditional tools (265.2 seconds); the difference was not statistically significant (p=0.429). Their scores using the two research methods were similar in all three content areas: antibiotics (p=0.797), analgesics (p=0.850), and local anesthetics (p=0.850). In a post-intervention survey, students were generally favorable about infobutton and UpToDate, reporting the tool was easy to use (62.5%), provided the answer they were looking for (53.1%), was fast (50%), and they would use it again (68.8%). This pilot study found that the time and accuracy of these students conducting DDI research with the infobutton and UpToDate were about the same as using traditional Internet resources.

  7. In vitro selective inhibition of human UDP-glucuronosyltransferase (UGT) 1A4 by finasteride, and prediction of in vivo drug-drug interactions.

    PubMed

    Lee, Seung Jun; Park, Jung Bae; Kim, Doyun; Bae, Soo Hyeon; Chin, Young-Won; Oh, Euichaul; Bae, Soo Kyung

    2015-01-22

    In the present study, we evaluated the inhibitory potentials of finasteride for the major human hepatic UDP-glucuronosyltransferases (UGTs) (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15) in vitro using LC-MS/MS by specific marker reactions in human liver microsomes (except for UGT2B15) or recombinant supersomes (UGT2B15). Of the seven tested UGTs, finasteride potently, selectively, and competitively inhibited UGT1A4-mediated trifluoperazine-N-glucuronidation in human liver microsomes with an IC₅₀ value of 11.5 ± 1.78 μM and Ki value of 6.03 ± 0.291 μM. This inhibitory potency was similar to that of hecogenin, a well-known inhibitor of UGT1A4. However, finasteride did not seem to inhibit any of the other six UGTs: UGT1A1, UGT1A3, UGT1A6, UGT1A9, UGT2B7, or UGT2B15. Similarly, finasteride markedly inhibited UGT1A4 activity in recombinant human UGT1A4 supersomes, with a Ki value of 6.05 ± 0.410 μM. In addition, finasteride strongly inhibited UGT1A4-catalyzed imipramine-N-β-D-glucuronidation. However, on the basis of an in vitro-in vivo extrapolation, our data strongly suggested that finasteride is unlikely to cause clinically significant drug-drug interactions mediated via inhibition of the hepatic UGT enzymes involved in drug metabolism in vivo.

  8. Time-dependent inhibition and estimation of CYP3A clinical pharmacokinetic drug-drug interactions using plated human cell systems.

    PubMed

    Albaugh, Daniel R; Fullenwider, Cody L; Fisher, Michael B; Hutzler, J Matthew

    2012-07-01

    The current studies assessed the utility of freshly plated hepatocytes, cryopreserved plated hepatocytes, and cryopreserved plated HepaRG cells for the estimation of inactivation parameters k(inact) and K(I) for CYP3A. This was achieved using a subset of CYP3A time-dependent inhibitors (fluoxetine, verapamil, clarithromycin, troleandomycin, and mibefradil) representing a range of potencies. The estimated k(inact) and K(I) values for each time-dependent inhibitor were compared with those obtained using human liver microsomes and used to estimate the magnitude of clinical pharmacokinetic drug-drug interaction (DDI). The inactivation kinetic parameter, k(inact), was most consistent across systems tested for clarithromycin, verapamil, and troleandomycin, with a high k(inact) of 0.91 min(-1) observed for mibefradil in HepaRG cells. The apparent K(I) estimates derived from the various systems displayed a range of variability from 3-fold for clarithromycin (5.4-17.7 μM) to 6-fold for verapamil (1.9-12.6 μM). In general, the inactivation kinetic parameters derived from the cell systems tested fairly replicated what was observed in time-dependent inhibition studies using human liver microsomes. Despite some of the observed differences in inactivation kinetic parameters, the estimated DDIs derived from each of the tested systems generally agreed with the clinically reported DDI within approximately 2-fold. In addition, a plated cell approach offered the ability to conduct longer primary incubations (greater than 30 min), which afforded improved ability to identify the weak time-dependent inhibitor fluoxetine. Overall, results from these studies suggest that in vitro inactivation parameters generated from plated cell systems may be a practical approach for identifying time-dependent inhibitors and for estimating the magnitude of clinical DDIs.

  9. How the Probability and Potential Clinical Significance of Pharmacokinetically Mediated Drug-Drug Interactions Are Assessed in Drug Development: Desvenlafaxine as an Example

    PubMed Central

    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 < 200%). Coadministration with ketoconazole resulted in a weak interaction with desvenlafaxine (AUC GM ratio of 143%). Desvenlafaxine was not a substrate (efflux ratio < 2) or inhibitor (50% inhibitory drug concentration values > 250 μM) of P-gp. Conclusions: A 2-step process based on FDA guidance can be used first to determine whether a pharmacokinetically mediated

  10. Variability in P-glycoprotein inhibitory potency (IC₅₀) using various in vitro experimental systems: implications for universal digoxin drug-drug interaction risk assessment decision criteria.

    PubMed

    Bentz, Joe; O'Connor, Michael P; Bednarczyk, Dallas; Coleman, Joann; Lee, Caroline; Palm, Johan; Pak, Y Anne; Perloff, Elke S; Reyner, Eric; Balimane, Praveen; Brännström, Marie; Chu, Xiaoyan; Funk, Christoph; Guo, Ailan; Hanna, Imad; Herédi-Szabó, Krisztina; Hillgren, Kate; Li, Libin; Hollnack-Pusch, Evelyn; Jamei, Masoud; Lin, Xuena; Mason, Andrew K; Neuhoff, Sibylle; Patel, Aarti; Podila, Lalitha; Plise, Emile; Rajaraman, Ganesh; Salphati, Laurent; Sands, Eric; Taub, Mitchell E; Taur, Jan-Shiang; Weitz, Dietmar; Wortelboer, Heleen M; Xia, Cindy Q; Xiao, Guangqing; Yabut, Jocelyn; Yamagata, Tetsuo; Zhang, Lei; Ellens, Harma

    2013-07-01

    A P-glycoprotein (P-gp) IC₅₀ working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC₅₀ determinations. Each laboratory followed its in-house protocol to determine in vitro IC₅₀ values for 16 inhibitors using four different test systems: human colon adenocarcinoma cells (Caco-2; eleven laboratories), Madin-Darby canine kidney cells transfected with MDR1 cDNA (MDCKII-MDR1; six laboratories), and Lilly Laboratories Cells--Porcine Kidney Nr. 1 cells transfected with MDR1 cDNA (LLC-PK1-MDR1; four laboratories), and membrane vesicles containing human P-glycoprotein (P-gp; five laboratories). For cell models, various equations to calculate remaining transport activity (e.g., efflux ratio, unidirectional flux, net-secretory-flux) were also evaluated. The difference in IC₅₀ values for each of the inhibitors across all test systems and equations ranged from a minimum of 20- and 24-fold between lowest and highest IC₅₀ values for sertraline and isradipine, to a maximum of 407- and 796-fold for telmisartan and verapamil, respectively. For telmisartan and verapamil, variability was greatly influenced by data from one laboratory in each case. Excluding these two data sets brings the range in IC₅₀ values for telmisartan and verapamil down to 69- and 159-fold. The efflux ratio-based equation generally resulted in severalfold lower IC₅₀ values compared with unidirectional or net-secretory-flux equations. Statistical analysis indicated that variability in IC₅₀ values was mainly due to interlaboratory variability, rather than an implicit systematic difference between test systems. Potential reasons for variability are discussed and the simplest, most robust experimental design for P-gp IC₅₀ determination proposed. The impact of these findings on drug-drug interaction risk assessment is discussed in the companion article (Ellens

  11. An update on pharmacological, pharmacokinetic properties and drug-drug interactions of rotigotine transdermal system in Parkinson's disease and restless legs syndrome.

    PubMed

    Elshoff, Jan-Peer; Cawello, Willi; Andreas, Jens-Otto; Mathy, Francois-Xavier; Braun, Marina

    2015-04-01

    This narrative review reports on the pharmacological and pharmacokinetic properties of rotigotine, a non-ergolinic D₃/D₂/D₁ dopamine receptor agonist approved for the treatment of early- and advanced-stage Parkinson's disease (PD) and moderate to severe restless legs syndrome (RLS). Rotigotine is formulated as a transdermal patch providing continuous drug delivery over 24 h, with a plasma concentration profile similar to that of administration via continuous intravenous infusion. Absolute bioavailability after 24 h transdermal delivery is 37 % of the applied rotigotine dose. Following a single administration of rotigotine transdermal system (24-h patch-on period), most of the absorbed drug is eliminated in urine and feces as sulphated and glucuronidated conjugates within 24 h of patch removal. The drug shows a high apparent volume of distribution (>2500 L) and a total body clearance of 300-600 L/h. Rotigotine transdermal system provides dose-proportional pharmacokinetics up to supratherapeutic dose rates of 24 mg/24 h, with steady-state plasma drug concentrations attained within 1-2 days of daily dosing. The pharmacokinetics of rotigotine transdermal patch are similar in healthy subjects, patients with early- or advanced-stage PD, and patients with RLS when comparing dose-normalized area under the plasma concentration-time curve (AUC) and maximum plasma drug concentration (Cmax), as well as half-life and other pharmacokinetic parameters. Also, it is not influenced in a relevant manner by age, sex, ethnicity, advanced renal insufficiency, or moderate hepatic impairment. No clinically relevant drug-drug interactions were observed following co-administration of rotigotine with levodopa/carbidopa, domperidone, or the CYP450 inhibitors cimetidine or omeprazole. Also, pharmacodynamics and pharmacokinetics of an oral hormonal contraceptive were not influenced by rotigotine co-administration. Rotigotine was generally well tolerated, with an adverse event profile

  12. Coproporphyrins in Plasma and Urine Can Be Appropriate Clinical Biomarkers to Recapitulate Drug-Drug Interactions Mediated by Organic Anion Transporting Polypeptide Inhibition.

    PubMed

    Lai, Yurong; Mandlekar, Sandhya; Shen, Hong; Holenarsipur, Vinay K; Langish, Robert; Rajanna, Prabhakar; Murugesan, Senthilkumar; Gaud, Nilesh; Selvam, Sabariya; Date, Onkar; Cheng, Yaofeng; Shipkova, Petia; Dai, Jun; Humphreys, William G; Marathe, Punit

    2016-09-01

    In the present study, an open-label, three-treatment, three-period clinical study of rosuvastatin (RSV) and rifampicin (RIF) when administered alone and in combination was conducted in 12 male healthy subjects to determine if coproporphyrin I (CP-I) and coproporphyrin III (CP-III) could serve as clinical biomarkers for organic anion transporting polypeptide 1B1 (OATP1B1) and 1B3 that belong to the solute carrier organic anion gene subfamily. Genotyping of the human OATP1B1 gene was performed in all 12 subjects and confirmed absence of OATP1B1*5 and OATP1B1*15 mutations. Average plasma concentrations of CP-I and CP-III prior to drug administration were 0.91 ± 0.21 and 0.15 ± 0.04 nM, respectively, with minimum fluctuation over the three periods. CP-I was passively eliminated, whereas CP-III was actively secreted from urine. Administration of RSV caused no significant changes in the plasma and urinary profiles of CP-I and CP-III. RIF markedly increased the maximum plasma concentration (Cmax) of CP-I and CP-III by 5.7- and 5.4-fold (RIF) or 5.7- and 6.5-fold (RIF+RSV), respectively, as compared with the predose values. The area under the plasma concentration curves from time 0 to 24 h (AUC0-24h) of CP-I and CP-III with RIF and RSV increased by 4.0- and 3.3-fold, respectively, when compared with RSV alone. In agreement with this finding, Cmax and AUC0-24h of RSV increased by 13.2- and 5.0-fold, respectively, when RIF was coadministered. Collectively, we conclude that CP-I and CP-III in plasma and urine can be appropriate endogenous biomarkers specifically and reliably reflecting OATP inhibition, and thus the measurement of these molecules can serve as a useful tool to assess OATP drug-drug interaction liabilities in early clinical studies.

  13. Downregulation of Organic Anion Transporting Polypeptide (OATP) 1B1 Transport Function by Lysosomotropic Drug Chloroquine: Implication in OATP-Mediated Drug-Drug Interactions.

    PubMed

    Alam, Khondoker; Pahwa, Sonia; Wang, Xueying; Zhang, Pengyue; Ding, Kai; Abuznait, Alaa H; Li, Lang; Yue, Wei

    2016-03-07

    and Drug Administration Adverse Event Reporting System indicated that CQ plus pitavastatin, rosuvastatin, and pravastatin, which are minimally metabolized by the cytochrome P450 enzymes, led to higher myopathy risk than these statins alone. In summary, the present studies report novel findings that lysosome is involved in degradation of OATP1B1 protein and that pre-incubation with lysosomotropic drug CQ downregulates OATP1B1 transport activity. Our in vitro data in combination with pharmacoepidemiologic studies support that CQ has potential to cause OATP-mediated drug-drug interactions.

  14. Metabolic Drug-Drug Interaction Potential of Macrolactin A and 7-O-Succinyl Macrolactin A Assessed by Evaluating Cytochrome P450 Inhibition and Induction and UDP-Glucuronosyltransferase Inhibition In Vitro

    PubMed Central

    Bae, Soo Hyeon; Kwon, Min Jo; Park, Jung Bae; Kim, Doyun; Kim, Dong-Hee; Kang, Jae-Seon; Kim, Chun-Gyu; Oh, Euichaul

    2014-01-01

    Macrolactin A (MA) and 7-O-succinyl macrolactin A (SMA), polyene macrolides containing a 24-membered lactone ring, show antibiotic effects superior to those of teicoplanin against vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. MA and SMA are currently being evaluated as antitumor agents in preclinical studies in Korea. We evaluated the potential of MA and SMA for the inhibition or induction of human liver cytochrome P450 (CYP) enzymes and UDP-glucuronosyltransferases (UGTs) in vitro to assess their safety as new molecular entities. We demonstrated that MA and SMA are potent competitive inhibitors of CYP2C9, with Ki values of 4.06 μM and 10.6 μM, respectively. MA and SMA also weakly inhibited UGT1A1 activity, with Ki values of 40.1 μM and 65.3 μM, respectively. However, these macrolactins showed no time-dependent inactivation of the nine CYPs studied. In addition, MA and SMA did not induce CYP1A2, CYP2B6, or CYP3A4/5. On the basis of an in vitro-in vivo extrapolation, our data strongly suggested that MA and SMA are unlikely to cause clinically significant drug-drug interactions mediated via inhibition or induction of most of the CYPs involved in drug metabolism in vivo, except for the inhibition of CYP2C9 by MA. Similarly, MA and SMA are unlikely to inhibit the activity of UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 enzymes in vivo. Although further investigations will be required to clarify the in vivo interactions of MA with CYP2C9-targeted drugs, our findings offer a clearer understanding and prediction of drug-drug interactions for the safe use of MA and SMA in clinical practice. PMID:24890600

  15. Metabolic drug-drug interaction potential of macrolactin A and 7-O-succinyl macrolactin A assessed by evaluating cytochrome P450 inhibition and induction and UDP-glucuronosyltransferase inhibition in vitro.

    PubMed

    Bae, Soo Hyeon; Kwon, Min Jo; Park, Jung Bae; Kim, Doyun; Kim, Dong-Hee; Kang, Jae-Seon; Kim, Chun-Gyu; Oh, Euichaul; Bae, Soo Kyung

    2014-09-01

    Macrolactin A (MA) and 7-O-succinyl macrolactin A (SMA), polyene macrolides containing a 24-membered lactone ring, show antibiotic effects superior to those of teicoplanin against vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. MA and SMA are currently being evaluated as antitumor agents in preclinical studies in Korea. We evaluated the potential of MA and SMA for the inhibition or induction of human liver cytochrome P450 (CYP) enzymes and UDP-glucuronosyltransferases (UGTs) in vitro to assess their safety as new molecular entities. We demonstrated that MA and SMA are potent competitive inhibitors of CYP2C9, with Ki values of 4.06 μM and 10.6 μM, respectively. MA and SMA also weakly inhibited UGT1A1 activity, with Ki values of 40.1 μM and 65.3 μM, respectively. However, these macrolactins showed no time-dependent inactivation of the nine CYPs studied. In addition, MA and SMA did not induce CYP1A2, CYP2B6, or CYP3A4/5. On the basis of an in vitro-in vivo extrapolation, our data strongly suggested that MA and SMA are unlikely to cause clinically significant drug-drug interactions mediated via inhibition or induction of most of the CYPs involved in drug metabolism in vivo, except for the inhibition of CYP2C9 by MA. Similarly, MA and SMA are unlikely to inhibit the activity of UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 enzymes in vivo. Although further investigations will be required to clarify the in vivo interactions of MA with CYP2C9-targeted drugs, our findings offer a clearer understanding and prediction of drug-drug interactions for the safe use of MA and SMA in clinical practice.

  16. An evaluation of the CYP2D6 and CYP3A4 inhibition potential of metoprolol metabolites and their contribution to drug-drug and drug-herb interaction by LC-ESI/MS/MS.

    PubMed

    Borkar, Roshan M; Bhandi, Murali Mohan; Dubey, Ajay P; Ganga Reddy, V; Komirishetty, Prashanth; Nandekar, Prajwal P; Sangamwar, Abhay T; Kamal, Ahmed; Banerjee, Sanjay K; Srinivas, R

    2016-10-01

    The aim of the present study was to evaluate the contribution of metabolites to drug-drug interaction and drug-herb interaction using the inhibition of CYP2D6 and CYP3A4 by metoprolol (MET) and its metabolites. The peak concentrations of unbound plasma concentration of MET, α-hydroxy metoprolol (HM), O-desmethyl metoprolol (ODM) and N-desisopropyl metoprolol (DIM) were 90.37 ± 2.69, 33.32 ± 1.92, 16.93 ± 1.70 and 7.96 ± 0.94 ng/mL, respectively. The metabolites identified, HM and ODM, had a ratio of metabolic area under the concentration-time curve (AUC) to parent AUC of ≥0.25 when either total or unbound concentration of metabolite was considered. In vitro CYP2D6 and CYP3A4 inhibition by MET, HM and ODM study revealed that MET, HM and ODM were not inhibitors of CYP3A4-catalyzed midazolam metabolism and CYP2D6-catalyzed dextromethorphan metabolism. However, DIM only met the criteria of >10% of the total drug related material and <25% of the parent using unbound concentrations. If CYP inhibition testing is solely based on metabolite exposure, DIM metabolite would probably not be considered. However, the present study has demonstrated that DIM contributes significantly to in vitro drug-drug interaction. Copyright © 2016 John Wiley & Sons, Ltd.

  17. Comparison of different algorithms for predicting clinical drug-drug interactions, based on the use of CYP3A4 in vitro data: predictions of compounds as precipitants of interaction.

    PubMed

    Fahmi, Odette A; Hurst, Susan; Plowchalk, David; Cook, Jack; Guo, Feng; Youdim, Kuresh; Dickins, Maurice; Phipps, Alex; Darekar, Amanda; Hyland, Ruth; Obach, R Scott

    2009-08-01

    Cytochrome P450 3A4 (CYP3A4) is the most important enzyme in drug metabolism and because it is the most frequent target for pharmacokinetic drug-drug interactions (DDIs) it is highly desirable to be able to predict CYP3A4-based DDIs from in vitro data. In this study, the prediction of clinical DDIs for 30 drugs on the pharmacokinetics of midazolam, a probe substrate for CYP3A4, was done using in vitro inhibition, inactivation, and induction data. Two DDI prediction approaches were used, which account for effects at both the liver and intestine. The first was a model that simultaneously combines reversible inhibition, time-dependent inactivation, and induction data with static estimates of relevant in vivo concentrations of the precipitant drug to provide point estimates of the average magnitude of change in midazolam exposure. This model yielded a success rate of 88% in discerning DDIs with a mean -fold error of 1.74. The second model was a computational physiologically based pharmacokinetic model that uses dynamic estimates of in vivo concentrations of the precipitant drug and accounts for interindividual variability among the population (Simcyp). This model yielded success rates of 88 and 90% (for "steady-state" and "time-based" approaches, respectively) and mean -fold errors of 1.59 and 1.47. From these findings it can be concluded that in vivo DDIs for CYP3A4 can be predicted from in vitro data, even when more than one biochemical phenomenon occurs simultaneously.

  18. Drug-drug interactions in older patients with cancer: a report from the 15th Conference of the International Society of Geriatric Oncology, Prague, Czech Republic, November 2015

    PubMed Central

    Stepney, Rob; Lichtman, Stuart M; Danesi, Romano

    2016-01-01

    Drugs taken for cancer can interact with each other, with agents taken as part of supportive care, with drugs taken for comorbid conditions (which are particularly common in the elderly patients), and with herbal supplements and complementary medicines. We tend to focus on the narrow therapeutic window of cytotoxics, but the metabolism of tyrosine kinase inhibitors by the cytochrome P450 3A4 enzyme (CYP3A4) makes some TKIs particularly prone to interference with or from other agents sharing this pathway. There is also potential for adverse pharmacokinetic interactions with new hormonal agents used in advanced prostate cancer. PMID:26823680

  19. Treatment of Plasmodium chabaudi Parasites with Curcumin in Combination with Antimalarial Drugs: Drug Interactions and Implications on the Ubiquitin/Proteasome System

    PubMed Central

    Neto, Zoraima; Machado, Marta; Lindeza, Ana; do Rosário, Virgílio; Gazarini, Marcos L.; Lopes, Dinora

    2013-01-01

    Antimalarial drug resistance remains a major obstacle in malaria control. Evidence from Southeast Asia shows that resistance to artemisinin combination therapy (ACT) is inevitable. Ethnopharmacological studies have confirmed the efficacy of curcumin against Plasmodium spp. Drug interaction assays between curcumin/piperine/chloroquine and curcumin/piperine/artemisinin combinations and the potential of drug treatment to interfere with the ubiquitin proteasome system (UPS) were analyzed. In vivo efficacy of curcumin was studied in BALB/c mice infected with Plasmodium chabaudi clones resistant to chloroquine and artemisinin, and drug interactions were analyzed by isobolograms. Subtherapeutic doses of curcumin, chloroquine, and artemisinin were administered to mice, and mRNA was collected following treatment for RT-PCR analysis of genes encoding deubiquitylating enzymes (DUBs). Curcumin was found be nontoxic in BALB/c mice. The combination of curcumin/chloroquine/piperine reduced parasitemia to 37% seven days after treatment versus the control group's 65%, and an additive interaction was revealed. Curcumin/piperine/artemisinin combination did not show a favorable drug interaction in this murine model of malaria. Treatment of mice with subtherapeutic doses of the drugs resulted in a transient increase in genes encoding DUBs indicating UPS interference. If curcumin is to join the arsenal of available antimalarial drugs, future studies exploring suitable drug partners would be of interest. PMID:23691276

  20. Virtual Clinical Trial Toward Polytherapy Safety Assessment: Combination of Physiologically Based Pharmacokinetic/Pharmacodynamic-Based Modeling and Simulation Approach With Drug-Drug Interactions Involving Terfenadine as an Example.

    PubMed

    Wiśniowska, Barbara; Polak, Sebastian

    2016-11-01

    A Quantitative Systems Pharmacology approach was utilized to predict the cardiac consequences of drug-drug interaction (DDI) at the population level. The Simcyp in vitro-in vivo correlation and physiologically based pharmacokinetic platform was used to predict the pharmacokinetic profile of terfenadine following co-administration of the drug. Electrophysiological effects were simulated using the Cardiac Safety Simulator. The modulation of ion channel activity was dependent on the inhibitory potential of drugs on the main cardiac ion channels and a simulated free heart tissue concentration. ten Tusscher's human ventricular cardiomyocyte model was used to simulate the pseudo-ECG traces and further predict the pharmacodynamic consequences of DDI. Consistent with clinical observations, predicted plasma concentration profiles of terfenadine show considerable intra-subject variability with recorded Cmax values below 5 ng/mL for most virtual subjects. The pharmacokinetic and pharmacodynamic effects of inhibitors were predicted with reasonable accuracy. In all cases, a combination of the physiologically based pharmacokinetic and physiology-based pharmacodynamic models was able to differentiate between the terfenadine alone and terfenadine + inhibitor scenario. The range of QT prolongation was comparable in the clinical and virtual studies. The results indicate that mechanistic in vitro-in vivo correlation can be applied to predict the clinical effects of DDI even without comprehensive knowledge on all mechanisms contributing to the interaction.

  1. Fluoxetine- and norfluoxetine-mediated complex drug-drug interactions: in vitro to in vivo correlation of effects on CYP2D6, CYP2C19, and CYP3A4.

    PubMed

    Sager, J E; Lutz, J D; Foti, R S; Davis, C; Kunze, K L; Isoherranen, N

    2014-06-01

    Fluoxetine and its circulating metabolite norfluoxetine comprise a complex multiple-inhibitor system that causes reversible or time-dependent inhibition of the cytochrome P450 (CYP) family members CYP2D6, CYP3A4, and CYP2C19 in vitro. Although significant inhibition of all three enzymes in vivo was predicted, the areas under the concentration-time curve (AUCs) for midazolam and lovastatin were unaffected by 2-week dosing of fluoxetine, whereas the AUCs of dextromethorphan and omeprazole were increased by 27- and 7.1-fold, respectively. This observed discrepancy between in vitro risk assessment and in vivo drug-drug interaction (DDI) profile was rationalized by time-varying dynamic pharmacokinetic models that incorporated circulating concentrations of fluoxetine and norfluoxetine enantiomers, mutual inhibitor-inhibitor interactions, and CYP3A4 induction. The dynamic models predicted all DDIs with less than twofold error. This study demonstrates that complex DDIs that involve multiple mechanisms, pathways, and inhibitors with their metabolites can be predicted and rationalized via characterization of all the inhibitory species in vitro.

  2. Transwell-grown HepG2 cell monolayers as in vitro permeability model to study drug-drug or drug-food interactions.

    PubMed

    Berginc, Katja; Kristl, Albin

    2011-01-01

    HepG2 cell monolayers, formed during cell growth on collagen-coated Transwell® (Corning® Inc., Corning, NY, USA) inserts, can be used for the evaluation of interactions between food supplements and drugs that are substrates for P-glycoprotein (Pgp) and/or multidrug resistance-associated protein 2 (MRP-2). Samples obtained during such permeability studies were relatively free of intracellular proteins or cell debris compared to usually performed uptake experiments with HepG2 cells; therefore no special preparation protocol prior to the analysis was needed. In the presence of aged garlic extract the activities of hepatic efflux transporters (Pgp, MRP-2) changed, which was observed as significant permeability changes of tested human immunodeficiency virus (HIV) protease inhibitors. Darunavir efflux significantly increased, whereas that of saquinavir significantly decreased. Because of the observed in vitro interactions between aged garlic extract and HIV protease inhibitors (darunavir, saquinavir), any alterations of in vivo liver transport in the presence of garlic phytochemicals could also significantly influence darunavir/saquinavir hepatocyte intracellular concentrations and hence their bioavailabilities. Therefore this aspect needs further in vivo animal evaluation.

  3. San-Huang-Xie-Xin-Tang Constituents Exert Drug-Drug Interaction of Mutual Reinforcement at Both Pharmacodynamics and Pharmacokinetic Level: A Review.

    PubMed

    Wu, Jiasi; Hu, Yingfan; Xiang, Li; Li, Sheng; Yuan, Yi; Chen, Xiaomei; Zhang, Yan; Huang, Wenge; Meng, Xianli; Wang, Ping

    2016-01-01

    Inflammatory disorders underlie varieties of human diseases. San-Huang-Xie-xin-Tang (SHXXT), composed with Rhizoma Rhei (Rheum palmatum L.), Rhizoma Coptidis (Coptis chinensis Franch), and Radix Scutellaria (Scutellaria baicalensis Georgi), is a famous formula which has been widely used in the fight against inflammatory abnormalities. Mutual reinforcement is one of the basic theories of traditional Chinese medicine. Here this article reviewed and analyzed the recent research on (1) How the main constituents of SHXXT impact on inflammation-associated signaling pathway molecules. (2) The interaction between the main constituents and efflux pumps or intestinal transporters. The goal of this work was to, (1) Provide evidence to support the theory of mutual reinforcement. (2) Clarify the key targets of SHXXT and suggest which targets need further investigation. (3) Give advice for the clinical use of SHXXT to elevated the absorption of main constituents and eventually promote oral bioavailability. We search literatures in scientific databases with key words of "each main SHXXT constituent," in combination with "each main inflammatory pathway target molecule" or each main intestinal transporter, respectively. We report the effect of five main constituents on target molecules which lies in three main inflammatory signaling pathways, we as well investigate the interaction between constituents and intestinal transporter. We conclude, (1) The synergistic effect of constituents at both levels confirm the mutual reinforcement theory of TCM as it is proven in this work. (2) The effect of main constituents on downstream targets in nuclear need more further investigation. (3) Drug elevating the absorption of rhein, berberine and baicalein can be employed to promote oral bioavailability of SHXXT.

  4. San-Huang-Xie-Xin-Tang Constituents Exert Drug-Drug Interaction of Mutual Reinforcement at Both Pharmacodynamics and Pharmacokinetic Level: A Review

    PubMed Central

    Wu, Jiasi; Hu, Yingfan; Xiang, Li; Li, Sheng; Yuan, Yi; Chen, Xiaomei; Zhang, Yan; Huang, Wenge; Meng, Xianli; Wang, Ping

    2016-01-01

    Inflammatory disorders underlie varieties of human diseases. San-Huang-Xie-xin-Tang (SHXXT), composed with Rhizoma Rhei (Rheum palmatum L.), Rhizoma Coptidis (Coptis chinensis Franch), and Radix Scutellaria (Scutellaria baicalensis Georgi), is a famous formula which has been widely used in the fight against inflammatory abnormalities. Mutual reinforcement is one of the basic theories of traditional Chinese medicine. Here this article reviewed and analyzed the recent research on (1) How the main constituents of SHXXT impact on inflammation-associated signaling pathway molecules. (2) The interaction between the main constituents and efflux pumps or intestinal transporters. The goal of this work was to, (1) Provide evidence to support the theory of mutual reinforcement. (2) Clarify the key targets of SHXXT and suggest which targets need further investigation. (3) Give advice for the clinical use of SHXXT to elevated the absorption of main constituents and eventually promote oral bioavailability. We search literatures in scientific databases with key words of “each main SHXXT constituent,” in combination with “each main inflammatory pathway target molecule” or each main intestinal transporter, respectively. We report the effect of five main constituents on target molecules which lies in three main inflammatory signaling pathways, we as well investigate the interaction between constituents and intestinal transporter. We conclude, (1) The synergistic effect of constituents at both levels confirm the mutual reinforcement theory of TCM as it is proven in this work. (2) The effect of main constituents on downstream targets in nuclear need more further investigation. (3) Drug elevating the absorption of rhein, berberine and baicalein can be employed to promote oral bioavailability of SHXXT. PMID:27965575

  5. Validated UPLC-MS/MS method for simultaneous determination of simvastatin, simvastatin hydroxy acid and berberine in rat plasma: Application to the drug-drug pharmacokinetic interaction study of simvastatin combined with berberine after oral administration in rats.

    PubMed

    Liu, Mei; Su, Xianying; Li, Guofei; Zhao, Guilian; Zhao, Limei

    2015-12-01

    A rapid and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay method was developed and validated for simultaneous quantification of simvastatin (SV), its metabolite simvastatin hydroxy acid (SVA) and berberine (BBR) in rat plasma. Separation was performed on Poroshell 120 EC-C18 column (4.6×50mm, 2.7μm) using gradient elution by mobile phase containing acetonitrile and 10mM ammonium acetate (pH 4.5). Polarity switch (positive-negative-positive ionization mode) was performed in a total run time of 4.0min. The lower limits of quantification (LLOQ) for SV, SVA and BBR were 0.10, 0.20 and 0.10ng/mL, respectively. The response function was established for concentration range of 0.10-100ng/mL for SV and BBR and 0.20-3000ng/mL for SVA, with a coefficient of correlation of >0.99 for all the compounds. The proposed method was applied to the drug-drug pharmacokinetic interaction study of SV combined with BBR after oral administration in rats.

  6. In vitro profiling of the metabolism and drug-drug interaction of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, using human liver microsomes, human hepatocytes, and recombinant human CYP.

    PubMed

    Yamane, Mizuki; Kawashima, Kosuke; Yamaguchi, Koji; Nagao, Shunsuke; Sato, Mika; Suzuki, Masayuki; Honda, Kiyofumi; Hagita, Hitoshi; Kuhlmann, Olaf; Poirier, Agnes; Fowler, Stephen; Funk, Christoph; Simon, Sandrine; Aso, Yoshinori; Ikeda, Sachiya; Ishigai, Masaki

    2015-03-01

    Abstract 1. The metabolism and drug-drug interaction (DDI) risk of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, were evaluated by in vitro studies using human liver microsomes, human hepatocytes, and recombinant human CYPs. 2. The main metabolite of tofogliflozin was the carboxylated derivative (M1) in human hepatocytes, which was the same as in vivo. The metabolic pathway of tofogliflozin to M1 was considered to be as follows: first, tofogliflozin was catalyzed to the primary hydroxylated derivative (M4) by CYP2C18, CYP4A11 and CYP4F3B, then M4 was oxidized to M1. 3. Tofogliflozin had no induction potential on CYP1A2 and CYP3A4. Neither tofogliflozin nor M1 had inhibition potential on CYPs, with the exception of a weak CYP2C19 inhibition by M1. 4. Not only are multiple metabolic enzymes involved in the tofogliflozin metabolism, but the drug is also excreted into urine after oral administration, indicating that tofogliflozin is eliminated through multiple pathways. Thus, the exposure of tofogliflozin would not be significantly altered by DDI caused by any co-administered drugs. Also, tofogliflozin seems not to cause significant DDI of co-administered drugs because tofogliflozin has no CYP induction or inhibition potency, and the main metabolite M1 has no clinically relevant CYP inhibition potency.

  7. A Prediction Method for P-glycoprotein-Mediated Drug-Drug Interactions at the Human Blood-Brain Barrier from Blood Concentration-Time Profiles, Validated with PET Data.

    PubMed

    Matsuda, Akihiro; Karch, Rudolf; Bauer, Martin; Traxl, Alexander; Zeitlinger, Markus; Langer, Oliver

    2017-04-03

    The purpose of this study was to establish physiologically based pharmacokinetic (PBPK) models to predict in humans the brain concentration-time profiles and P-glycoprotein (Pgp)-mediated brain drug-drug interactions (DDIs) between the model Pgp substrate (R)-[(11)C]verapamil (VPM), the model dual Pgp/breast cancer resistance protein (BCRP) substrate [(11)C]tariquidar (TQD) and the Pgp inhibitor tariquidar. The model predictions were validated with results from positron emission tomography (PET) studies in humans. Using these PBPK models, the differences between predicted and observed areas under the concentration-time curves (AUC) of VPM and TQD in the brain were within a 1.2-fold and 2.5-fold range, respectively. Also, brain AUC increases of VPM and TQD following Pgp inhibitor administration were predicted with 2.5-fold accuracy when in vitro inhibition constant or half-maximum inhibitory concentration values of tariquidar were used. The predicted rank order of the magnitude of AUC increases reflected the results of the clinical PET studies. Our results suggest that the established models can predict brain exposure from the respective blood concentration-time profiles and rank the magnitude of the Pgp-mediated brain DDI potential for both Pgp and Pgp/BCRP substrates in humans.

  8. Utilizing structures of CYP2D6 and BACE1 complexes to reduce risk of drug-drug interactions with a novel series of centrally efficacious BACE1 inhibitors.

    PubMed

    Brodney, Michael A; Beck, Elizabeth M; Butler, Christopher R; Barreiro, Gabriela; Johnson, Eric F; Riddell, David; Parris, Kevin; Nolan, Charles E; Fan, Ying; Atchison, Kevin; Gonzales, Cathleen; Robshaw, Ashley E; Doran, Shawn D; Bundesmann, Mark W; Buzon, Leanne; Dutra, Jason; Henegar, Kevin; LaChapelle, Erik; Hou, Xinjun; Rogers, Bruce N; Pandit, Jayvardhan; Lira, Ricardo; Martinez-Alsina, Luis; Mikochik, Peter; Murray, John C; Ogilvie, Kevin; Price, Loren; Sakya, Subas M; Yu, Aijia; Zhang, Yong; O'Neill, Brian T

    2015-04-09

    In recent years, the first generation of β-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer's disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Herein, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5. Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for victim-based drug-drug interactions (DDI) and variable exposure in the clinic due to the polymorphic nature of this enzyme. To guide future design, we solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6, which provided insight into the binding mode and movements between substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal structures, we designed and synthesized analogues with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins.

  9. Phase 1 and Pharmacokinetic Drug-Drug Interaction Study of Metformin, Losartan, and Linagliptin Coadministered With DW1029M in Healthy Volunteers.

    PubMed

    Moon, Seol Ju; Kim, Sun-Young; Lim, Cheol-Hee; Jang, Hwan Bong; Kim, Min-Gul; Jeon, Ji-Young

    2016-10-14

    We investigated botanical drug-pharmaceutical drug interactions between DW1029M (a botanical extract of Morus alba linne root bark and Puerariae radix) and metformin, losartan, and linagliptin in the steady state. Three studies were conducted as randomized, open-label, 2-period, 2-treatment, multiple-dose, 2-way crossover designs. Eligible subjects received metformin (500 mg twice daily), losartan (50 mg once daily), or linagliptin (5 mg once daily) with DW1029M (300 mg × 2T twice daily) every 12 hours on days 1 through 6 and a single dose on the morning of day 7. Coadministration of DW1029M with metformin, losartan, or linagliptin had no clinically relevant effects based on the area under the plasma concentration-time curve (AUCτ ) geometric least-squares mean ratio (GMR) - AUCτ GMR, 89.7; 90% confidence interval (CI), 81.0-99.4 for metformin; AUCτ GMR, 96.2; 90%CI, 86.3-107.1 for losartan; and AUCτ GMR, 89.7; 90%CI, 83.2-96.6 for linagliptin. In addition, coadministration of DW1029M did not have any clinically meaningful effect on the maximum plasma concentration (Cmax,ss ) - Cmax,ss GMR, 87.3; 90%CI, 76.2-100.0 for metformin; Cmax,ss GMR, 90.5; 90%CI, 78.3-104.6 for losartan; and Cmax,ss GMR, 81.4; 90%CI, 69.5-95.3 for linagliptin. Coadministration of DW1029M with metformin, losartan, or linagliptin was well tolerated.

  10. In Vitro and In Vivo Drug-Drug Interaction Studies to Assess the Effect of Abiraterone Acetate, Abiraterone, and Metabolites of Abiraterone on CYP2C8 Activity.

    PubMed

    Monbaliu, Johan; Gonzalez, Martha; Bernard, Apexa; Jiao, James; Sensenhauser, Carlo; Snoeys, Jan; Stieltjes, Hans; Wynant, Inneke; Smit, Johan W; Chien, Caly

    2016-10-01

    Abiraterone acetate, the prodrug of the cytochrome P450 C17 inhibitor abiraterone, plus prednisone is approved for treatment of metastatic castration-resistant prostate cancer. We explored whether abiraterone interacts with drugs metabolized by CYP2C8, an enzyme responsible for the metabolism of many drugs. Abiraterone acetate and abiraterone and its major metabolites, abiraterone sulfate and abiraterone sulfate N-oxide, inhibited CYP2C8 in human liver microsomes, with IC50 values near or below the peak total concentrations observed in patients with metastatic castration-resistant prostate cancer (IC50 values: 1.3-3.0 µM, 1.6-2.9 µM, 0.044-0.15 µM, and 5.4-5.9 µM, respectively). CYP2C8 inhibition was reversible and time-independent. To explore the clinical relevance of the in vitro data, an open-label, single-center study was conducted comprising 16 healthy male subjects who received a single 15-mg dose of the CYP2C8 substrate pioglitazone on day 1 and again 1 hour after the administration of abiraterone acetate 1000 mg on day 8. Plasma concentrations of pioglitazone, its active M-III (keto derivative) and M-IV (hydroxyl derivative) metabolites, and abiraterone were determined for up to 72 hours after each dose. Abiraterone acetate increased exposure to pioglitazone; the geometric mean ratio (day 8/day 1) was 125 [90% confidence interval (CI), 99.9-156] for Cmax and 146 (90% CI, 126-171) for AUClast Exposure to M-III and M-IV was reduced by 10% to 13%. Plasma abiraterone concentrations were consistent with previous studies. These results show that abiraterone only weakly inhibits CYP2C8 in vivo.

  11. Prediction of the overall renal tubular secretion and hepatic clearance of anionic drugs and a renal drug-drug interaction involving organic anion transporter 3 in humans by in vitro uptake experiments.

    PubMed

    Watanabe, Takao; Kusuhara, Hiroyuki; Watanabe, Tomoko; Debori, Yasuyuki; Maeda, Kazuya; Kondo, Tsunenori; Nakayama, Hideki; Horita, Shigeru; Ogilvie, Brian W; Parkinson, Andrew; Hu, Zhuohan; Sugiyama, Yuichi

    2011-06-01

    The present study investigated prediction of the overall renal tubular secretion and hepatic clearances of anionic drugs based on in vitro transport studies. The saturable uptake of eight drugs, most of which were OAT3 substrates (rosuvastatin, pravastatin, pitavastatin, valsartan, olmesartan, trichlormethiazide, p-aminohippurate, and benzylpenicillin) by freshly prepared human kidney slices underestimated the overall intrinsic clearance of the tubular secretion; therefore, a scaling factor of 10 was required for in vitro-in vivo extrapolation. We examined the effect of gemfibrozil and its metabolites, gemfibrozil glucuronide and the carboxylic metabolite, gemfibrozil M3, on pravastatin uptake by human kidney slices. The inhibition study using human kidney slices suggests that OAT3 plays a predominant role in the renal uptake of pravastatin. Comparison of unbound concentrations and K(i) values (1.5, 9.1, and 4.0 μM, for gemfibrozil, gemfibrozil glucuronide, and gemfibrozil M3, respectively) suggests that the mechanism of the interaction is due mainly to inhibition by gemfibrozil and gemfibrozil glucuronide. Furthermore, extrapolation of saturable uptake by cryopreserved human hepatocytes predicts clearance comparable with the observed hepatic clearance although fluvastatin and rosuvastatin required a scaling factor of 11 and 6.9, respectively. This study suggests that in vitro uptake assays using human kidney slices and hepatocytes provide a good prediction of the overall tubular secretion and hepatic clearances of anionic drugs and renal drug-drug interactions. It is also recommended that in vitro-in vivo extrapolation be performed in animals to obtain more reliable prediction.

  12. The consequence of regional gradients of P-gp and CYP3A4 for drug-drug interactions by P-gp inhibitors and the P-gp/CYP3A4 interplay in the human intestine ex vivo.

    PubMed

    Li, Ming; de Graaf, Inge A M; van de Steeg, Evita; de Jager, Marina H; Groothuis, Geny M M

    2017-04-01

    Intestinal P-gp and CYP3A4 work coordinately to reduce the intracellular concentration of drugs, and drug-drug interactions (DDIs) based on this interplay are of clinical importance and require pre-clinical investigation. Using precision-cut intestinal slices (PCIS) of human jejunum, ileum and colon, we investigated the P-gp/CYP3A4 interplay and related DDIs with P-gp inhibitors at the different regions of the human intestine with quinidine (Qi), dual substrate of P-gp and CYP3A4, as probe. All the P-gp inhibitors increased the intracellular concentrations of Qi by 2.1-2.6 fold in jejunum, 2.6-3.8 fold in ileum but only 1.2-1.3 fold in colon, in line with the different P-gp expression in these intestinal regions. The selective P-gp inhibitors (CP100356 and PSC833) enhanced 3-hydroxy-quinidine (3OH-Qi) in jejunum and ileum, while dual inhibitors of P-gp and CYP3A4 (verapamil and ketoconazole) decreased the 3OH-Qi production, despite of the increased intracellular Qi concentration, due to inhibition of CYP3A4. The outcome of DDIs based on P-gp/CYP3A4 interplay, shown as remarkable changes in the intracellular concentration of both the parent drug and the metabolite, varied among the intestinal regions, probably due to the different expression of P-gp and CYP3A4, and were different from those found in rat PCIS, which may have important implications for the disposition and toxicity of drugs and their metabolites.

  13. Validation of membrane vesicle-based breast cancer resistance protein and multidrug resistance protein 2 assays to assess drug transport and the potential for drug-drug interaction to support regulatory submissions.

    PubMed

    Elsby, Robert; Smith, Veronica; Fox, Lisa; Stresser, David; Butters, Caroline; Sharma, Pradeep; Surry, Dominic D

    2011-09-01

    Breast cancer resistance protein (BCRP) and multidrug resistance protein 2 (MRP2) can play a role in the absorption, distribution, metabolism, and excretion of drugs, impacting on the potential for drug-drug interactions. This study has characterized insect cell- and mammalian cell-derived ABC-transporter-expressing membrane vesicle test systems and validated methodologies for evaluation of candidate drugs as substrates or inhibitors of BCRP or MRP2. Concentration-dependent uptake of BCRP ([³H]oestrone 3-sulfate, [³H]methotrexate, [³H]rosuvastatin) and MRP2 ([³H]oestradiol 17β-glucuronide, [³H]pravastatin, carboxydichlorofluorescein) substrates, and inhibitory potencies (IC₅₀) of BCRP (sulfasalazine, novobiocin, fumitremorgin C) and MRP2 (benzbromarone, MK-571, terfenadine) inhibitors were determined. The apparent K(m) for probes [³H]oestrone 3-sulfate and [³H]oestradiol 17β-glucuronide was determined in insect cell vesicles to be 7.4 ± 1.7 and 105 ± 8.3 µM, respectively. All other substrates exhibited significant uptake ratios. Positive control inhibitors sulfasalazine and benzbromarone gave IC₅₀ values of 0.74 ± 0.18 and 36 ± 6.1 µM, respectively. All other inhibitors exhibited concentration-dependent inhibition. There was no significant difference in parameters generated between test systems. On the basis of the validation results, acceptance criteria to identify substrates/inhibitors of BCRP and MRP2 were determined for insect cell vesicles. The approach builds on earlier validations to support drug registration and extends from those cell-based systems to encompass assay formats using membrane vesicles.

  14. Development of an enantioselective assay for simultaneous separation of venlafaxine and O-desmethylvenlafaxine by micellar electrokinetic chromatography-tandem mass spectrometry: Application to the analysis of drug-drug interaction.

    PubMed

    Liu, Yijin; Jann, Michael; Vandenberg, Chad; Eap, Chin B; Shamsi, Shahab A

    2015-11-13

    To-date, there has been no effective chiral capillary electrophoresis-mass spectrometry (CE-MS) method reported for the simultaneous enantioseparation of the antidepressant drug, venlafaxine (VX) and its structurally-similar major metabolite, O-desmethylvenlafaxine (O-DVX). This is mainly due to the difficulty of identifying MS compatible chiral selector, which could provide both high enantioselectivity and sensitive MS detection. In this work, poly-sodium N-undecenoyl-L,L-leucylalaninate (poly-L,L-SULA) was employed as a chiral selector after screening several dipeptide polymeric chiral surfactants. Baseline separation of both O-DVX and VX enantiomers was achieved in 15 min after optimizing the buffer pH, poly-L,L-SULA concentration, nebulizer pressure and separation voltage. Calibration curves in spiked plasma (recoveries higher than 80%) were linear over the concentration range 150-5000 ng/mL for both VX and O-DVX. The limit of detection (LOD) was found to be as low as 30 ng/mL and 21 ng/mL for O-DVX and VX, respectively. This method was successfully applied to measure the plasma concentrations of human volunteers receiving VX or O-DVX orally when co-administered without and with indinivar therapy. The results suggest that micellar electrokinetic chromatography electrospray ionization-tandem mass spectrometry (MEKC-ESI-MS/MS) is an effective low cost alternative technique for the pharmacokinetics and pharmacodynamics studies of both O-DVX and VX enantiomers. The technique has potential to identify drug-drug interaction involving VX and O-DVX enantiomers while administering indinivar therapy.

  15. Development of an enantioselective assay for simultaneous separation of venlafaxine and O-desmethylvenlafaxine by micellar electrokinetic chromatography-tandem mass spectrometry: Application to the analysis of drug-drug interaction

    PubMed Central

    Liu, Yijin; Jann, Michael; Vandenberg, Chad; Eap, Chin B.; A.Shamsi, Shahab

    2016-01-01

    To-date, there has been no effective chiral capillary electrophoresis-mass spectrometry (CE-MS) method reported for the simultaneous enantioseparation of the antidepressant drug, venlafaxine (VX) and its structurally-similar major metabolite, O-desmethylvenlafaxine (O-DVX). This is mainly due to the difficulty of identifying MS compatible chiral selector, which could provide both high enantioselectivity and sensitive MS detection. In this work, poly-sodium N-undecenoyl-L,L-leucylalaninate (poly-L,L-SULA) was employed as a chiral selector after screening several dipeptide polymeric chiral surfactants. Baseline separation of both O-DVX and VX enantiomers was achieved in 15 min after optimizing the buffer pH, poly-L L-SULA concentration, nebulizer pressure and separation voltage. Calibration curves in spiked plasma (recoveries higher than 80%) were linear over the concentration range 150–5,000 ng/mL for both VX and O-DVX. The limit of detection (LOD) was found to be as low as 30 ng/mL and 21 ng/mL for O-DVX and VX, respectively. This method was successfully applied to measure the plasma concentrations of human volunteers receiving VX or O-DVX orally when co-administered without and with indinivar therapy. The results suggest that micellar electrokinetic chromatography electrospray ionization-tandem mass spectrometry (MEKC-ESI-MS/MS) is an effective low cost alternative technique for the pharmacokinetics and pharmacodynamics studies of both O-DVX and VX enantiomers. The technique has potential to identify drug-drug interaction involving VX and O-DVX enantiomers while administering indinivar therapy. PMID:26460073

  16. Parameter-free determination of actual temperature at chemical freeze-out in nuclear interactions

    NASA Astrophysics Data System (ADS)

    Panagiotou, A. D.; Mavromanolakis, G.; Tzoulis, J.

    1995-07-01

    We propose a method to determine the actual temperature at chemical freeze-out in relativistic nucleus-nucleus collisions, using the experimental μq/T and μs/T values, obtained from strange particle ratios. We employ the Hadron Gas formalism, assuming only local thermal equilibration, to relate the quarkchemical potential and temperature. This relation constrains the allowed values of μq/T, μs/T and T, enabling the determination of the actual temperature. Comparison of the inverse slope parameter of the mT-distributions with the actual temperature determines the transverse flow velocity of the fireball matter. Knowledge of these quantities is essential in determining the EoS of nuclear matter and in evaluating interactions with regard to a possible phase transition to QGP.

  17. Real-life data on potential drug-drug interactions in patients with chronic hepatitis C viral infection undergoing antiviral therapy with interferon-free DAAs in the PITER Cohort Study

    PubMed Central

    Kondili, Loreta A.; Gaeta, Giovanni Battista; Ieluzzi, Donatella; Zignego, Anna Linda; Monti, Monica; Gori, Andrea; Soria, Alessandro; Raimondo, Giovanni; Filomia, Roberto; Di Leo, Alfredo; Iannone, Andrea; Massari, Marco; Corsini, Romina; Gulminetti, Roberto; Gatti Comini, Alberto; Toniutto, Pierluigi; Dissegna, Denis; Russo, Francesco Paolo; Zanetto, Alberto; Rumi, Maria Grazia; Brancaccio, Giuseppina; Danieli, Elena; Brunetto, Maurizia Rossana; Weimer, Liliana Elena; Quaranta, Maria Giovanna; Vella, Stefano; Puoti, Massimo

    2017-01-01

    Background There are few real-life data on the potential drug-drug interactions (DDIs) between anti-HCV direct-acting antivirals (DAAs) and the comedications used. Aim To assess the potential DDIs of DAAs in HCV-infected outpatients, according to the severity of liver disease and comedication used in a prospective multicentric study. Methods Data from patients in 15 clinical centers who had started a DAA regimen and were receiving comedications during March 2015 to March 2016 were prospectively evaluated. The DDIs for each regimen and comedication were assigned according to HepC Drug Interactions (www.hep-druginteractions.org). Results Of the 449 patients evaluated, 86 had mild liver disease and 363 had moderate-to-severe disease. The use of a single comedication was more frequent among patients with mild liver disease (p = 0.03), whereas utilization of more than three drugs among those with moderate-to-severe disease (p = 0.05). Of the 142 comedications used in 86 patients with mild disease, 27 (20%) may require dose adjustment/closer monitoring, none was contraindicated. Of the 322 comedications used in 363 patients with moderate-to-severe liver disease, 82 (25%) were classified with potential DDIs that required only monitoring and dose adjustments; 10 (3%) were contraindicated in severe liver disease. In patients with mild liver disease 30% (26/86) used at least one drug with a potential DDI whereas of the 363 patients with moderate-to-severe liver disease, 161 (44%) were at risk for one or more DDI. Conclusions Based on these results, we can estimate that 30–44% of patients undergoing DAA and taking comedications are at risk of a clinically significant DDI. This data indicates the need for increased awareness of potential DDI during DAA therapy, especially in patients with moderate-to-severe liver disease. For several drugs, the recommendation related to the DDI changes from “dose adjustment/closer monitoring”, in mild to moderate liver disease, to

  18. Competitive inhibition of the luminal efflux by multidrug and toxin extrusions, but not basolateral uptake by organic cation transporter 2, is the likely mechanism underlying the pharmacokinetic drug-drug interactions caused by cimetidine in the kidney.

    PubMed

    Ito, Sumito; Kusuhara, Hiroyuki; Yokochi, Miyu; Toyoshima, Junko; Inoue, Katsuhisa; Yuasa, Hiroaki; Sugiyama, Yuichi

    2012-02-01

    Cimetidine, an H₂ receptor antagonist, has been used to investigate the tubular secretion of organic cations in human kidney. We report a systematic comprehensive analysis of the inhibition potency of cimetidine for the influx and efflux transporters of organic cations [human organic cation transporter 1 (hOCT1) and hOCT2 and human multidrug and toxin extrusion 1 (hMATE1) and hMATE2-K, respectively]. Inhibition constants (K(i)) of cimetidine were determined by using five substrates [tetraethylammonium (TEA), metformin, 1-methyl-4-phenylpyridinium, 4-(4-(dimethylamino)styryl)-N-methylpyridinium, and m-iodobenzylguanidine]. They were 95 to 146 μM for hOCT2, providing at most 10% inhibition based on its clinically reported plasma unbound concentrations (3.6-7.8 μM). In contrast, cimetidine is a potent inhibitor of MATE1 and MATE2-K with K(i) values (μM) of 1.1 to 3.8 and 2.1 to 6.9, respectively. The same tendency was observed for mouse Oct1 (mOct1), mOct2, and mouse Mate1. Cimetidine showed a negligible effect on the uptake of metformin by mouse kidney slices at 20 μM. Cimetidine was administered to mice by a constant infusion to achieve a plasma unbound concentration of 21.6 μM to examine its effect on the renal disposition of Mate1 probes (metformin, TEA, and cephalexin) in vivo. The kidney- and liver-to-plasma ratios of metformin both were increased 2.4-fold by cimetidine, whereas the renal clearance was not changed. Cimetidine also increased the kidney-to-plasma ratio of TEA and cephalexin 8.0- and 3.3-fold compared with a control and decreased the renal clearance from 49 to 23 and 11 to 6.6 ml/min/kg, respectively. These results suggest that the inhibition of MATEs, but not OCT2, is a likely mechanism underlying the drug-drug interactions with cimetidine in renal elimination.

  19. Shadow-Reading Effect on Reading Comprehension: Actualization of Interactive Reading Comprehension: (A Vygotskyan View!)

    ERIC Educational Resources Information Center

    Sadeghi, Elahe; Afghari, Akbar; Zarei, Gholam-Reza

    2016-01-01

    Reading comprehension has been the main concern for second language learners and researchers. Today with rising interests towards Vygotskyan Sociocultural Theory (SCT), attempts have been made to insert Vygotskyan approach into Foreign/Second Language classrooms emphasizing the role of scaffolding and meaningful interactions to promote learners'…

  20. Development and application of a UPLC-MS/MS method for simultaneous determination of fenofibric acid and berberine in rat plasma: application to the drug-drug pharmacokinetic interaction study of fenofibrate combined with berberine after oral administration in rats.

    PubMed

    Li, Guofei; Yang, Fan; Liu, Mei; Su, Xianying; Zhao, Mingming; Zhao, Limei

    2016-07-01

    With the purpose of carrying out pharmacokinetic interaction studies ofnberberine (BBR) and fenofibrate (FBT), an UPLC-MS/MS method has been developed and validated. The analytes, BBR and fenofibric acid (FBA, metabolite of FBT) and the internal standard, tetrahydropalmatine, were extracted with dichloromethane-diethyl ether (3:2, v/v) and separated on an Agilent Eclipse XDB C18 column using a mobile phase composed of acetonitrile and water. With positive ion electrospray ionization, the analytes were monitored on a triple quadrupole mass spectrometer in multiple reaction monitoring mode. Linear calibration curves were obtained over the concentration ranges of 0.1-100.0 ng/mL for BBR and 10.0-50,000.0 ng/mL for FBA. For BBR and FBA, the intra- and inter-day precisions were <11.5 and 11.9%, respectively. The accuracy was within 11.7% and 11.3%. The mean recoveries of BBR at three concentrations of 0.2, 20.0, 80.0 ng/mL were >85.6%, and those of FBA at three concentrations of 20.0, 2500.0, 40,000.0 ng/mL were >87.9%. Consequently, the proposed method was applied to the pharmacokinetic interaction study of FBT combined with BBR after oral administration in rats and was proved to be sensitive, specific and reliable to analyze BBR and FBA in biological samples simultaneously. Copyright © 2016 John Wiley & Sons, Ltd.

  1. Pharmacokinetic drug-drug interaction between ethinyl estradiol and gestodene, administered as a transdermal fertility control patch, and two CYP3A4 inhibitors and a CYP3A4 substrate.

    PubMed

    Winkler, Julia; Goldammer, Mark; Ludwig, Matthias; Rohde, Beate; Zurth, Christian

    2015-12-01

    Pharmacokinetic (PK) interactions between the cytochrome P450 3A4 (CYP3A4) pathway and transdermally administered ethinyl estradiol (EE) and gestodene (GSD) were investigated. This paper reports the findings of three open-label, intra-individual, one-way crossover, Phase I trials. In two studies, women used a novel contraceptive patch for 3 weeks during two 4-week study periods; in the second period, the CYP3A4 inhibitors erythromycin (Study 1) or ketoconazole (Study 2) were administered concurrently. In a third study, women received single doses of the CYP3A4 model substrate midazolam, alone and after 3 weeks of concurrent patch application. In each period, the EE/GSD patch (delivering low EE and GSD doses resulting in the same systemic exposure as a combined oral contraceptive containing 0.02 mg EE and 0.06 mg GSD) was applied once weekly for 3 weeks, with one patch-free week. Erythromycin, ketoconazole, and midazolam were administered orally. Main outcome measures were area under the curves (AUCs) and maximum plasma concentration (C max) of EE, and total and unbound GSD (Studies 1 and 2). AUC and C max of midazolam (Study 3). Co-administration of CYP3A4 inhibitors did not affect EE metabolism, and had only weak effects on the PK of total and unbound GSD. The patch had no clinically relevant effect on metabolism of the CYP3A4 substrate midazolam.

  2. Comparison of Observed Beta Cloth Interactions with Simulated and Actual Space Environment

    NASA Technical Reports Server (NTRS)

    Kamenetzy, R. R.; Finckenor, M. M.

    1999-01-01

    A common component of multilayer insulation blankets is beta cloth, a woven fiberglass cloth impregnated with Teflon(TM). It is planned for extensive use on the International Space Station. The Environmental Etl'ects Group of the Marshall Space Flight Center Materials, Processing, and Manufacturing Department has investigated the impact of atomic oxygen (AO) and ultraviolet (UV) radiation on the optical properties of plain and aluminized beta cloth. both in the laboratory and as part of long-duration flight experiments. These investigations indicate that beta cloth is susceptible to darkening in the presence of UV radiation, dependent on the additives used. AO interactions resulted in bleaching of the beta cloth.

  3. Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, Part II.

    PubMed

    Armstrong, Scott C; Cozza, Kelly L

    2003-01-01

    Pharmacokinetic drug-drug interactions with codeine, dihydrocodeine, hydrocodone, oxycodone, and buprenorphine are reviewed in this column. These compounds have a very similar chemical structure to morphine. Unlike morphine, which is metabolized chiefly through conjugation reactions with uridine diphosphate glucuronosyl transferase (UGT) enzymes, these five drugs are metabolized both through oxidative reactions by the cytochrome P450 (CYP450) enzyme and conjugation by UGT enzymes. There is controversy as to whether codeine, dihydrocodeine, and hydrocodone are actually prodrugs requiring activation by the CYP450 2D6 enzyme or UGT enzymes. Oxycodone and buprenorphine, however, are clearly not prodrugs and are metabolized by the CYP450 2D6 and 3A4 enzymes, respectively. Knowledge of this metabolism assists in the understanding for the potential of drug-drug interactions with these drugs. This understanding is important so that clinicians can choose the proper dosages for analgesia and anticipate potential drug-drug interactions.

  4. Lipopolysaccharide Density and Structure Govern the Extent and Distance of Nanoparticle Interaction with Actual and Model Bacterial Outer Membranes

    DOE PAGES

    Jacobson, Kurt H.; Gunsolus, Ian L.; Kuech, Thomas R.; ...

    2015-07-24

    We report that design of nanomedicines and nanoparticle-based antimicrobial and antifouling formulations, and assessment of the potential implications of nanoparticle release into the environment require understanding nanoparticle interaction with bacterial surfaces. Here we demonstrate electrostatically driven association of functionalized nanoparticles with lipopolysaccharides of Gram-negative bacterial outer membranes and find that lipopolysaccharide structure influences the extent and location of binding relative to the lipid-solution interface. By manipulating the lipopolysaccharide content in Shewanella oneidensis outer membranes, we observed electrostatically driven interaction of cationic gold nanoparticles with the lipopolysaccharide-containing leaflet. We probed this interaction by quartz crystal microbalance with dissipation monitoring (QCM-D) andmore » second harmonic generation (SHG) using solid-supported lipopolysaccharide-containing bilayers. Association of cationic nanoparticles increased with lipopolysaccharide content, while no association of anionic nanoparticles was observed. The harmonic-dependence of QCM-D measurements suggested that a population of the cationic nanoparticles was held at a distance from the outer leaflet-solution interface of bilayers containing smooth lipopolysaccharides (those bearing a long O-polysaccharide). Additionally, smooth lipopolysaccharides held the bulk of the associated cationic particles outside of the interfacial zone probed by SHG. Lastly, our results demonstrate that positively charged nanoparticles are more likely to interact with Gram-negative bacteria than are negatively charged particles, and this interaction occurs primarily through lipopolysaccharides.« less

  5. Lipopolysaccharide Density and Structure Govern the Extent and Distance of Nanoparticle Interaction with Actual and Model Bacterial Outer Membranes

    SciTech Connect

    Jacobson, Kurt H.; Gunsolus, Ian L.; Kuech, Thomas R.; Troiano, Julianne M.; Melby, Eric S.; Lohse, Samuel E.; Hu, Dehong; Chrisler, William B.; Murphy, Catherine J.; Orr, Galya; Geiger, Franz M.; Haynes, Christy L.; Pedersen, Joel A.

    2015-07-24

    We report that design of nanomedicines and nanoparticle-based antimicrobial and antifouling formulations, and assessment of the potential implications of nanoparticle release into the environment require understanding nanoparticle interaction with bacterial surfaces. Here we demonstrate electrostatically driven association of functionalized nanoparticles with lipopolysaccharides of Gram-negative bacterial outer membranes and find that lipopolysaccharide structure influences the extent and location of binding relative to the lipid-solution interface. By manipulating the lipopolysaccharide content in Shewanella oneidensis outer membranes, we observed electrostatically driven interaction of cationic gold nanoparticles with the lipopolysaccharide-containing leaflet. We probed this interaction by quartz crystal microbalance with dissipation monitoring (QCM-D) and second harmonic generation (SHG) using solid-supported lipopolysaccharide-containing bilayers. Association of cationic nanoparticles increased with lipopolysaccharide content, while no association of anionic nanoparticles was observed. The harmonic-dependence of QCM-D measurements suggested that a population of the cationic nanoparticles was held at a distance from the outer leaflet-solution interface of bilayers containing smooth lipopolysaccharides (those bearing a long O-polysaccharide). Additionally, smooth lipopolysaccharides held the bulk of the associated cationic particles outside of the interfacial zone probed by SHG. Lastly, our results demonstrate that positively charged nanoparticles are more likely to interact with Gram-negative bacteria than are negatively charged particles, and this interaction occurs primarily through lipopolysaccharides.

  6. Lipopolysaccharide Density and Structure Govern the Extent and Distance of Nanoparticle Interaction with Actual and Model Bacterial Outer Membranes

    PubMed Central

    Jacobson, Kurt H.; Gunsolus, Ian L.; Kuech, Thomas R.; Troiano, Julianne M.; Melby, Eric S.; Lohse, Samuel E.; Hu, Dehong; Chrisler, William B.; Murphy, Catherine J.; Orr, Galya; Geiger, Franz M.; Haynes, Christy L.; Pedersen, Joel A.

    2015-01-01

    Design of nanomedicines and nanoparticle-based antimicrobial and antifouling formulations and assessment of the potential implications of nanoparticle release into the environment requires understanding nanoparticle interaction with bacterial surfaces. Here we demonstrate the electrostatically driven association of functionalized nanoparticles with lipopolysaccharides of Gram-negative bacterial outer membranes and find that lipopolysaccharide structure influences the extent and location of binding relative to the outer leaflet-solution interface. By manipulating the lipopolysaccharide content in Shewanella oneidensis outer membranes, we observed the electrostatically driven interaction of cationic gold nanoparticles with the lipopolysaccharide-containing leaflet. We probed this interaction by quartz crystal microbalance with dissipation monitoring (QCM-D) and second harmonic generation (SHG) using solid-supported lipopolysaccharide-containing bilayers. The association of cationic nanoparticles increased with lipopolysaccharide content, while no association of anionic nanoparticles was observed. The harmonic-dependence of QCM-D measurements suggested that a population of the cationic nanoparticles was held at a distance from the outer leaflet-solution interface of bilayers containing smooth lipopolysaccharides (those bearing a long O-polysaccharide). Additionally, smooth lipopolysaccharides held the bulk of the associated cationic particles outside of the interfacial zone probed by SHG. Our results demonstrate that positively charged nanoparticles are more likely to interact with Gram-negative bacteria than are negatively charged particles, and this interaction occurs primarily through lipopolysaccharides. PMID:26207769

  7. Elucidation of the biochemical basis for a clinical drug-drug interaction between atorvastatin and 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid (CP-778875), a subtype selective agonist of the peroxisome proliferator-activated receptor alpha.

    PubMed

    Kalgutkar, Amit S; Chen, Danny; Varma, Manthena V; Feng, Bo; Terra, Steven G; Scialis, Renato J; Rotter, Charles J; Frederick, Kosea S; West, Mark A; Goosen, Theunis C; Gosset, James R; Walsky, Robert L; Francone, Omar L

    2013-11-01

    1. 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid (CP-778875), an agonist of the peroxisome proliferator-activated receptor alpha, has been evaluated in the clinic to treat dyslipidemia and type 2 diabetes mellitus. Herein, we investigate the effect of CP-778875 on the pharmacokinetics of atorvastatin acid and its metabolites in humans. 2. The study incorporated a fixed-sequence design conducted in two groups. Group A was designed to estimate the effects of multiple doses of CP-778875 on the single dose pharmacokinetics of atorvastatin. Subjects in group A (n = 26) received atorvastatin (40 mg) on days 1 and 9 and CP-778875 (1.0 mg QD) on days 5-12. Group B was designed to examine the effects of multiple doses of atorvastatin on the single dose pharmacokinetics of CP-778875. Subjects in group B (n = 29) received CP-778875 (0.3 mg) on days 1 and 9 and atorvastatin (40 mg QD) on days 5-12. 3. Mean maximum serum concentration (Cmax) and area under the curve of atorvastatin were increased by 45% and 20%, respectively, upon co-administration with CP-778875. Statistically significant increases in the systemic exposure of ortho- and para-hydroxyatorvastatin were also observed upon concomitant dosing with CP-778875. CP-778875 pharmacokinetics, however, were not impacted upon concomitant dosing with atorvastatin. 4.  Inhibition of organic anion transporting polypeptide 1B1 by CP-778875 (IC50 = 2.14 ± 0.40 μM) could be the dominant cause of the pharmacokinetic interaction as CP-778875 did not exhibit significant inhibition of cytochrome P450 3A4/3A5, multidrug resistant protein 1 or breast cancer resistant protein, which are also involved in the hepatobiliary disposition of atorvastatin.

  8. Theoretical and experimental studies of the stability of drug-drug interact

    NASA Astrophysics Data System (ADS)

    Soares, Monica F. R.; Alves, Lariza D. S.; Nadvorny, Daniela; Soares-Sobrinho, José L.; Rolim-Neto, Pedro J.

    2016-11-01

    Several factors can intervene in the molecular properties and consequently in the stability of drugs. The molecular complexes formation often occur due to favor the formation of hydrogen bonds, leading the system to configuration more energy stable. This work we aim to investigate through theoretical and experimental methods the relation between stability and properties of molecular complexes the molecular complex formed between the drugs, efavirenz (EFV), lamivudine (3TC) and zidovudine (AZT). With this study was possible determining the most stable complex formed between the compounds evaluated. In addition the energy and structural properties of the complex formed in relation to its individual components allowed us to evaluate the stability of the same.

  9. An Appraisal of Drug-Drug Interactions with Green Tea (Camellia sinensis).

    PubMed

    Albassam, Ahmed A; Markowitz, John S

    2017-01-24

    This review summarizes published in vitro, animal, and clinical studies investigating the effects of green tea (Camellia sinensis) extract and associated catechins on drug-metabolizing enzymes and drug transporters. In vitro studies suggest that green tea extract and its main catechin, (-)-epigallocatechin-3-gallate, to varying degrees, inhibit the activity of CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A4. UGT1A1 and UGT1A4 isoforms were also inhibited by (-)-epigallocatechin-3-gallate. Animal studies suggest green tea extract and/or (-)-epigallocatechin-3-gallate significantly increase the bioavailability of diltazem, verapamil, tamoxifen simvastatin, 5-fluorouracil, and nicardipine. Conversely, green tea extract and/or (-)-epigallocatechin-3-gallate reduce the bioavailability of quetiapine, sunitinib, clozapine, and nadolol. Of the few clinical studies available for review, it appears neither green tea extract nor (-)-epigallocatechin-3-gallate inhibit any major cytochrome P450 enzyme. Regarding drug transporters, in vitro studies indicate P-glycoprotein, organic anion transporting polypeptide 1A1, organic anion transporting polypeptide 1B1, organic anion transporting polypeptide 1B3, organic anion transporting polypeptide 2B1, organic cation transporter 1, organic cation transporter 2, multidrug and toxin extrusion 1, and multidrug and toxin extrusion 2-K are potentially inhibited by green tea extract. A clinical study indicates the organic anion transporting polypeptide 1A1 transporter is inhibited by (-)-epigallocatechin-3-gallate while P-glycoprotein is unaffected. In conclusion, the ingestion of green tea extract or its associated catechins is not expected to result in clinically significant influences on major cytochrome P450 or uridine 5'-diphospho-glucuronosyltransferase enzyme substrates or drugs serving as substrates of P-glycoprotein. However, some caution is advised in the consumption of significant amounts of green tea beverages or green tea extract in patients prescribed known substrates of organic anion transporting polypeptide, particularly those with a narrow therapeutic index.

  10. Design, Characterization, and Optimization of Controlled Drug Delivery System Containing Antibiotic Drug/s

    PubMed Central

    Shelate, Pragna; Dave, Divyang

    2016-01-01

    The objective of this work was design, characterization, and optimization of controlled drug delivery system containing antibiotic drug/s. Osmotic drug delivery system was chosen as controlled drug delivery system. The porous osmotic pump tablets were designed using Plackett-Burman and Box-Behnken factorial design to find out the best formulation. For screening of three categories of polymers, six independent variables were chosen for Plackett-Burman design. Osmotic agent sodium chloride and microcrystalline cellulose, pore forming agent sodium lauryl sulphate and sucrose, and coating agent ethyl cellulose and cellulose acetate were chosen as independent variables. Optimization of osmotic tablets was done by Box-Behnken design by selecting three independent variables. Osmotic agent sodium chloride, pore forming agent sodium lauryl sulphate, and coating agent cellulose acetate were chosen as independent variables. The result of Plackett-Burman and Box-Behnken design and ANOVA studies revealed that osmotic agent and pore former had significant effect on the drug release up to 12 hr. The observed independent variables were found to be very close to predicted values of most satisfactory formulation which demonstrates the feasibility of the optimization procedure in successful development of porous osmotic pump tablets containing antibiotic drug/s by using sodium chloride, sodium lauryl sulphate, and cellulose acetate as key excipients. PMID:27610247

  11. The Course of Actualization

    ERIC Educational Resources Information Center

    De Smet, Hendrik

    2012-01-01

    Actualization is traditionally seen as the process following syntactic reanalysis whereby an item's new syntactic status manifests itself in new syntactic behavior. The process is gradual in that some new uses of the reanalyzed item appear earlier or more readily than others. This article accounts for the order in which new uses appear during…

  12. How do patients actually experience and use art in hospitals? The significance of interaction: a user-oriented experimental case study

    PubMed Central

    Nielsen, Stine L.; Fich, Lars B.; Roessler, Kirsten K.; Mullins, Michael F.

    2017-01-01

    ABSTRACT This article aims to understand patient wellbeing and satisfaction and to qualify the current guidelines for the application of art in hospitals. Employing anthropological methods, we focus on the interactional aspects of art in health interventions. A user-oriented study ranked 20 paintings, followed by an experiment using paintings in the dayroom of five medical wards. Fieldwork was done over a two-week period. During the first week, dayrooms were configured without the presence of art and in the second week were configured with the artworks. Semi-structured interviews, observation, participant observation and informal conversation were carried out and were informed by thermal cameras, which monitored the usage, patient occupation and flow in two of the dayrooms. The study shows that art contributes to creating an environment and atmosphere where patients can feel safe, socialize, maintain a connection to the world outside the hospital and support their identity. We conclude that the presence of visual art in hospitals contributes to health outcomes by improving patient satisfaction as an extended form of health care. The article draws attention to further research perspectives and methods associated with the development of art in hospitals.

  13. The Drug-Drug Effects of Rhein on the Pharmacokinetics and Pharmacodynamics of Clozapine in Rat Brain Extracellular Fluid by In Vivo Microdialysis.

    PubMed

    Hou, Mei-Ling; Lin, Chi-Hung; Lin, Lie-Chwen; Tsai, Tung-Hu

    2015-10-01

    Clozapine, an atypical antipsychotic agent, is highly effective in treatment-resistant schizophrenia; however, its major side effect is constipation. Instead of laxatives, rhein is a pharmacologically active component found in Rheum palmatum L., a medicinal herbal remedy for constipation. The purpose of this study is to determine whether rhein impacts the pharmacokinetics (PK) and pharmacodynamics (PD) of clozapine in brain when used to relieve clozapine-induced constipation. Here, we have investigated not only the PK of clozapine in blood but also the effects of rhein on the PK of clozapine in blood and in brain extracellular fluid together with the PD effects on neurotransmitters in extracellular fluid. The concentrations of clozapine and norclozapine in biologic samples were measured by ultra-performance liquid chromatography-tandem mass spectrometry. The drug-drug effects of rhein on extracellular neurotransmitter efflux in the rat medial prefrontal cortex (mPFC) produced by clozapine were assayed by high-performance liquid chromatography-electrochemical detection. The results demonstrate that the clozapine PK was nonlinear. Pretreatment with rhein for 7 days increased the total blood concentration of clozapine, but significantly reduced the unbound clozapine concentrations in the mPFC by approximately 3-fold. Furthermore, 7 days of rhein pretreatment thoroughly abolished the efflux of dopamine and its metabolite (3,4-dihydroxyphenylacetic acid) and altered the profile of homovanillic acid, another metabolite of dopamine, in the mPFC. In conclusion, rhein was found to substantially decrease clozapine and norclozapine concentrations in the mPFC dialysate, and this is accompanied by lower concentrations in the neurotransmitters in the same biophase. These findings suggest that a detailed clinical study for drug-drug interactions is recommended.

  14. Drug-Drug Molecular Salt Hydrate of an Anticancer Drug Gefitinib and a Loop Diuretic Drug Furosemide: An Alternative for Multidrug Treatment.

    PubMed

    Thorat, Shridhar H; Sahu, Sanjay Kumar; Patwadkar, Manjusha V; Badiger, Manohar V; Gonnade, Rajesh G

    2015-12-01

    A 1:1 monohydrate salt containing gefitinib, an orally administrated chemotherapy treatment for lung and breast cancers and furosemide, a loop diuretic drug, commonly used in the treatment of hypertension and edema, has been prepared. The molecular salt crystallized in triclinic P-1 space group. The C-O bond lengths (~1.26 Å) in the COOH group show that proton transfer has occurred from furosemide to morpholine moiety of the gefitinib suggesting cocrystal to be ionic. The morpholine moiety of the gefitinib showed significant conformational change because of its involvement in conformation dictating the strong N-H···O hydrogen bonding interaction. The strong hydrogen bonding interaction between gefitinib and furosemide places their benzene rings in stacking mode to facilitate the generation of π-stack dimers. The neighboring dimers are bridged to each other via water molecule through N-H···O, C-H···O, O-H···N, and O-H···O interactions. The remarkable stability of the salt hydrate could be attributed to the strong hydrogen bonding interactions in the crystal structure. Interestingly, release of water from the lattice at 140°C produced new anhydrous salt that has better solubility and dissolution rate than salt hydrate. The drug-drug molecular salt may have some bearing on the treatment of patient suffering from anticancer and hypertension.

  15. Management of HIV/AIDS in older patients–drug/drug interactions and adherence to antiretroviral therapy

    PubMed Central

    Burgess, Mary J; Zeuli, John D; Kasten, Mary J

    2015-01-01

    Patients with human immunodeficiency virus (HIV) are living longer with their disease, as HIV has become a chronic illness managed with combination antiretroviral therapy (cART). This has led to an increasing number of patients greater than 50 years old living successfully with HIV. As the number of older adults with HIV has increased, there are special considerations for the management of HIV. Older adults with HIV must be monitored for drug side effects and toxicities. Their other non-HIV comorbidities should also be considered when choosing a cART regimen. Older adults with HIV have unique issues related to medication compliance. They are more likely than the younger HIV patients to have vision loss, cognitive impairment, and polypharmacy. They may have lower expectations of their overall health status. Depression and financial concerns, especially if they are on a fixed income, may also contribute to noncompliance in the aging HIV population. PMID:26604826

  16. Impact on abiraterone pharmacokinetics and safety: Open-label drug-drug interaction studies with ketoconazole and rifampicin.

    PubMed

    Bernard, Apexa; Vaccaro, Nicole; Acharya, Milin; Jiao, James; Monbaliu, Johan; De Vries, Ronald; Stieltjes, Hans; Yu, Margaret; Tran, Namphuong; Chien, Caly

    2015-01-01

    We evaluated the impact of a strong CYP3A4 inhibitor, ketoconazole, and a strong inducer, rifampicin, on the pharmacokinetic (PK) exposure of abiraterone in two studies in healthy men. All subjects received 1,000 mg of abiraterone acetate on Days 1 and 14. Study A subjects (n = 20) received 400 mg ketoconazole on Days 11-16. Study B subjects (n = 19) received 600 mg rifampicin on Days 8-13. Serial PK sampling was done on Days 1 and 14. Study A: When given with ketoconazole, abiraterone exposure increased by 9% for maximum plasma concentration (Cmax ) and 15% for area under the plasma concentration-time curve from 0 to time of the last quantifiable concentration (AUClast ) and AUC from time 0 to infinity (AUC∞ ) compared to abiraterone acetate alone. Study B: When given with rifampicin, abiraterone exposure was reduced to 45% for Cmax and AUC∞ and to 42% for AUClast compared to abiraterone acetate alone. Ketoconazole had no clinically meaningful impact on abiraterone exposure. Rifampicin decreased abiraterone exposure by half. Hence, strong CYP3A4 inducers should be avoided or used with careful evaluation of clinical efficacy when administered with abiraterone acetate.

  17. Linguistic Theory and Actual Language.

    ERIC Educational Resources Information Center

    Segerdahl, Par

    1995-01-01

    Examines Noam Chomsky's (1957) discussion of "grammaticalness" and the role of linguistics in the "correct" way of speaking and writing. It is argued that the concern of linguistics with the tools of grammar has resulted in confusion, with the tools becoming mixed up with the actual language, thereby becoming the central…

  18. Potential drug interactions in patients given antiretroviral therapy

    PubMed Central

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

    2016-01-01

    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. PMID:27878224

  19. How People Actually Use Thermostats

    SciTech Connect

    Meier, Alan; Aragon, Cecilia; Hurwitz, Becky; Mujumdar, Dhawal; Peffer, Therese; Perry, Daniel; Pritoni, Marco

    2010-08-15

    Residential thermostats have been a key element in controlling heating and cooling systems for over sixty years. However, today's modern programmable thermostats (PTs) are complicated and difficult for users to understand, leading to errors in operation and wasted energy. Four separate tests of usability were conducted in preparation for a larger study. These tests included personal interviews, an on-line survey, photographing actual thermostat settings, and measurements of ability to accomplish four tasks related to effective use of a PT. The interviews revealed that many occupants used the PT as an on-off switch and most demonstrated little knowledge of how to operate it. The on-line survey found that 89% of the respondents rarely or never used the PT to set a weekday or weekend program. The photographic survey (in low income homes) found that only 30% of the PTs were actually programmed. In the usability test, we found that we could quantify the difference in usability of two PTs as measured in time to accomplish tasks. Users accomplished the tasks in consistently shorter times with the touchscreen unit than with buttons. None of these studies are representative of the entire population of users but, together, they illustrate the importance of improving user interfaces in PTs.

  20. The actual goals of geoethics

    NASA Astrophysics Data System (ADS)

    Nemec, Vaclav

    2014-05-01

    The most actual goals of geoethics have been formulated as results of the International Conference on Geoethics (October 2013) held at the geoethics birth-place Pribram (Czech Republic): In the sphere of education and public enlightenment an appropriate needed minimum know how of Earth sciences should be intensively promoted together with cultivating ethical way of thinking and acting for the sustainable well-being of the society. The actual activities of the Intergovernmental Panel of Climate Changes are not sustainable with the existing knowledge of the Earth sciences (as presented in the results of the 33rd and 34th International Geological Congresses). This knowledge should be incorporated into any further work of the IPCC. In the sphere of legislation in a large international co-operation following steps are needed: - to re-formulate the term of a "false alarm" and its legal consequences, - to demand very consequently the needed evaluation of existing risks, - to solve problems of rights of individuals and minorities in cases of the optimum use of mineral resources and of the optimum protection of the local population against emergency dangers and disasters; common good (well-being) must be considered as the priority when solving ethical dilemmas. The precaution principle should be applied in any decision making process. Earth scientists presenting their expert opinions are not exempted from civil, administrative or even criminal liabilities. Details must be established by national law and jurisprudence. The well known case of the L'Aquila earthquake (2009) should serve as a serious warning because of the proven misuse of geoethics for protecting top Italian seismologists responsible and sentenced for their inadequate superficial behaviour causing lot of human victims. Another recent scandal with the Himalayan fossil fraud will be also documented. A support is needed for any effort to analyze and to disclose the problems of the deformation of the contemporary

  1. Student Exposure to Actual Patients in the Classroom.

    ERIC Educational Resources Information Center

    Chisholm, Marie A.; McCall, Charles Y.; Francisco, George E., Jr.; Poirier, Sylvie

    1997-01-01

    Two clinical courses for first-year dental students were designed to develop students' interaction skills through actual patient case presentations and discussions and an interdisciplinary teaching approach. Results indicate students preferred the case presentations, with or without lecture, to the lecture-only approach and felt they learned more…

  2. Unified QSAR approach to antimicrobials. 4. Multi-target QSAR modeling and comparative multi-distance study of the giant components of antiviral drug-drug complex networks.

    PubMed

    Prado-Prado, Francisco J; Martinez de la Vega, Octavio; Uriarte, Eugenio; Ubeira, Florencio M; Chou, Kuo-Chen; González-Díaz, Humberto

    2009-01-15

    One limitation of almost all antiviral Quantitative Structure-Activity Relationships (QSAR) models is that they predict the biological activity of drugs against only one species of virus. Consequently, the development of multi-tasking QSAR models (mt-QSAR) to predict drugs activity against different species of virus is of the major vitally important. These mt-QSARs offer also a good opportunity to construct drug-drug Complex Networks (CNs) that can be used to explore large and complex drug-viral species databases. It is known that in very large CNs we can use the Giant Component (GC) as a representative sub-set of nodes (drugs) and but the drug-drug similarity function selected may strongly determines the final network obtained. In the three previous works of the present series we reported mt-QSAR models to predict the antimicrobial activity against different fungi [Gonzalez-Diaz, H.; Prado-Prado, F. J.; Santana, L.; Uriarte, E. Bioorg.Med.Chem.2006, 14, 5973], bacteria [Prado-Prado, F. J.; Gonzalez-Diaz, H.; Santana, L.; Uriarte E. Bioorg.Med.Chem.2007, 15, 897] or parasite species [Prado-Prado, F.J.; González-Díaz, H.; Martinez de la Vega, O.; Ubeira, F.M.; Chou K.C. Bioorg.Med.Chem.2008, 16, 5871]. However, including these works, we do not found any report of mt-QSAR models for antivirals drug, or a comparative study of the different GC extracted from drug-drug CNs based on different similarity functions. In this work, we used Linear Discriminant Analysis (LDA) to fit a mt-QSAR model that classify 600 drugs as active or non-active against the 41 different tested species of virus. The model correctly classifies 143 of 169 active compounds (specificity=84.62%) and 119 of 139 non-active compounds (sensitivity=85.61%) and presents overall training accuracy of 85.1% (262 of 308 cases). Validation of the model was carried out by means of external predicting series, classifying the model 466 of 514, 90.7% of compounds. In order to illustrate the performance of the

  3. Drug interactions in general dental practice--considerations for the dental practitioner.

    PubMed

    Dawoud, B E S; Roberts, A; Yates, J M

    2014-01-01

    The aim of this article is to explore the diverse and complex nature of pharmacological drug-drug interactions in the general dental practice setting. Using published NHS statistics, this article will highlight medications for common medical conditions that could interact with frequently prescribed drugs by the general dental practitioner.

  4. HIV/HCV Antiviral Drug Interactions in the Era of Direct-acting Antivirals

    PubMed Central

    Rice, Donald P.; Faragon, John J.; Banks, Sarah; Chirch, Lisa M.

    2016-01-01

    Abstract Therapy for human immunodeficiency virus (HIV) and chronic hepatitis C has evolved over the past decade, resulting in better control of infection and clinical outcomes; however, drug-drug interactions remain a significant hazard. Joint recommendations from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America regarding drug-drug interactions between HIV antiretroviral agents and direct-acting antiviral agents for treatment of hepatitis C virus (HCV) infection are reviewed here. This review is oriented to facilitate appropriate selection of an antiviral therapy regimen for HCV infection based on the choice of antiretroviral therapy being administered and, if necessary, switching antiretroviral regimens. PMID:27777891

  5. Drug-Drug Interaction between the Direct-Acting Antiviral Regimen of Ombitasvir-Paritaprevir-Ritonavir plus Dasabuvir and the HIV Antiretroviral Agent Dolutegravir or Abacavir plus Lamivudine.

    PubMed

    Khatri, Amit; Trinh, Roger; Zhao, Weihan; Podsadecki, Thomas; Menon, Rajeev

    2016-10-01

    The direct-acting antiviral regimen of 25 mg ombitasvir-150 mg paritaprevir-100 mg ritonavir once daily (QD) plus 250 mg dasabuvir twice daily (BID) is approved for the treatment of hepatitis C virus genotype 1 infection, including patients coinfected with human immunodeficiency virus. This study was performed to evaluate the pharmacokinetic, safety, and tolerability effects of coadministering the regimen of 3 direct-acting antivirals with two antiretroviral therapies (dolutegravir or abacavir plus lamivudine). Healthy volunteers (n = 24) enrolled in this phase I, single-center, open-label, multiple-dose study received 50 mg dolutegravir QD for 7 days or 300 mg abacavir plus 300 mg lamivudine QD for 4 days, the 3-direct-acting-antiviral regimen for 14 days, followed by the 3-direct-acting-antiviral regimen with dolutegravir or abacavir plus lamivudine for 10 days. Pharmacokinetic parameters were calculated to compare combination therapy with 3-direct-acting-antiviral or antiretroviral therapy alone, and safety/tolerability were assessed throughout the study. Coadministration of the 3-direct-acting-antiviral regimen increased the geometric mean maximum plasma concentration (Cmax) and the area under the curve (AUC) of dolutegravir by 22% (central value ratio [90% confidence intervals], 1.219 [1.153, 1.288]) and 38% (1.380 [1.295, 1.469]), respectively. Abacavir geometric mean Cmax and AUC values decreased by 13% (0.873 [0.777, 0.979]) and 6% (0.943 [0.901, 0.986]), while those for lamivudine decreased by 22% (0.778 [0.719, 0.842]) and 12% (0.876 [0.821, 0.934]). For the 3-direct-acting-antiviral regimen, geometric mean Cmax and AUC during coadministration were within 18% of measurements made during administration of the 3-direct-acting-antiviral regimen alone, although trough concentrations for paritaprevir were 34% (0.664 [0.585, 0.754]) and 27% (0.729 [0.627, 0.847]) lower with dolutegravir and abacavir-lamivudine, respectively. All study treatments were generally well tolerated, with no evidence of increased rates of adverse events during combination administration. These data indicate that the 3-direct-acting-antiviral regimen can be administered with dolutegravir or abacavir plus lamivudine without dose adjustment.

  6. Cardiac drug-drug interaction between HCV-NS5B pronucleotide inhibitors and amiodarone is determined by their specific diastereochemistry

    PubMed Central

    Lagrutta, Armando; Regan, Christopher P.; Zeng, Haoyu; Imredy, John P.; Koeplinger, Kenneth; Morissette, Pierre; Liu, Liping; Wollenberg, Gordon; Brynczka, Christopher; Lebrón, José; DeGeorge, Joseph; Sannajust, Frederick

    2017-01-01

    Severe bradycardia/bradyarrhythmia following coadministration of the HCV-NS5B prodrug sofosbuvir with amiodarone was recently reported. Our previous preclinical in vivo experiments demonstrated that only certain HCV-NS5B prodrugs elicit bradycardia when combined with amiodarone. In this study, we evaluate the impact of HCV-NS5B prodrug phosphoramidate diastereochemistry (D-/L-alanine, R-/S-phosphoryl) in vitro and in vivo. Co-applied with amiodarone, L-ala,SP prodrugs increased beating rate and decreased beat amplitude in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), but D-ala,RP produgs, including MK-3682, did not. Stereochemical selectivity on emerging bradycardia was confirmed in vivo. Diastereomer pairs entered cells equally well, and there was no difference in intracellular accumulation of L-ala,SP metabolites ± amiodarone, but no D-ala,RP metabolites were detected. Cathepsin A (CatA) inhibitors attenuated L-ala,SP prodrug metabolite formation, yet exacerbated L-ala,SP + amiodarone effects, implicating the prodrugs in these effects. Experiments indicate that pharmacological effects and metabolic conversion to UTP analog are L-ala,SP prodrug-dependent in cardiomyocytes. PMID:28327633

  7. Quantitative Prediction of CYP3A4 Induction: Impact of Measured, Free and Intracellular Perpetrator Concentrations from Human Hepatocyte Induction Studies on Drug-Drug Interaction Predictions.

    PubMed

    Sun, Yongkai; Chothe, Paresh P; Sager, Jennifer; Tsao, Hong; Moore, Amanda; Laitinen, Leena; Hariparsad, Niresh

    2017-03-23

    Typically, concentration-response curves are generated based upon nominal new chemical entity (NCE) concentrations for in-vitro-to-in-vivo extrapolation of CYP3A4 induction. These data are then used to determine the induction risk of an NCE employing various modeling approaches. The limitation to this practice is that it assumes the hepatocyte culture model to be a static system. In the current study, we assessed whether correcting for; 1) changes in perpetrator concentration in the induction medium during the assay incubation period, 2) perpetrator binding to proteins in the induction medium and 3) non-specific binding of perpetrator can improve the accuracy of CYP3A4 induction predictions. Of the seven validation compounds used in our studies, we noted significant parent loss and a high degree of medium protein binding with pioglitazone and rosiglitazone while pleconaril had very high non-specific binding. Predictions of clinical induction were determined using the relative induction score, basic-static, and mechanistic static models. In general, we observed that the precision and accuracy of our predictions improved when corrections were made for measured medium concentrations, medium protein binding, and non-specific binding of the perpetrator. As a follow-up, we noted that for substrates of uptake transporters, the use of free intracellular concentrations could result in improved predictions of CYP3A4 induction. In conclusion, our data indicates that quantifying perpetrator levels in induction medium can improve the accuracy and precision of CYP3A4 induction predictions. Continued efforts are necessary to improve our understanding of the impact of free intracellular concentrations on induction predictions.

  8. Single concentration loss of activity assay provides an improved assessment of drug-drug interaction risk compared to IC50-shift.

    PubMed

    Wong, Simon G; Lee, Mey; Wong, Bradley K

    2016-11-01

    1. The utility of two abbreviated, higher-throughput assays [IC50-shift and the loss of activity (LOA) assay] to evaluate time-dependent inhibition (TDI) of 24 structurally related compounds was compared. 2. Good correlation (R(2)  = 0.90) between % inhibition and kinact/KI suggested that the LOA assay has utility as an indicator of TDI potential. Weaker correlation was observed for the shifted IC50 (IC50(T = 30)) (R(2) = 0.61) and the fold-shift in IC50 (R(2) = 0.17). 3. Primary mechanism for poor correlation was depletion of active enzyme at concentrations > 1 μM leading to greater than predicted inhibition in the IC50-shift assay. 4. Previously reported strong correlations between IC50(T = 30) and kinact/KI were found to be dependent on potent TDI compounds with kinact/KI > 30; correlation was reduced for moderate inhibitors (kinact/KI < 30). LOA assay maintained good correlation even when strong TDI compounds were excluded. 5. LOA assay (% Inhibition at 30 min, 10 μM) was a good predictor of in vivo DDI (AUCr), providing a graded response with low potential for false negatives or positives. IC50-shift assay had bias for over-predicting in vivo DDI and was more likely to identify false positives.

  9. Cardiac drug-drug interaction between HCV-NS5B pronucleotide inhibitors and amiodarone is determined by their specific diastereochemistry.

    PubMed

    Lagrutta, Armando; Regan, Christopher P; Zeng, Haoyu; Imredy, John P; Koeplinger, Kenneth; Morissette, Pierre; Liu, Liping; Wollenberg, Gordon; Brynczka, Christopher; Lebrón, José; DeGeorge, Joseph; Sannajust, Frederick

    2017-03-22

    Severe bradycardia/bradyarrhythmia following coadministration of the HCV-NS5B prodrug sofosbuvir with amiodarone was recently reported. Our previous preclinical in vivo experiments demonstrated that only certain HCV-NS5B prodrugs elicit bradycardia when combined with amiodarone. In this study, we evaluate the impact of HCV-NS5B prodrug phosphoramidate diastereochemistry (D-/L-alanine, R-/S-phosphoryl) in vitro and in vivo. Co-applied with amiodarone, L-ala,SP prodrugs increased beating rate and decreased beat amplitude in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), but D-ala,RP produgs, including MK-3682, did not. Stereochemical selectivity on emerging bradycardia was confirmed in vivo. Diastereomer pairs entered cells equally well, and there was no difference in intracellular accumulation of L-ala,SP metabolites ± amiodarone, but no D-ala,RP metabolites were detected. Cathepsin A (CatA) inhibitors attenuated L-ala,SP prodrug metabolite formation, yet exacerbated L-ala,SP + amiodarone effects, implicating the prodrugs in these effects. Experiments indicate that pharmacological effects and metabolic conversion to UTP analog are L-ala,SP prodrug-dependent in cardiomyocytes.

  10. Characterization of the Effect of Drug-Drug Interaction on Protein Binding in Concurrent Administration of Sulfamethoxazol and Diclofenac Sodium Using Bovine Serum Albumin

    PubMed Central

    Hossain, Md Kamal; Khatun, Amina; Rahman, Mahmudur; Akter, Md Nahid; Chowdhury, Sadia Afreen; Alam, SM Mahbubul

    2016-01-01

    Purpose: This project was aimed to determine the effect of concurrent administration of sulfamethoxazole and diclofenac sodium. Methods: Equilibrium dialysis method was adopted to study different protein binding aspects of sulfamethoxazole and diclofenac sodium. Results: Sulfamethoxazole showed two types of association constants; high affinity constant 29.0±0.20×106 M-1 with lower number of binding sites of 0.7±1 and low affinity constant 1.13±0.20×106 M-1 with higher number of binding sites of 3.45±1 at pH 7.4 and 40 °C temperature. Diclofenac sodium showed high affinity constant 33.66±0.20×106 M-1 with lower number of binding sites of 1.01±1 and low affinity constant 1.72±0.20×106 M-1 with higher number of binding sites of 6.40±1 at the same condition. Site specific probe displacement data implied that site-I, warfarin sodium site, was the high affinity site, while site-II, diazepam site, was the low affinity site for these drugs. During concurrent administration, sulfamethoxazole increased the free concentration of diclofenac sodium from 17.5±0.14% to 70.0±0.014% in absence and from 22.5±0.07% to 83.0±0.014% in presence of site-I specific probe. Diclofenac sodium also increased the free concentration of sulfamethoxazole from 2.8±0.07% to 52.0±0.14% and from 8.5±0.014% to 64.4±0.07% in absence and presence of site-I specific probe respectively. Conclusion: The study revealed that the concurrent administration of sulfamethoxazole and diclofenac sodium may result drug concentration alteration in blood. PMID:28101466

  11. Investigation of drug-drug interaction via mechanism-based inhibition of cytochrome P450 3A by macrolides in dexamethasone-treated female rats.

    PubMed

    Kanazu, Takushi; Sato, Norihito; Kadono, Kyoko; Touchi, Akira; Takeda, Yuri; Yamaguchi, Yoshitaka; Baba, Takahiko

    2012-05-01

    The in vitro and in vivo inhibition of cytochrome P450 (CYP) 3A with mechanism-based inhibition (MBI) by macrolides was investigated using dexamethasone-treated female rats (DEX-female rats). In the in vitro CYP inhibition studies using erythromycin (ERM) and clarithromycin (CAM), similar inhibition responses were observed between human and DEX-female rat liver microsomes, however, there were fewer effects in intact male rats. The ex vivo study showed that midazolam (MDZ) metabolism in liver microsomes of DEX-female rats was reduced by ERM administration and the inhibitory effect was increased with increasing ERM doses, indicating that metabolite intermediate complex formation caused irreversible inhibition of CYP3A activity in DEX-female rats as well as in humans. In the in vivo studies, ERM and CAM significantly increased the area under the plasma concentration-time curve of MDZ and decreased the total clearance in DEX-female rats. It was concluded that the DDIs via MBI of CYP3A following macrolide administration in humans could be reproduced in female rats, suggesting that DEX-female rats can serve as an in vivo model for assessing this DDI in humans.

  12. Assessment of Drug-Drug Interaction between Warfarin and Aprepitant and Its Effects on PT-INR of Patients Receiving Anticancer Chemotherapy.

    PubMed

    Takaki, Junpei; Ohno, Yoshiyuki; Yamada, Maiko; Yamaguchi, Ryo; Hisaka, Akihiro; Suzuki, Hiroshi

    2016-05-01

    Aprepitant is a known inducer of CYP2C9, the main warfarin-metabolizing enzyme. Consequently, co-administration of these two drugs may result in reduction of the anticoagulation activity of warfarin. However, the nature and degree of time-dependent changes in prothrombin time international normalized ratio (PT-INR) after aprepitant and warfarin co-treatment in patients receiving anticancer chemotherapy has not been elucidated. We retrospectively examined the changes in warfarin dose, PT-INR, and warfarin sensitivity index (WSI; average of PT-INR value/average of daily warfarin dose) during four weeks, i.e., one week before and three weeks after aprepitant administration. The mean and standard deviation values of WSI for one week before and one, two, and three weeks after the beginning of aprepitant administration were 0.51±0.22 (1.00, n=34), 0.74±0.30 (1.53±0.59, n=30), 0.38±0.15 (0.82±0.22, n=28), and 0.46±0.29 (0.87±0.23, n=24), respectively. Values in parentheses represent relative changes versus WSI of one week before and number of subjects. Although the mean value of WSI significantly increased one week after aprepitant administration compared to that at one week before the administration, it in turn significantly decreased two weeks after compared to one week before (paired t-test, p<0.05 after Bonferoni correction). In patients taking warfarin, PT-INR should be carefully monitored for at least two weeks after the beginning of aprepitant administration because it may fluctuate with both aprepitant and chemotherapy during this period.

  13. Realizing actual feedback control of complex network

    NASA Astrophysics Data System (ADS)

    Tu, Chengyi; Cheng, Yuhua

    2014-06-01

    In this paper, we present the concept of feedbackability and how to identify the Minimum Feedbackability Set of an arbitrary complex directed network. Furthermore, we design an estimator and a feedback controller accessing one MFS to realize actual feedback control, i.e. control the system to our desired state according to the estimated system internal state from the output of estimator. Last but not least, we perform numerical simulations of a small linear time-invariant dynamics network and a real simple food network to verify the theoretical results. The framework presented here could make an arbitrary complex directed network realize actual feedback control and deepen our understanding of complex systems.

  14. Children's Rights and Self-Actualization Theory.

    ERIC Educational Resources Information Center

    Farmer, Rod

    1982-01-01

    Educators need to seriously reflect upon the concept of children's rights. Though the idea of children's rights has been debated numerous times, the idea remains vague and shapeless; however, Maslow's theory of self-actualization can provide the children's rights idea with a needed theoretical framework. (Author)

  15. Group Counseling for Self-Actualization.

    ERIC Educational Resources Information Center

    Streich, William H.; Keeler, Douglas J.

    Self-concept, creativity, growth orientation, an integrated value system, and receptiveness to new experiences are considered to be crucial variables to the self-actualization process. A regular, year-long group counseling program was conducted with 85 randomly selected gifted secondary students in the Farmington, Connecticut Public Schools. A…

  16. Culture Studies and Self-Actualization Theory.

    ERIC Educational Resources Information Center

    Farmer, Rod

    1983-01-01

    True citizenship education is impossible unless students develop the habit of intelligently evaluating cultures. Abraham Maslow's theory of self-actualization, a theory of innate human needs and of human motivation, is a nonethnocentric tool which can be used by teachers and students to help them understand other cultures. (SR)

  17. Humanistic Education and Self-Actualization Theory.

    ERIC Educational Resources Information Center

    Farmer, Rod

    1984-01-01

    Stresses the need for theoretical justification for the development of humanistic education programs in today's schools. Explores Abraham Maslow's hierarchy of needs and theory of self-actualization. Argues that Maslow's theory may be the best available for educators concerned with educating the whole child. (JHZ)

  18. Developing Human Resources through Actualizing Human Potential

    ERIC Educational Resources Information Center

    Clarken, Rodney H.

    2012-01-01

    The key to human resource development is in actualizing individual and collective thinking, feeling and choosing potentials related to our minds, hearts and wills respectively. These capacities and faculties must be balanced and regulated according to the standards of truth, love and justice for individual, community and institutional development,…

  19. 50 CFR 253.16 - Actual cost.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 50 Wildlife and Fisheries 9 2011-10-01 2011-10-01 false Actual cost. 253.16 Section 253.16 Wildlife and Fisheries NATIONAL MARINE FISHERIES SERVICE, NATIONAL OCEANIC AND ATMOSPHERIC ADMINISTRATION, DEPARTMENT OF COMMERCE AID TO FISHERIES FISHERIES ASSISTANCE PROGRAMS Fisheries Finance Program §...

  20. Whiteheadian Actual Entitities and String Theory

    NASA Astrophysics Data System (ADS)

    Bracken, Joseph A.

    2012-06-01

    In the philosophy of Alfred North Whitehead, the ultimate units of reality are actual entities, momentary self-constituting subjects of experience which are too small to be sensibly perceived. Their combination into "societies" with a "common element of form" produces the organisms and inanimate things of ordinary sense experience. According to the proponents of string theory, tiny vibrating strings are the ultimate constituents of physical reality which in harmonious combination yield perceptible entities at the macroscopic level of physical reality. Given that the number of Whiteheadian actual entities and of individual strings within string theory are beyond reckoning at any given moment, could they be two ways to describe the same non-verifiable foundational reality? For example, if one could establish that the "superject" or objective pattern of self- constitution of an actual entity vibrates at a specific frequency, its affinity with the individual strings of string theory would be striking. Likewise, if one were to claim that the size and complexity of Whiteheadian 'societies" require different space-time parameters for the dynamic interrelationship of constituent actual entities, would that at least partially account for the assumption of 10 or even 26 instead of just 3 dimensions within string theory? The overall conclusion of this article is that, if a suitably revised understanding of Whiteheadian metaphysics were seen as compatible with the philosophical implications of string theory, their combination into a single world view would strengthen the plausibility of both schemes taken separately. Key words: actual entities, subject/superjects, vibrating strings, structured fields of activity, multi-dimensional physical reality.

  1. Interactions of anabolic steroids.

    PubMed

    Kopera, H

    1993-01-01

    Drug-drug interactions, or interference between drugs and other treatments, depend on many factors and are therefore difficult to predict. However, a number are clearly established in the case of anabolic-androgenic steroids. The beneficial interactions between anabolic steroids and radiotherapy or cytostatic drugs respectively are of therapeutic value. Adjuvant treatment with anabolic compounds in patients undergoing radiation and/or cytostatic therapy is beneficial because it can prevent or reduce depression of erythropoiesis, granulopoiesis and thrombopoiesis. It also diminishes protein catabolism, supports recovery, improves the general condition of the patient and minimizes radiation sickness. Potentially adverse interactions with anabolic steroids must be expected in the case of oral anticoagulants and antidiabetic drugs, since sensitivity to each of the latter is increased. This makes it particularly advisable to monitor patients receiving either oral anticoagulants or antidiabetic treatment concurrently with anabolic drugs.

  2. Role of cytochrome P450 in drug interactions

    PubMed Central

    Bibi, Zakia

    2008-01-01

    Drug-drug interactions have become an important issue in health care. It is now realized that many drug-drug interactions can be explained by alterations in the metabolic enzymes that are present in the liver and other extra-hepatic tissues. Many of the major pharmacokinetic interactions between drugs are due to hepatic cytochrome P450 (P450 or CYP) enzymes being affected by previous administration of other drugs. After coadministration, some drugs act as potent enzyme inducers, whereas others are inhibitors. However, reports of enzyme inhibition are very much more common. Understanding these mechanisms of enzyme inhibition or induction is extremely important in order to give appropriate multiple-drug therapies. In future, it may help to identify individuals at greatest risk of drug interactions and adverse events. PMID:18928560

  3. The Actual Apollo 13 Prime Crew

    NASA Technical Reports Server (NTRS)

    1970-01-01

    The actual Apollo 13 lunar landing mission prime crew from left to right are: Commander, James A. Lovell Jr., Command Module pilot, John L. Swigert Jr.and Lunar Module pilot, Fred W. Haise Jr. The original Command Module pilot for this mission was Thomas 'Ken' Mattingly Jr. but due to exposure to German measles he was replaced by his backup, Command Module pilot, John L. 'Jack' Swigert Jr.

  4. Explosive Percolation Transition is Actually Continuous

    NASA Astrophysics Data System (ADS)

    da Costa, R. A.; Dorogovtsev, S. N.; Goltsev, A. V.; Mendes, J. F. F.

    2010-12-01

    Recently a discontinuous percolation transition was reported in a new “explosive percolation” problem for irreversible systems [D. Achlioptas, R. M. D’Souza, and J. Spencer, Science 323, 1453 (2009)SCIEAS0036-807510.1126/science.1167782] in striking contrast to ordinary percolation. We consider a representative model which shows that the explosive percolation transition is actually a continuous, second order phase transition though with a uniquely small critical exponent of the percolation cluster size. We describe the unusual scaling properties of this transition and find its critical exponents and dimensions.

  5. Neoadjuvant Treatment in Rectal Cancer: Actual Status

    PubMed Central

    Garajová, Ingrid; Di Girolamo, Stefania; de Rosa, Francesco; Corbelli, Jody; Agostini, Valentina; Biasco, Guido; Brandi, Giovanni

    2011-01-01

    Neoadjuvant (preoperative) concomitant chemoradiotherapy (CRT) has become a standard treatment of locally advanced rectal adenocarcinomas. The clinical stages II (cT3-4, N0, M0) and III (cT1-4, N+, M0) according to International Union Against Cancer (IUCC) are concerned. It can reduce tumor volume and subsequently lead to an increase in complete resections (R0 resections), shows less toxicity, and improves local control rate. The aim of this review is to summarize actual approaches, main problems, and discrepancies in the treatment of locally advanced rectal adenocarcinomas. PMID:22295206

  6. Air resistance measurements on actual airplane parts

    NASA Technical Reports Server (NTRS)

    Weiselsberger, C

    1923-01-01

    For the calculation of the parasite resistance of an airplane, a knowledge of the resistance of the individual structural and accessory parts is necessary. The most reliable basis for this is given by tests with actual airplane parts at airspeeds which occur in practice. The data given here relate to the landing gear of a Siemanms-Schuckert DI airplane; the landing gear of a 'Luftfahrzeug-Gesellschaft' airplane (type Roland Dlla); landing gear of a 'Flugzeugbau Friedrichshafen' G airplane; a machine gun, and the exhaust manifold of a 269 HP engine.

  7. Internet Radicalization: Actual Threat or Phantom Menace?

    DTIC Science & Technology

    2012-09-01

    interaction set by the communicated message.26 The unique global social network functionality of the Internet may facilitate group formation analogous to...correlations and interactions . Future research can apply the same method to evaluate and synthesize the different disciplinary approaches employed by the social ...functionalities. A framework is used to evaluate vulnerabilities identified by the psychological, sociological and social -psychological elements of

  8. 7 CFR 1437.101 - Actual production history.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 10 2010-01-01 2010-01-01 false Actual production history. 1437.101 Section 1437.101... Determining Yield Coverage Using Actual Production History § 1437.101 Actual production history. Actual production history (APH) is the unit's record of crop yield by crop year for the APH base period. The...

  9. 7 CFR 1437.101 - Actual production history.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 10 2012-01-01 2012-01-01 false Actual production history. 1437.101 Section 1437.101... Determining Yield Coverage Using Actual Production History § 1437.101 Actual production history. Actual production history (APH) is the unit's record of crop yield by crop year for the APH base period. The...

  10. 7 CFR 1437.101 - Actual production history.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 10 2011-01-01 2011-01-01 false Actual production history. 1437.101 Section 1437.101... Determining Yield Coverage Using Actual Production History § 1437.101 Actual production history. Actual production history (APH) is the unit's record of crop yield by crop year for the APH base period. The...

  11. 7 CFR 1437.101 - Actual production history.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 10 2014-01-01 2014-01-01 false Actual production history. 1437.101 Section 1437.101... Determining Yield Coverage Using Actual Production History § 1437.101 Actual production history. Actual production history (APH) is the unit's record of crop yield by crop year for the APH base period. The...

  12. 7 CFR 1437.101 - Actual production history.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 10 2013-01-01 2013-01-01 false Actual production history. 1437.101 Section 1437.101... Determining Yield Coverage Using Actual Production History § 1437.101 Actual production history. Actual production history (APH) is the unit's record of crop yield by crop year for the APH base period. The...

  13. The actual status of Astronomy in Moldova

    NASA Astrophysics Data System (ADS)

    Gaina, A.

    The astronomical research in the Republic of Moldova after Nicolae Donitch (Donici)(1874-1956(?)) were renewed in 1957, when a satellites observations station was open in Chisinau. Fotometric observations and rotations of first Soviet artificial satellites were investigated under a program SPIN put in action by the Academy of Sciences of former Socialist Countries. The works were conducted by Assoc. prof. Dr. V. Grigorevskij, which conducted also research in variable stars. Later, at the beginning of 60-th, an astronomical Observatory at the Chisinau State University named after Lenin (actually: the State University of Moldova), placed in Lozovo-Ciuciuleni villages was open, which were coordinated by Odessa State University (Prof. V.P. Tsesevich) and the Astrosovet of the USSR. Two main groups worked in this area: first conducted by V. Grigorevskij (till 1971) and second conducted by L.I. Shakun (till 1988), both graduated from Odessa State University. Besides this research areas another astronomical observations were made: Comets observations, astroclimate and atmospheric optics in collaboration with the Institute of the Atmospheric optics of the Siberian branch of the USSR (V. Chernobai, I. Nacu, C. Usov and A.F. Poiata). Comets observations were also made since 1988 by D. I. Gorodetskij which came to Chisinau from Alma-Ata and collaborated with Ukrainean astronomers conducted by K.I. Churyumov. Another part of space research was made at the State University of Tiraspol since the beggining of 70-th by a group of teaching staff of the Tiraspol State Pedagogical University: M.D. Polanuer, V.S. Sholokhov. No a collaboration between Moldovan astronomers and Transdniestrian ones actually exist due to War in Transdniestria in 1992. An important area of research concerned the Radiophysics of the Ionosphere, which was conducted in Beltsy at the Beltsy State Pedagogical Institute by a group of teaching staff of the University since the beginning of 70-th: N. D. Filip, E

  14. Caustic-Side Solvent Extraction: Prediction of Cesium Extraction for Actual Wastes and Actual Waste Simulants

    SciTech Connect

    Delmau, L.H.; Haverlock, T.J.; Sloop, F.V., Jr.; Moyer, B.A.

    2003-02-01

    This report presents the work that followed the CSSX model development completed in FY2002. The developed cesium and potassium extraction model was based on extraction data obtained from simple aqueous media. It was tested to ensure the validity of the prediction for the cesium extraction from actual waste. Compositions of the actual tank waste were obtained from the Savannah River Site personnel and were used to prepare defined simulants and to predict cesium distribution ratios using the model. It was therefore possible to compare the cesium distribution ratios obtained from the actual waste, the simulant, and the predicted values. It was determined that the predicted values agree with the measured values for the simulants. Predicted values also agreed, with three exceptions, with measured values for the tank wastes. Discrepancies were attributed in part to the uncertainty in the cation/anion balance in the actual waste composition, but likely more so to the uncertainty in the potassium concentration in the waste, given the demonstrated large competing effect of this metal on cesium extraction. It was demonstrated that the upper limit for the potassium concentration in the feed ought to not exceed 0.05 M in order to maintain suitable cesium distribution ratios.

  15. The role of hepatic transport and metabolism in the interactions between pravastatin or repaglinide and two rOatp inhibitors in rats.

    PubMed

    Badolo, Lassina; Bundgaard, Christoffer; Garmer, Mats; Jensen, Bente

    2013-07-16

    A change in the function or expression of hepatic drug transporters may have significant effect on the efficacy or safety of orally administered drugs. Although a number of clinical drug-drug interactions associated with hepatic transport proteins have been reported, in practice it is not always straightforward to discriminate other pathways (e.g. drug metabolism) from being involved in these interactions. The present study was designed to assess the interactions between organic anion transporting polypeptide (Oatp) substrates (pravastatin or repaglinide) and inhibitors (spironolactone or diphenhydramine) in vivo in rats. The mechanisms behind the interactions were then investigated using in vitro tools (isolated hepatocytes and rat liver microsomes). The results showed a significant increase in the systemic exposures of pravastatin (2.5-fold increase in AUC) and repaglinide (1.8-fold increase in AUC) after co-administration of spironolactone to rats. Diphenhydramine increased the AUC of repaglinide by 1.4-fold. The in vivo interactions observed in rats between Oatp substrates and inhibitors may a priori be classified as transport-mediated drug-drug interactions. However, mechanistic studies performed in vitro using both isolated rat hepatocytes and rat liver microsomes showed that the interaction between pravastatin and spironolactone may be solely linked to the inhibition of pravastatin uptake in liver. On the contrary, the inhibition of cytochrome P450 seemed to be the reason for the interactions observed between repaglinide and spironolactone. Although the function and structure of transport proteins may vary between rats and humans, the approach used in the present study can be applied to humans and help to understand the role of drug transport and drug metabolism in a given drug-drug interaction. This is important to predict and mitigate the risk of drug-drug interactions for a candidate drug in pre-clinical development, it is also important for the optimal

  16. Food and drug interactions: a general review.

    PubMed

    Ötles, Semih; Senturk, Ahmet

    2014-01-01

    Although it is well known and identified that drug-drug interactions exist, the recognition of importance of food and drug interactions to practice has been growing much slower. On the other hand, drug-food/nutrient interactions continue to grow with the common use of medications. Beside the awareness of this type of interactions, food-drug interaction studies are critical to evaluate appropriate dosing, timing, and formulation of new drug candidates. Drug-food interactions take place mechanistically due to altered intestinal transport and metabolism, or systemic distribution, metabolism and excretion. In addition, some people have greater risk of food and drug interactions who have a poor diet, have serious health problems, childrens and pregnant women. In this article, basic informations about importance, classifications, transporters and enzymes of drug and nutrient interaction are given and some specific examples of both drug and nutrients and influences on each other are included.

  17. Consequences of Predicted or Actual Asteroid Impacts

    NASA Astrophysics Data System (ADS)

    Chapman, C. R.

    2003-12-01

    Earth impact by an asteroid could have enormous physical and environmental consequences. Impactors larger than 2 km diameter could be so destructive as to threaten civilization. Since such events greatly exceed any other natural or man-made catastrophe, much extrapolation is necessary just to understand environmental implications (e.g. sudden global cooling, tsunami magnitude, toxic effects). Responses of vital elements of the ecosystem (e.g. agriculture) and of human society to such an impact are conjectural. For instance, response to the Blackout of 2003 was restrained, but response to 9/11 terrorism was arguably exaggerated and dysfunctional; would society be fragile or robust in the face of global catastrophe? Even small impacts, or predictions of impacts (accurate or faulty), could generate disproportionate responses, especially if news media reports are hyped or inaccurate or if responsible entities (e.g. military organizations in regions of conflict) are inadequately aware of the phenomenology of small impacts. Asteroid impact is the one geophysical hazard of high potential consequence with which we, fortunately, have essentially no historical experience. It is thus important that decision makers familiarize themselves with the hazard and that society (perhaps using a formal procedure, like a National Academy of Sciences study) evaluate the priority of addressing the hazard by (a) further telescopic searches for dangerous but still-undiscovered asteroids and (b) development of mitigation strategies (including deflection of an oncoming asteroid and on- Earth civil defense). I exemplify these issues by discussing several representative cases that span the range of parameters. Many of the specific physical consequences of impact involve effects like those of other geophysical disasters (flood, fire, earthquake, etc.), but the psychological and sociological aspects of predicted and actual impacts are distinctive. Standard economic cost/benefit analyses may not

  18. Neuromuscular adaptation to actual and simulated weightlessness

    NASA Technical Reports Server (NTRS)

    Edgerton, V. R.; Roy, R. R.

    1994-01-01

    The chronic "unloading" of the neuromuscular system during spaceflight has detrimental functional and morphological effects. Changes in the metabolic and mechanical properties of the musculature can be attributed largely to the loss of muscle protein and the alteration in the relative proportion of the proteins in skeletal muscle, particularly in the muscles that have an antigravity function under normal loading conditions. These adaptations could result in decrements in the performance of routine or specialized motor tasks, both of which may be critical for survival in an altered gravitational field, i.e., during spaceflight and during return to 1 G. For example, the loss in extensor muscle mass requires a higher percentage of recruitment of the motor pools for any specific motor task. Thus, a faster rate of fatigue will occur in the activated muscles. These consequences emphasize the importance of developing techniques for minimizing muscle loss during spaceflight, at least in preparation for the return to 1 G after spaceflight. New insights into the complexity and the interactive elements that contribute to the neuromuscular adaptations to space have been gained from studies of the role of exercise and/or growth factors as countermeasures of atrophy. The present chapter illustrates the inevitable interactive effects of neural and muscular systems in adapting to space. It also describes the considerable progress that has been made toward the goal of minimizing the functional impact of the stimuli that induce the neuromuscular adaptations to space.

  19. Non-actual motion: phenomenological analysis and linguistic evidence.

    PubMed

    Blomberg, Johan; Zlatev, Jordan

    2015-09-01

    Sentences with motion verbs describing static situations have been seen as evidence that language and cognition are geared toward dynamism and change (Talmy in Toward a cognitive semantics, MIT Press, Cambridge, 2000; Langacker in Concept, image, and symbol: the cognitive basis of grammar, Mouton de Gruyter, Berlin and New York, 1990). Different concepts have been used in the literature, e.g., fictive motion, subjective motion and abstract motion to denote this. Based on phenomenological analysis, we reinterpret such concepts as reflecting different motivations for the use of such constructions (Blomberg and Zlatev in Phenom Cogn Sci 13(3):395-418, 2014). To highlight the multifaceted character of the phenomenon, we propose the concept non-actual motion (NAM), which we argue is more compatible with the situated cognition approach than explanations such as "mental simulation" (e.g., Matlock in Studies in linguistic motivation, Mouton de Gruyter, Berlin, 2004). We investigate the expression of NAM by means of a picture-based elicitation task with speakers of Swedish, French and Thai. Pictures represented figures that either afford human motion or not (±afford); crossed with this, the figure extended either across the picture from a third-person perspective (3 pp) or from a first-person perspective (1 pp). All picture types elicited NAM-sentences with the combination [+afford, 1 pp] producing most NAM-sentences in all three languages. NAM-descriptions also conformed to language-specific patterns for the expression of actual motion. We conclude that NAM shows interaction between pre-linguistic motivations and language-specific conventions.

  20. Nutritional toxicology: basic principles and actual problems.

    PubMed

    Hathcock, J N

    1990-01-01

    Nutritional toxicology is a specialty that combines the backgrounds and research approaches of nutrition and toxicology. Many problems of substantial importance to health and food safety involve interactions of nutrition process and requirement with the effects of toxicological impact. Solution of these problems requires research that meets the procedural and design criteria of experimental nutrition and these of experimental toxicology. The relationships may be described in three basic categories: (1) influence of nutrition on toxicities; (2) influence of toxicants on nutrition; and (3) toxicities of nutrients. Trypsin inhibitor research, an example of diet impacting on toxicological response, illustrates the necessity of controlling nutritional composition aspects that can confound the results. Prolonged acetaminophen administration provides an example of the effects of toxicants on nutritional requirement and function which could be important for persons with marginal sulphur amino acid intake.

  1. External Validity of Contingent Valuation: Comparing Hypothetical and Actual Payments.

    PubMed

    Ryan, Mandy; Mentzakis, Emmanouil; Jareinpituk, Suthi; Cairns, John

    2016-10-09

    Whilst contingent valuation is increasingly used in economics to value benefits, questions remain concerning its external validity that is do hypothetical responses match actual responses? We present results from the first within sample field test. Whilst Hypothetical No is always an Actual No, Hypothetical Yes exceed Actual Yes responses. A constant rate of response reversals across bids/prices could suggest theoretically consistent option value responses. Certainty calibrations (verbal and numerical response scales) minimise hypothetical-actual discrepancies offering a useful solution. Helping respondents resolve uncertainty may reduce the discrepancy between hypothetical and actual payments and thus lead to more accurate policy recommendations. Copyright © 2016 John Wiley & Sons, Ltd.

  2. Food-drug interactions.

    PubMed

    Bushra, Rabia; Aslam, Nousheen; Khan, Arshad Yar

    2011-03-01

    The effect of drug on a person may be different than expected because that drug interacts with another drug the person is taking (drug-drug interaction), food, beverages, dietary supplements the person is consuming (drug-nutrient/food interaction) or another disease the person has (drug-disease interaction). A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. These interactions may occur out of accidental misuse or due to lack of knowledge about the active ingredients involved in the relevant substances. Regarding food-drug interactions physicians and pharmacists recognize that some foods and drugs, when taken simultaneously, can alter the body's ability to utilize a particular food or drug, or cause serious side effects. Clinically significant drug interactions, which pose potential harm to the patient, may result from changes in pharmaceutical, pharmacokinetic, or pharmacodynamic properties. Some may be taken advantage of, to the benefit of patients, but more commonly drug interactions result in adverse drug events. Therefore it is advisable for patients to follow the physician and doctors instructions to obtain maximum benefits with least food-drug interactions. The literature survey was conducted by extracting data from different review and original articles on general or specific drug interactions with food. This review gives information about various interactions between different foods and drugs and will help physicians and pharmacists prescribe drugs cautiously with only suitable food supplement to get maximum benefit for the patient.

  3. Evaluation of resources for analyzing drug interactions*†

    PubMed Central

    Patel, Risha I.; Beckett, Robert D.

    2016-01-01

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

  4. [Hypothyroidism as the result of drug interaction between ferrous sulfate and levothyroxine].

    PubMed

    Fiaux, E; Kadri, K; Levasseur, C; Le Guillou, C; Chassagne, P

    2010-10-01

    We report a case of drug-drug interaction between ferrous sulfate and l-thyroxin. A 95-year-old woman treated successfully with l-thyroxin for many years received ferrous sulfate for anemia. This association led rapidly to recurrence of hypothyroidism with elevated serum than TSH level which completely resolved after withdrawal of iron therapy. Interaction was confirmed after both drugs were daily administrated separately without recurrence of hypothyroidism.

  5. Is transferring an educational innovation actually a process of transformation?

    PubMed

    Varpio, Lara; Bell, Robert; Hollingworth, Gary; Jalali, Alireza; Haidet, Paul; Levine, Ruth; Regehr, Glenn

    2012-08-01

    Recent debates question the extent to which adopting an educational innovation requires compromise between the innovation's original design and the adoption site's context. Through compromises, the innovation's fundamental principles may be transferred, transformed, or abandoned. This paper analyzes such compromises during the piloting of Team-Based Learning (TBL). We ask: When is the process of transferring an innovation actually a process of transformation? This study is an autoethnography of our research team's implementation process. Autoethnographies are personalized accounts where authors draw on their own experiences to extend understanding of a particular topic. To conduct this autoethnography, we used an in-depth, interactive interview with the piloting clinician educator. In the analysis of TBL's fundamental principles, some aspects of the principles transferred easily, while others were transformed. Analysis raised concerns that the transformations threatened the foundational principles of TBL. While an educational innovation's techniques may seem to be surface structures, they are realizations of deeper fundamental principles. The fundamental principles are themselves realizations of the innovation's foundational philosophy. When techniques and/or principles are modified to a context, it is important to analyze if the modifications continue to uphold the innovation's philosophy.

  6. Clinical nutrition and drug interactions

    PubMed Central

    Ekincioğlu, Aygin Bayraktar; Demirkan, Kutay

    2013-01-01

    A drug’s plasma level, pharmacological effects or side effects, elimination, physicochemical properties or stability could be changed by interactions of drug-drug or drug-nutrition products in patients who receive enteral or parenteral nutritional support. As a result, patients might experience ineffective outcomes or unexpected effects of therapy (such as drug toxicity, embolism). Stability or incompatibility problems between parenteral nutrition admixtures and drugs might lead to alterations in expected therapeutic responses from drug and/or parenteral nutrition, occlusion in venous catheter or symptoms or mortality due to infusion of composed particles. Compatibilities between parenteral nutrition and drugs are not always guaranteed in clinical practice. Although the list of compatibility or incompatibilities of drugs are published for the use of clinicians in their practices, factors such as composition of parenteral nutrition admixture, drug concentration, contact time in catheter, temperature of the environment and exposure to light could change the status of compatibilities between drugs and nutrition admixtures. There could be substantial clinical changes occurring in the patient’s nutritional status and pharmacological effects of drugs due to interactions between enteral nutrition and drugs. Drug toxicity and ineffective nutritional support might occur as a result of those predictable interactions. Although administration of drugs via feeding tube is a complex and problematic route for drug usage, it is possible to minimise the risk of tube occlusion, decreased effects of drug and drug toxicity by using an appropriate technique. Therefore, it is important to consider pharmacological dosage forms of drugs while administering drugs via a feeding tube. In conclusion, since the pharmacists are well-experienced and more knowledgeable professionals in drugs and drug usage compared to other healthcare providers, it is suggested that provision of information

  7. Self-Actualization and the Effective Social Studies Teacher.

    ERIC Educational Resources Information Center

    Farmer, Rodney B.

    1980-01-01

    Discusses a study undertaken to investigate the relationship between social studies teachers' degrees of self-actualization and their teacher effectiveness. Investigates validity of using Maslow's theory of self-actualization as a way of identifying the effective social studies teacher personality. (Author/DB)

  8. Self-Actualization Effects Of A Marathon Growth Group

    ERIC Educational Resources Information Center

    Jones, Dorothy S.; Medvene, Arnold M.

    1975-01-01

    This study examined the effects of a marathon group experience on university student's level of self-actualization two days and six weeks after the experience. Gains in self-actualization as a result of marathon group participation depended upon an individual's level of ego strength upon entering the group. (Author)

  9. Self-actualization: Its Use and Misuse in Teacher Education.

    ERIC Educational Resources Information Center

    Ivie, Stanley D.

    1982-01-01

    The writings of Abraham Maslow are analyzed to determine the meaning of the psychological term "self-actualization." After pointing out that self-actualization is a rare quality and that it has little to do with formal education, the author concludes that the concept has little practical relevance for teacher education. (PP)

  10. The Self-Actualization of Polk Community College Students.

    ERIC Educational Resources Information Center

    Pearsall, Howard E.; Thompson, Paul V., Jr.

    This article investigates the concept of self-actualization introduced by Abraham Maslow (1954). A summary of Maslow's Needs Hierarchy, along with a description of the characteristics of the self-actualized person, is presented. An analysis of humanistic education reveals it has much to offer as a means of promoting the principles of…

  11. 26 CFR 1.953-2 - Actual United States risks.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 10 2010-04-01 2010-04-01 false Actual United States risks. 1.953-2 Section 1... (CONTINUED) INCOME TAXES Controlled Foreign Corporations § 1.953-2 Actual United States risks. (a) In general. For purposes of paragraph (a) of § 1.953-1, the term “United States risks” means risks described...

  12. 26 CFR 1.953-2 - Actual United States risks.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 10 2011-04-01 2011-04-01 false Actual United States risks. 1.953-2 Section 1... (CONTINUED) INCOME TAXES (CONTINUED) Controlled Foreign Corporations § 1.953-2 Actual United States risks. (a) In general. For purposes of paragraph (a) of § 1.953-1, the term “United States risks” means...

  13. 26 CFR 1.953-2 - Actual United States risks.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 10 2014-04-01 2013-04-01 true Actual United States risks. 1.953-2 Section 1... (CONTINUED) INCOME TAXES (CONTINUED) Controlled Foreign Corporations § 1.953-2 Actual United States risks. (a) In general. For purposes of paragraph (a) of § 1.953-1, the term “United States risks” means...

  14. 26 CFR 1.953-2 - Actual United States risks.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 10 2013-04-01 2013-04-01 false Actual United States risks. 1.953-2 Section 1... (CONTINUED) INCOME TAXES (CONTINUED) Controlled Foreign Corporations § 1.953-2 Actual United States risks. (a) In general. For purposes of paragraph (a) of § 1.953-1, the term “United States risks” means...

  15. 26 CFR 1.953-2 - Actual United States risks.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 10 2012-04-01 2012-04-01 false Actual United States risks. 1.953-2 Section 1... (CONTINUED) INCOME TAXES (CONTINUED) Controlled Foreign Corporations § 1.953-2 Actual United States risks. (a) In general. For purposes of paragraph (a) of § 1.953-1, the term “United States risks” means...

  16. Facebook as a Library Tool: Perceived vs. Actual Use

    ERIC Educational Resources Information Center

    Jacobson, Terra B.

    2011-01-01

    As Facebook has come to dominate the social networking site arena, more libraries have created their own library pages on Facebook to create library awareness and to function as a marketing tool. This paper examines reported versus actual use of Facebook in libraries to identify discrepancies between intended goals and actual use. The results of a…

  17. School Guidance Counselors' Perceptions of Actual and Preferred Job Duties

    ERIC Educational Resources Information Center

    Edwards, John Dexter

    2010-01-01

    The purpose of this study was to provide process data for school counselors, administrators, and the public, regarding school counselors' actual roles within the guidance counselor preferred job duties and actual job duties. In addition, factors including National Certification or no National Certification, years of counseling experience, and…

  18. Actual 10-Year Survivors Following Resection of Adrenocortical Carcinoma

    PubMed Central

    Tran, Thuy B.; Postlewait, Lauren M.; Maithel, Shishir K.; Prescott, Jason D.; Wang, Tracy S.; Glenn, Jason; Phay, John E.; Keplinger, Kara; Fields, Ryan C.; Jin, Linda X.; Weber, Sharon M.; Salem, Ahmed; Sicklick, Jason K.; Gad, Shady; Yopp, Adam C.; Mansour, John C.; Duh, Quan-Yang; Seiser, Natalie; Solorzano, Carmen C.; Kiernan, Colleen M.; Votanopoulos, Konstantinos I.; Levine, Edward A.; Hatzaras, Ioannis; Shenoy, Rivfka; Pawlik, Timothy M.; Norton, Jeffrey A.; Poultsides, George A.

    2017-01-01

    Background Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited therapeutic options beyond surgical resection. The characteristics of actual long-term survivors following surgical resection for ACC have not been previously reported. Method Patients who underwent resection for ACC at one of 13 academic institutions participating in the US Adrenocortical Carcinoma Group from 1993 to 2014 were analyzed. Patients were stratified into four groups: early mortality (died within 2 years), late mortality (died within 2–5 years), actual 5-year survivor (survived at least 5 years), and actual 10-year survivor (survived at least 10 years). Patients with less than 5 years of follow-up were excluded. Results Among the 180 patients available for analysis, there were 49 actual 5-year survivors (27%) and 12 actual 10-year survivors (7%). Patients who experienced early mortality had higher rates of cortisol-secreting tumors, nodal metastasis, synchronous distant metastasis, and R1 or R2 resections (all P < 0.05). The need for multi-visceral resection, perioperative blood transfusion, and adjuvant therapy correlated with early mortality. However, nodal involvement, distant metastasis, and R1 resection did not preclude patients from becoming actual 10-year survivors. Ten of twelve actual 10-year survivors were women, and of the seven 10-year survivors who experienced disease recurrence, five had undergone repeat surgery to resect the recurrence. Conclusion Surgery for ACC can offer a 1 in 4 chance of actual 5-year survival and a 1 in 15 chance of actual 10-year survival. Long-term survival was often achieved with repeat resection for local or distant recurrence, further underscoring the important role of surgery in managing patients with ACC. PMID:27633419

  19. Gender differences, polypharmacy, and potential pharmacological interactions in the elderly

    PubMed Central

    Venturini, Carina Duarte; Engroff, Paula; Ely, Luísa Scheer; de Araújo Zago, Luísa Faria; Schroeter, Guilherme; Gomes, Irenio; De Carli, Geraldo Attilio; Morrone, Fernanda Bueno

    2011-01-01

    OBJECTIVE: This study aims to analyze pharmacological interactions among drugs taken by elderly patients and their age and gender differences in a population from Porto Alegre, Brazil. METHODS: We retrospectively analyzed the database provided by the Institute of Geriatric and Gerontology, Porto Alegre, Brazil. The database was composed of 438 elderly and includes information about the patients' disease, therapy regimens, utilized drugs. All drugs reported by the elderly patients were classified using the Anatomical Therapeutic and Chemical Classification System. The drug-drug interactions and their severity were assessed using the Micromedex® Healthcare Series. RESULTS: Of the 438 elderly patients in the data base, 376 (85.8%) used pharmacotherapy, 274 were female, and 90.4% of females used drugs. The average number of drugs used by each individual younger than 80 years was 3.2±2.6. Women younger than 80 years old used more drugs than men in the same age group whereas men older than 80 years increased their use of drugs in relation to other age groups. Therefore, 32.6% of men and 49.2% of women described at least one interaction, and 8.1% of men and 10.6% of women described four or more potential drug-drug interactions. Two-thirds of drug-drug interactions were moderate in both genders, and most of them involved angiotensin-converting enzyme inhibitor, non-steroidal anti-inflammatory, loop and thiazide diuretics, and β-blockers. CONCLUSION: Elderly patients should be closely monitored, based on drug class, gender, age group and nutritional status. PMID:22086515

  20. Electrodermal responses to implied versus actual violence on television.

    PubMed

    Kalamas, A D; Gruber, M L

    1998-01-01

    The electrodermal response (EDR) of children watching a violent show was measured. Particular attention was paid to the type of violence (actual or implied) that prompted an EDR. In addition, the impact of the auditory component (sounds associated with violence) of the show was evaluated. Implied violent stimuli, such as the villain's face, elicited the strongest EDR. The elements that elicited the weakest responses were the actual violent stimuli, such as stabbing. The background noise and voices of the sound track enhanced the total number of EDRs. The results suggest that implied violence may elicit more fear (as measured by EDRs) than actual violence does and that sounds alone contribute significantly to the emotional response to television violence. One should not, therefore, categorically assume that a show with mostly actual violence evokes less fear than one with mostly implied violence.

  1. 40. Photocopy of plan of the Castillo c. 1779 (Actual ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    40. Photocopy of plan of the Castillo c. 1779 (Actual Negative 4'x5') STAR PLAN, COURTYARD FACADE PROFILE AND DEFENSIVE LINKS - Castillo de San Marcos, 1 Castillo Drive, Saint Augustine, St. Johns County, FL

  2. Actuarial and actual analysis of surgical results: empirical validation.

    PubMed

    Grunkemeier, G L; Anderson, R P; Starr, A

    2001-06-01

    This report validates the use of the Kaplan-Meier (actuarial) method of computing survival curves by comparing 12-year estimates published in 1978 with current assessments. It also contrasts cumulative incidence curves, referred to as "actual" analysis in the cardiac-related literature with Kaplan-Meier curves for thromboembolism and demonstrates that with the former estimate the percentage of events that will actually occur.

  3. Interaction of grapefruit juice and calcium channel blockers.

    PubMed

    Sica, Domenic A

    2006-07-01

    Drug-drug interactions are commonly recognized occurrences in the hypertensive population. Drug-nutrient interactions, however, are less well appreciated. The grapefruit juice-calcium channel blocker interaction is one that has been known since 1989. The basis for this interaction has been diligently explored and appears to relate to both flavanoid and nonflavanoid components of grapefruit juice interfering with enterocyte CYP3A4 activity. In the process, presystemic clearance of susceptible drugs decreases and bioavailability increases. A number of calcium channel blockers are prone to this interaction, with the most prominent interaction occurring with felodipine. The calcium channel blocker and grapefruit juice interaction should be incorporated into the knowledge base of rational therapeutics for the prescribing physician.

  4. Pharmacokinetic drug interactions of the selective androgen receptor modulator GTx-024(Enobosarm) with itraconazole, rifampin, probenecid, celecoxib and rosuvastatin.

    PubMed

    Coss, Christopher C; Jones, Amanda; Dalton, James T

    2016-08-01

    GTx-024 (also known as enobosarm) is a first in class selective androgen receptor modulator being developed for diverse indications in oncology. Preclinical studies of GTx-024 supported the evaluation of several potential drug-drug interactions in a clinical setting. A series of open-label Phase I GTx-024 drug-drug interaction studies were designed to interrogate potential interactions with CYP3A4 inhibitor (itraconazole), a CYP3A4 inducer (rifampin), a pan-UGT inhibitor (probenecid), a CYP2C9 substrate (celecoxib) and a BCRP substrate (rosuvastatin). The plasma pharmacokinetics of GTx-024, its major metabolite (GTx-024 glucuronide), and each substrate were characterized in detail. Itraconazole administration had no effect on GTx-024 pharmacokinetics. Likewise, GTx-024 administration did not significantly change the pharmacokinetics of celecoxib or rosuvastatin. Rifampin administration had the largest impact on GTx-024 pharmacokinetics of any co-administered agent and reduced the maximal plasma concentration (Cmax) by 23 % and the area under the curve (AUC∞) by 43 %. Probenecid had a complex interaction with GTx-024 whereby both GTx-024 plasma levels and GTx-024 glucuronide plasma levels (AUC∞) were increased by co-administration of the UGT inhibitor (50 and 112 %, respectively). Overall, GTx-024 was well tolerated and poses very little risk of generating clinically relevant drug-drug interactions.

  5. Antiretroviral Drug Interactions: Overview of Interactions Involving New and Investigational Agents and the Role of Therapeutic Drug Monitoring for Management

    PubMed Central

    Rathbun, R. Chris; Liedtke, Michelle D.

    2011-01-01

    Antiretrovirals are prone to drug-drug and drug-food interactions that can result in subtherapeutic or supratherapeutic concentrations. Interactions between antiretrovirals and medications for other diseases are common due to shared metabolism through cytochrome P450 (CYP450) and uridine diphosphate glucuronosyltransferase (UGT) enzymes and transport by membrane proteins (e.g., p-glycoprotein, organic anion-transporting polypeptide). The clinical significance of antiretroviral drug interactions is reviewed, with a focus on new and investigational agents. An overview of the mechanistic basis for drug interactions and the effect of individual antiretrovirals on CYP450 and UGT isoforms are provided. Interactions between antiretrovirals and medications for other co-morbidities are summarized. The role of therapeutic drug monitoring in the detection and management of antiretroviral drug interactions is also briefly discussed. PMID:24309307

  6. Progressive Digressions: Home Schooling for Self-Actualization.

    ERIC Educational Resources Information Center

    Rivero, Lisa

    2002-01-01

    Maslow's (1971) theory of primary creativeness is used as the basis for a self-actualization model of education. Examples of how to use the model in creative homeschooling are provided. Key elements include digressive and immersion learning, self-directed learning, and the integration of work and play. Teaching suggestions are provided. (Contains…

  7. A Taxometric Analysis of Actual Internet Sports Gambling Behavior

    ERIC Educational Resources Information Center

    Braverman, Julia; LaBrie, Richard A.; Shaffer, Howard J.

    2011-01-01

    This article presents findings from the first taxometric study of actual gambling behavior to determine whether we can represent the characteristics of extreme gambling as qualitatively distinct (i.e., taxonic) or as a point along a dimension. We analyzed the bets made during a 24-month study period by the 4,595 most involved gamblers among a…

  8. William Brennan and the Failed "Theory" of Actual Malice.

    ERIC Educational Resources Information Center

    Gillmor, Donald M.

    This paper contains an analysis of Justice William Brennan's Supreme Court opinions concerning cases on freedom of expression and his interpretations of Alexander Meiklejohn's theory of actual malice in cases of libel. Particular attention is paid to Brennan's landmark contribution to the law of libel, his opinion in "New York Times v.…

  9. MLCMS Actual Use, Perceived Use, and Experiences of Use

    ERIC Educational Resources Information Center

    Asiimwe, Edgar Napoleon; Grönlund, Åke

    2015-01-01

    Mobile learning involves use of mobile devices to participate in learning activities. Most e-learning activities are available to participants through learning systems such as learning content management systems (LCMS). Due to certain challenges, LCMS are not equally accessible on all mobile devices. This study investigates actual use, perceived…

  10. Venture actualization in nursing. An analysis of innovation.

    PubMed

    Neidlinger, S H; Bartleson, B J; Drews, N; Hukari, D

    1992-01-01

    From innovations shared by nurse executives and nurse intrapreneurs in acute care hospitals, The Venture Actualization in Nursing Model emerged. Derived from a nursing perspective, this model captures the steps of the nurse innovation process, linking the nurse executive and nurse intrapreneur role components to the process that leads to venture success.

  11. Comparison of Actual Surgical Outcomes and 3D Surgical Simulations

    PubMed Central

    Tucker, Scott; Cevidanes, Lucia; Styner, Martin; Kim, Hyungmin; Reyes, Mauricio; Proffit, William; Turvey, Timothy

    2009-01-01

    Purpose The advent of imaging software programs have proved to be useful for diagnosis, treatment planning, and outcome measurement, but precision of 3D surgical simulation still needs to be tested. This study was conducted to determine if the virtual surgery performed on 3D models constructed from Cone-beam CT (CBCT) can correctly simulate the actual surgical outcome and to validate the ability of this emerging technology to recreate the orthognathic surgery hard tissue movements in 3 translational and 3 rotational planes of space. Methods Construction of pre- and post-surgery 3D models from CBCTs of 14 patients who had combined maxillary advancement and mandibular setback surgery and 6 patients who had one-piece maxillary advancement surgery was performed. The post-surgery and virtually simulated surgery 3D models were registered at the cranial base to quantify differences between simulated and actual surgery models. Hotelling T-test were used to assess the differences between simulated and actual surgical outcomes. Results For all anatomic regions of interest, there was no statistically significant difference between the simulated and the actual surgical models. The right lateral ramus was the only region that showed a statistically significant, but small difference when comparing two- and one-jaw surgeries. Conclusions Virtual surgical methods were reliably reproduced, oral surgery residents could benefit from virtual surgical training, and computer simulation has the potential to increase predictability in the operating room. PMID:20591553

  12. 24 CFR 200.96 - Certificates of actual cost.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... URBAN DEVELOPMENT GENERAL INTRODUCTION TO FHA PROGRAMS Requirements for Application, Commitment, and... Continuing Eligibility Requirements for Existing Projects Cost Certification § 200.96 Certificates of actual... before final endorsement, except that in the case of an existing project that does not...

  13. 24 CFR 200.96 - Certificates of actual cost.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... URBAN DEVELOPMENT GENERAL INTRODUCTION TO FHA PROGRAMS Requirements for Application, Commitment, and... Continuing Eligibility Requirements for Existing Projects Cost Certification § 200.96 Certificates of actual... before final endorsement, except that in the case of an existing project that does not...

  14. Computer/PERT technique monitors actual versus allocated costs

    NASA Technical Reports Server (NTRS)

    Houry, E.; Walker, J. D.

    1967-01-01

    A computer method measures the users performance in cost-type contracts utilizing the existing nasa program evaluation review technique without imposing any additional reporting requirements. progress is measured by comparing actual costs with a value of work performed in a specific period.

  15. Fair Equality of Opportunity in Our Actual World

    ERIC Educational Resources Information Center

    Sachs, Benjamin

    2016-01-01

    Fair equality of opportunity, a principle that governs the competition for desirable jobs, can seem irrelevant in our actual world, for two reasons. First, parents have broad liberty to raise their children as they see fit, which seems to undermine the fair equality of opportunity-based commitment to eliminating the effects of social circumstances…

  16. Actualizing Concepts in Home Management: Proceedings of a National Conference.

    ERIC Educational Resources Information Center

    American Home Economics Association, Washington, DC.

    The booklet prints the following papers delivered at a national conference: Actualizing Concepts in Home Management: Decision Making, Dorothy Z. Price; Innovations in Teaching: Ergonomics, Fern E. Hunt; Relevant Concepts of Home Management: Innovations in Teaching, Kay P. Edwards; Standards in a Managerial Context, Florence S. Walker; Organizing:…

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

    SciTech Connect

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

    2010-03-01

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

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

    PubMed

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

    2010-03-01

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

  19. Large-Scale Identification and Analysis of Suppressive Drug Interactions

    PubMed Central

    Cokol, Murat; Weinstein, Zohar B.; Yilancioglu, Kaan; Tasan, Murat; Doak, Allison; Cansever, Dilay; Mutlu, Beste; Li, Siyang; Rodriguez-Esteban, Raul; Akhmedov, Murodzhon; Guvenek, Aysegul; Cokol, Melike; Cetiner, Selim; Giaever, Guri; Iossifov, Ivan; Nislow, Corey; Shoichet, Brian; Roth, Frederick P.

    2014-01-01

    SUMMARY One drug may suppress the effects of another. Although knowledge of drug suppression is vital to avoid efficacy-reducing drug interactions or discover countermeasures for chemical toxins, drug-drug suppression relationships have not been systematically mapped. Here, we analyze the growth response of Saccharomyces cerevisiae to anti-fungal compound (“drug”) pairs. Among 440 ordered drug pairs, we identified 94 suppressive drug interactions. Using only pairs not selected on the basis of their suppression behavior, we provide an estimate of the prevalence of suppressive interactions between anti-fungal compounds as 17%. Analysis of the drug suppression network suggested that Bromopyruvate is a frequently suppressive drug and Staurosporine is a frequently suppressed drug. We investigated potential explanations for suppressive drug interactions, including chemogenomic analysis, coaggregation, and pH effects, allowing us to explain the interaction tendencies of Bromopyruvate. PMID:24704506

  20. Clinically significant drug interactions with atypical antipsychotics.

    PubMed

    Kennedy, William Klugh; Jann, Michael W; Kutscher, Eric C

    2013-12-01

    Atypical antipsychotics [also known as second-generation antipsychotics (SGAs)] have become a mainstay therapeutic treatment intervention for patients with schizophrenia, bipolar disorders and other psychotic conditions. These agents are commonly used with other medications--most notably, antidepressants and antiepileptic drugs. Drug interactions can take place by various pharmacokinetic, pharmacodynamic and pharmaceutical mechanisms. The pharmacokinetic profile of each SGA, especially with phase I and phase II metabolism, can allow for potentially significant drug interactions. Pharmacodynamic interactions arise when agents have comparable receptor site activity, which can lead to additive or competitive effects without alterations in measured plasma drug concentrations. Additionally, the role of drug transporters in drug interactions continues to evolve and may effect both pharmacokinetic and pharmacodynamic interactions. Pharmaceutical interactions occur when physical incompatibilities take place between agents prior to drug absorption. Approximate therapeutic plasma concentration ranges have been suggested for a number of SGAs. Drug interactions that markedly increase or decrease the concentrations of these agents beyond their ranges can lead to adverse events or diminished clinical efficacy. Most clinically significant drug interactions with SGAs occur via the cytochrome P450 (CYP) system. Many but not all drug interactions with SGAs are identified during drug discovery and pre-clinical development by employing a series of standardized in vitro and in vivo studies with known CYP inducers and inhibitors. Later therapeutic drug monitoring programmes, clinical studies and case reports offer methods to identify additional clinically significant drug interactions. Some commonly co-administered drugs with a significant potential for drug-drug interactions with selected SGAs include some SSRIs. Antiepileptic mood stabilizers such as carbamazepine and valproate, as

  1. FRACTIONAL CRYSTALLIZATION FLOWSHEET TESTS WITH ACTUAL TANK WASTE

    SciTech Connect

    HERTING, D.L.

    2007-04-13

    Laboratory-scale flowsheet tests of the fractional crystallization process were conducted with actual tank waste samples in a hot cell at the 2224 Laboratory. The process is designed to separate medium-curie liquid waste into a low-curie stream for feeding to supplemental treatment and a high-curie stream for double-shell tank storage. Separations criteria (for Cesium-137 sulfate and sodium) were exceeded in all three of the flowsheet tests that were performed.

  2. FRACTIONAL CRYSTALLIZATION FLOWSHEET TESTS WITH ACTUAL TANK WASTE

    SciTech Connect

    HERTING, D.L.

    2006-10-18

    Laboratory-scale flowsheet tests of the fractional crystallization process were conducted with actual tank waste samples in a hot cell at the 222-S Laboratory. The process is designed to separate medium-curie liquid waste into a low-curie stream for feeding to supplemental treatment and a high-curie stream for double-shell tank storage. Separations criteria (for Cs-137 sulfate, and sodium) were exceeded in all three of the flowsheet tests that were performed.

  3. 63. VIEW OF AUTOTRANSFERS. THE ACTUAL AUTOTRANSFERS ARE ENCLOSED IN ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    63. VIEW OF AUTOTRANSFERS. THE ACTUAL AUTOTRANSFERS ARE ENCLOSED IN THE OIL FILLED CYLINDERS ON THE RIGHT OF THE PHOTOGRAPH. THESE ELECTRICAL DEVICES BOOSTED THE GENERATOR OUTPUT OF 11,000 VOLTS TO 22,000 VOLTS PRIOR TO TRANSMISSION OUT TO THE MAIN FEEDER LINES. A SPARE INNER UNIT IS CONTAINED IN THE METAL BOX AT THE LEFT OF THE PHOTOGRAPH. - New York, New Haven & Hartford Railroad, Cos Cob Power Plant, Sound Shore Drive, Greenwich, Fairfield County, CT

  4. The actual citation impact of European oncological research.

    PubMed

    López-Illescas, Carmen; de Moya-Anegón, Félix; Moed, Henk F

    2008-01-01

    This study provides an overview of the research performance of major European countries in the field Oncology, the most important journals in which they published their research articles, and the most important academic institutions publishing them. The analysis was based on Thomson Scientific's Web of Science (WoS) and calculated bibliometric indicators of publication activity and actual citation impact. Studying the time period 2000-2006, it gives an update of earlier studies, but at the same time it expands their methodologies, using a broader definition of the field, calculating indicators of actual citation impact, and analysing new and policy relevant aspects. Findings suggest that the emergence of Asian countries in the field Oncology has displaced European articles more strongly than articles from the USA; that oncologists who have published their articles in important, more general journals or in journals covering other specialties, rather than in their own specialist journals, have generated a relatively high actual citation impact; and that universities from Germany, and--to a lesser extent--those from Italy, the Netherlands, UK, and Sweden, dominate a ranking of European universities based on number of articles in oncology. The outcomes illustrate that different bibliometric methodologies may lead to different outcomes, and that outcomes should be interpreted with care.

  5. Drugs, drugs--who has the drugs?

    PubMed

    Blair, James

    2012-01-01

    Drug diversion, although on the increase, is not the only problem involving drugs that hospital security officials should be concerned with. Growing drug shortages, offshore production, counterfeiting, and weaknesses in the drug supply chain in case of a world-wide pandemic, are even greater causes for concern, the author claims.

  6. Low potential for interactions between melagatran/ximelagatran and other drugs, food, or alcohol.

    PubMed

    Wolzt, Michael; Sarich, Troy S; Eriksson, Ulf G

    2005-08-01

    Vitamin K antagonists including warfarin are associated with numerous interactions with other drugs and foods. In clinical practice, this complicates the task of maintaining plasma levels of warfarin within a narrow therapeutic window and so maximizing protection against thromboembolic events while minimizing the risk of complications, particularly bleeding. In contrast, ximelagatran has a low potential for pharmacokinetic drug:drug and food interactions. There is no significant metabolism of melagatran, and the main route of elimination of melagatran is renal excretion that appears to occur via glomerular filtration. Most importantly, cytochrome P450 isoenzymes that mediate many drug:drug interactions are not involved in the biotransformation of ximelagatran to melagatran. No significant pharmacokinetic interactions have been observed when oral ximelagatran is administered with a range of agents, including diclofenac, diazepam, nifedipine, digoxin, atorvastatin, or amiodarone. The low potential for drug:drug interactions with ximelagatran is also supported by an analysis of the pharmacokinetic data from clinical studies in patients with atrial fibrillation receiving long-term treatment with oral ximelagatran. Increases of mean melagatran area under the curve and maximum plasma concentration ( Cmax) of up to approximately 80% have been observed when ximelagatran is co-administered with the macrolide antibiotics erythromycin or azithromycin, and the mechanism for this interaction is currently under investigation. The bioavailability of melagatran is not altered by co-administration with food or alcohol. The melagatran-induced prolongation of activated partial thromboplastin time (APTT), an ex vivo coagulation time assay used as a measure of thrombin inhibition, is not altered by other drugs [including digoxin, atorvastatin, acetylsalicylic acid (ASA), and amiodarone], food, or alcohol. The effect of melagatran on capillary bleeding time, which is prolonged as a

  7. An adverse drug interaction of haloperidol with levodopa.

    PubMed

    Lucca, Jisha M; Ramesh, Madhan; Parthasarathi, Gurumurthy; Raman, Rajesh

    2015-01-01

    Drug interactions are known to play a significant role in the incidence of adverse drug reactions (ADRs) both in the community and in hospitals. Both the newer atypical antipsychotics and their more traditional counterparts are subject to drug - drug interactions amongst themselves, with other psychotropics, and with the agents used in the treatment of various physical ailments. The most common interactions encountered in clinical practice are pharmacodynamic in nature. It is well established that antipsychotic drugs reduce the efficacy of levodopa in parkinson's disease by blockade of dopamine receptors in the corpus striatum. The case reported here illustrates a common pharmacodynamic drug interaction of haloperidol with levodopa in a 60-year-old female patient.

  8. Actual drawing of histological images improves knowledge retention.

    PubMed

    Balemans, Monique C M; Kooloos, Jan G M; Donders, A Rogier T; Van der Zee, Catharina E E M

    2016-01-01

    Medical students have to process a large amount of information during the first years of their study, which has to be retained over long periods of nonuse. Therefore, it would be beneficial when knowledge is gained in a way that promotes long-term retention. Paper-and-pencil drawings for the uptake of form-function relationships of basic tissues has been a teaching tool for a long time, but now seems to be redundant with virtual microscopy on computer-screens and printers everywhere. Several studies claimed that, apart from learning from pictures, actual drawing of images significantly improved knowledge retention. However, these studies applied only immediate post-tests. We investigated the effects of actual drawing of histological images, using randomized cross-over design and different retention periods. The first part of the study concerned esophageal and tracheal epithelium, with 384 medical and biomedical sciences students randomly assigned to either the drawing or the nondrawing group. For the second part of the study, concerning heart muscle cells, students from the previous drawing group were now assigned to the nondrawing group and vice versa. One, four, and six weeks after the experimental intervention, the students were given a free recall test and a questionnaire or drawing exercise, to determine the amount of knowledge retention. The data from this study showed that knowledge retention was significantly improved in the drawing groups compared with the nondrawing groups, even after four or six weeks. This suggests that actual drawing of histological images can be used as a tool to improve long-term knowledge retention.

  9. Dieting: really harmful, merely ineffective or actually helpful?

    PubMed

    Lowe, Michael R; Timko, C Alix

    2004-08-01

    Dieting has developed a negative reputation among many researchers and health care professionals. However, 'dieting' can refer to a variety of behavioural patterns that are associated with different effects on eating and body weight. The wisdom of dieting depends on what kind of dieting is involved, who is doing it, and why. Thus, depending on what one means by the term, dieting can be quite harmful, merely ineffective or actually beneficial. The present paper considers examples of all three. In particular, we argue that judgements about the desirability of dieting should consider the likely consequences to particular individuals of engaging in, or not engaging in, dieting behaviour.

  10. The Frictional Force with Respect to the Actual Contact Surface

    NASA Technical Reports Server (NTRS)

    Holm, Ragnar

    1944-01-01

    Hardy's statement that the frictional force is largely adhesion, and to a lesser extent, deformation energy is proved by a simple experiment. The actual contact surface of sliding contacts and hence the friction per unit of contact surface was determined in several cases. It was found for contacts in normal atmosphere to be about one-third t-one-half as high as the macroscopic tearing strength of the softest contact link, while contacts annealed in vacuum and then tested, disclosed frictional forces which are greater than the macroscopic strength.

  11. Power Delivery from an Actual Thermoelectric Generation System

    NASA Astrophysics Data System (ADS)

    Kaibe, Hiromasa; Kajihara, Takeshi; Nagano, Kouji; Makino, Kazuya; Hachiuma, Hirokuni; Natsuume, Daisuke

    2014-06-01

    Similar to photovoltaic (PV) and fuel cells, thermoelectric generators (TEGs) supply direct-current (DC) power, essentially requiring DC/alternating current (AC) conversion for delivery as electricity into the grid network. Use of PVs is already well established through power conditioning systems (PCSs) that enable DC/AC conversion with maximum-power-point tracking, which enables commercial use by customers. From the economic, legal, and regulatory perspectives, a commercial PCS for PVs should also be available for TEGs, preferably as is or with just simple adjustment. Herein, we report use of a PV PCS with an actual TEG. The results are analyzed, and proper application for TEGs is proposed.

  12. Assessment of DoD Wounded Warrior Matters - Wounded Warrior Battalion - West Headquarters and Southern California Units

    DTIC Science & Technology

    2012-08-22

    herbal interactions. o Warrior compliance with prescribed therapy. o Poly-pharmacy challenges. o Assessment of need for restrictive dispensing...monitoring. o Assessment of drug-drug, drug-disease, and drug-food/ herbal interactions. o Wounded Warrior compliance with prescribed therapy. o Poly...the list is what they are actually taking and if they are taking any supplements or medication that are not on the list. Furthermore, the

  13. Actual ratio of triacylglycerol positional isomers in milk and cheese.

    PubMed

    Gotoh, Naohiro; Matsumoto, Yumiko; Nagai, Toshiharu; Mizobe, Hoyo; Yoshinaga, Kazuaki; Kojima, Koichi; Kuroda, Ikuma; Kitamura, Yohei; Shimizu, Takashi; Ishida, Hiroki; Wada, Shun

    2012-01-01

    Actual ratios of triacylglycerol (TAG) positional isomers in human, rat, and cow milk fat and cow, buffalo, goat, and sheep cheese fat were analyzed using HPLC-UV-atmospheric pressure chemical ionization-MS/MS system equipped with an octacosyl silylation column or polymeric ODS column. We substituted cheese fats for milk fats in parts of our study because milks from ruminants, with the exception of cows, are difficult to get in Japan. The actual ratio of β-PPC (the TAG consisting of two palmitic acids (P) and one capric acid (C), with the palmitic acid located at the β position) and β-PCP in human milk was different from those in ruminants, with more than half of the medium-chain fatty acids located at the β position even though other fats possessed it mainly at the α position. Palmitic acid was mainly located at the β position for human milk and rat milk; however, the location in ruminant cheese fat was mainly at the α position. The location of fatty acids is thought to be very important for infant nutrition. Particularly, the location of palmitic acid in case of human milk and of medium-chain fatty acids in case of ruminant milk was very characteristic and is considered to be very important to the fatty acids in milk fat.

  14. Actual and actuarial probabilities of competing risks: apples and lemons.

    PubMed

    Grunkemeier, Gary L; Jin, Ruyun; Eijkemans, Marinus J C; Takkenberg, Johanna J M

    2007-05-01

    The probability of a type of failure that is not inevitable, but can be precluded by other events such as death, is given by the cumulative incidence function. In cardiac research articles, it has become known as the actual probability, in contrast to the actuarial methods of estimation, usually implemented by the Kaplan-Meier (KM) estimate. Unlike cumulative incidence, KM attempts to predict what the latent failure probability would be if death were eliminated. To do this, the KM method assumes that the risk of dying and the risk of failure are independent. But this assumption is not true for many cardiac applications in which the risks of failure and death are negatively correlated (ie, patients with a higher risk of dying have a lower risk of failure, and patients with a lower risk of death have a higher risk of failure, which is a condition called informative censoring). Recent editorials in two cardiac journals have promoted the use of the KM method (actuarial estimate) for competing risk events (specifically for heart valve performance) and criticized the use of the cumulative incidence (actual) estimates. This report has two aims: to explain the difference between these two estimates and to show why the KM is generally not appropriate. In the process we will rely on alternative representations of the KM estimator (using redistribution to the right and inverse probability weighting) to explain the difference between the two estimates and to show how it may be possible to adjust KM to overcome the informative censoring.

  15. Experimental study on the regenerator under actual operating conditions

    NASA Astrophysics Data System (ADS)

    Nam, Kwanwoo; Jeong, Sangkwon

    2002-05-01

    An experimental apparatus was prepared to investigate thermal and hydrodynamic characteristics of the regenerator under its actual operating conditions. The apparatus included a compressor to pressurize and depressurize regenerator with various operating frequencies. Cold end of the regenerator was maintained around 100 K by means of liquid nitrogen container and heat exchanger. Instantaneous gas temperature and mass flow rate were measured at both ends of the regenerator during the whole pressure cycle. Pulsating pressure and pressure drop across the regenerator were also measured. The operating frequency of the pressure cycle was varied between 3 and 60 Hz, which are typical operating frequencies of Gifford-McMahon, pulse tube, and Stirling cryocoolers. First, friction factor for the wire screen mesh was directly determined from room temperature experiments. When the operating frequency was less than 9 Hz, the oscillating flow friction factor was nearly same as the steady flow friction factor for Reynolds number up to 100. For 60 Hz operations, the ratio of oscillating flow friction factor to steady flow one was increased as hydraulic Reynolds number became high. When the Reynolds number was 100, this ratio was about 1.6. Second, ineffectiveness of the regenerator was obtained when the cold-end was maintained around 100 K and the warm-end at 300 K to simulate the actual operating condition of the regenerator in cryocooler. Effect of the operating frequency on ineffectiveness of regenerator was discussed at low frequency range.

  16. What do tests of formal reasoning actually measure?

    NASA Astrophysics Data System (ADS)

    Lawson, Anton E.

    Tests of formal operational reasoning derived from Piagetian theory have been found to be effective predictors of academic achievement. Yet Piaget's theory regarding the underlying nature of formal operations and their employment in specific contexts has run into considerable empirical difficulty. The primary purpose of this study was to present the core of an alternative theory of the nature of advanced scientific reasoning. That theory, referred to as the multiple-hypothesis theory, argues that tests of formal operational reasoning actually measure the extent to which persons have acquired the ability to initiate reasoning with more than one specific antecedent condition, or if they are unable to imagine more than one antecedent condition, they are aware that more than one is possible; therefore conclusions that are drawn are tempered by this possibility. As a test of this multiple-hypothesis theory of advanced reasoning and the contrasting Piagetian theory of formal operations, a sample of 922 college students were first classified as concrete operational, transitional, or formal operational, based upon responses to standard Piagetian measures of formal operational reasoning. They were then administered seven logic tasks. Actual response patterns to the tasks were analyzed and found to be similar to predicted response patterns derived from the multiple-hypothesis theory and were different from those predicted by Piagetian theory. Therefore, support was obtained for the multiple-hypothesis theory. The terms intuitive and reflective were suggested to replace the terms concrete operational and formal operational to refer to persons at varying levels of intellectual development.

  17. Drug interactions in dermatology: what the dermatologist should know.

    PubMed

    Coondoo, Arijit; Chattopadhyay, Chandan

    2013-07-01

    A drug interaction is a process by which a drug or any other substance interacts with another drug and affects its activity by increasing or decreasing its effect, causing a side effect or producing a new effect unrelated to the effect of either. Interactions may be of various types-drug-drug interactions, drug-food interactions, drug-medical condition interactions, or drug-herb interactions. Interactions may occur by single or multiple mechanisms. They may occur in vivo or in vitro (pharmaceutical reactions). In vivo interactions may be further subdivided into pharmacodynamic or pharmacokinetic reactions. Topical drug interactions which may be agonistic or antagonistic may occur between two drugs applied topically or between a topical and a systemic drug. Topical drug-food interaction (for example, grape fruit juice and cyclosporine) and drug-disease interactions (for example, topical corticosteroid and aloe vera) may also occur. It is important for the dermatologist to be aware of such interactions to avoid complications of therapy in day-to-day practice.

  18. Self-Actualization in a Marathon Growth Group: Do the Strong Get Stronger?

    ERIC Educational Resources Information Center

    Kimball, Ronald; Gelso, Charles J.

    1974-01-01

    This study examined the effects of a weekend marathon on the level of self-actualization of college students and the relationship between ego strength and extent of change in self-actualization. The group experience did increase self-actualization, but participants' initial level of ego strength was unrelated to changes in self-actualization.…

  19. Catalytic combustion of actual low and medium heating value gases

    NASA Technical Reports Server (NTRS)

    Bulzan, D. L.

    1982-01-01

    Catalytic combustion of both low and medium heating value gases using actual coal derived gases obtained from operating gasifiers was demonstrated. A fixed bed gasifier with a complete product gas cleanup system was operated in an air blown mode to produce low heating value gas. A fluidized bed gasifier with a water quench product gas cleanup system was operated in both an air enriched and an oxygen blown mode to produce low and medium, heating value gas. Noble metal catalytic reactors were evaluated in 12 cm flow diameter test rigs on both low and medium heating value gases. Combustion efficiencies greater than 99.5% were obtained with all coal derived gaseous fuels. The NOx emissions ranged from 0.2 to 4 g NO2 kg fuel.

  20. Photovoltaic performance models: an evaluation with actual field data

    NASA Astrophysics Data System (ADS)

    TamizhMani, Govindasamy; Ishioye, John-Paul; Voropayev, Arseniy; Kang, Yi

    2008-08-01

    Prediction of energy production is crucial to the design and installation of the building integrated photovoltaic systems. This prediction should be attainable based on the commonly available parameters such as system size, orientation and tilt angle. Several commercially available as well as free downloadable software tools exist to predict energy production. Six software models have been evaluated in this study and they are: PV Watts, PVsyst, MAUI, Clean Power Estimator, Solar Advisor Model (SAM) and RETScreen. This evaluation has been done by comparing the monthly, seasonaly and annually predicted data with the actual, field data obtained over a year period on a large number of residential PV systems ranging between 2 and 3 kWdc. All the systems are located in Arizona, within the Phoenix metropolitan area which lies at latitude 33° North, and longitude 112 West, and are all connected to the electrical grid.

  1. An evaluation of contractor projected and actual costs

    NASA Technical Reports Server (NTRS)

    Kwiatkowski, K. A.; Buffalano, C.

    1974-01-01

    GSFC contractors with cost-plus contracts provide cost estimates for each of the next four quarters on a quarterly basis. Actual expenditures over a two-year period were compared to the estimates, and the data were sorted in different ways to answer several questions and give quantification to observations, such as how much does the accuracy of estimates degrade as they are made further into the future? Are estimates made for small dollar amounts more accurate than for large dollar estimates? Other government agencies and private companies with cost-plus contracts may be interested in this analysis as potential methods of contract management for their organizations. It provides them with the different methods one organization is beginning to use to control costs.

  2. Motion fading is driven by perceived, not actual angular velocity.

    PubMed

    Kohler, P J; Caplovitz, G P; Hsieh, P-J; Sun, J; Tse, P U

    2010-06-01

    After prolonged viewing of a slowly drifting or rotating pattern under strict fixation, the pattern appears to slow down and then momentarily stop. Here we examine the relationship between such 'motion fading' and perceived angular velocity. Using several different dot patterns that generate emergent virtual contours, we demonstrate that whenever there is a difference in the perceived angular velocity of two patterns of dots that are in fact rotating at the same angular velocity, there is also a difference in the time to undergo motion fading for those two patterns. Conversely, whenever two patterns show no difference in perceived angular velocity, even if in fact rotating at different angular velocities, we find no difference in the time to undergo motion fading. Thus, motion fading is driven by the perceived rather than actual angular velocity of a rotating stimulus.

  3. Thermoregulation during prolonged actual and laboratory-simulated bicycling.

    PubMed

    Brown, S L; Banister, E W

    1985-01-01

    Thermoregulatory and cardiorespiratory responses to bicycling 55 km (mean speed 9.7 m X s-1) outdoors (15 degrees C DB) were compared to equivalent cycle ergometry (90 min at 65% VO2max) in the laboratory (20-23 degrees C DB, 50% RH) in 7 trained cyclists. Outdoor environmental conditions were simulated with fans and lamps, and were contrasted with standard no-wind, no-sun laboratory conditions. Sweating rate was similar during outdoor and laboratory simulated outdoor cycling (0.90 and 0.87 to 0.94 1 X h-1 respectively). During outdoor bicycling, mean heart rate (161 bt X min-1) was 7-13% higher (p less than .05) than under laboratory conditions, suggesting a greater strain for a similar external work rate. The increase in rectal temperature (0.8 degrees C) was 33-50% less (p less than 0.05) at the cooler outdoor ambient temperature than in the laboratory. Thermoregulatory stress was greater under the no-fan, no-lamp laboratory condition than during simulated outdoor conditions (36-38% greater (p less than 0.05) sweating rate, 15-18% greater (p less than 0.01) mean skin temperature, 6.4 to 7.8 fold greater (p less than 0.01) amount of clothing-retrained sweat). The cooling wind encountered in actual road bicycling apparently reduces thermoregulatory and circulatory demands compared with stationary cycle ergometry indoors. Failure to account for this enhanced cooling may result in overestimation of the physiological stress of actual road cycling.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. [Actual respiratory technologies in thoracic surgery: traditional problems and innovative solutions].

    PubMed

    Vyzhigina, M A; Parshin, V D; Titov, V A; Alekseev, A V

    2015-01-01

    The problem of efficient gas exchange maintenance is always actual in anesthetic management of thoracic surgery and determines the selection of appropriate method of anesthesia. The article presents an experience of anesthesia during operations on lungs, trachea, bronchi and mediastinal structures performed from 1963 to 2015. Current concept of safety and efficacy of anesthetic management in thoracic surgery is presented. The role of actual current respiratory technologies and methods of anesthesia per se to maximize the efficiency of gas exchange in all stages of thoracicsurgery is emphasized. Absolute coherence of anesthesiologist and surgeon based on correct interaction is the most important condition of successful surgery. Effectiveness of special respiratory technologies for thoracic surgery associated with one-lung ventilation and prolonged wide dissection of airways is described. The research results and pathophysiological rationale for the use of special respiratory technologies including different variants of differentiated independent lung ventilation especially important for patients with concomitant cardiorespiratory pathology are presented. We reported experience of effective gas exchange maintenance in reconstructive surgery of trachea and main bronchi including traditional mechanical ventilation with "shunt-breath" system, use of jet high-frequency ventilation and relatively new respiratory technology such as flow apnoeic oxygenation.

  5. Clinically relevant drug interactions with anti-Alzheimer's drugs.

    PubMed

    Caraci, Filippo; Sultana, Janet; Drago, Filippo; Spina, Edoardo

    2017-03-03

    The aging world population had led to an increase in the prevalence of Alzheimer's disease (AD). The drugs used to slow down the onset of AD, galantamine, donepezil, rivastigmine and memantine, are generally well-tolerated. However, drug interactions between these drugs and other drugs are an important aspect of patient safety that should be borne in mind, particularly given the high burden of polypharmacy in the elderly. The aim of this review is to provide an updated review of clinically significant drug-drug interactions concerning drugs approved for AD. PubMed was searched for relevant keywords. No time limit was imposed but only articles in English published in peer-reviewed journals were selected. Relevant literature was also identified from the references of identified articles. Further information was obtained from drug summary of product characteristics. The major pharmacokinetic interactions identified concerned fluoxetine, paroxetine and ketoconazole when used with galantamine or donepezil. On the other hand, the major potential pharmacodynamic interactions concerned anti-dementia drugs and general anesthesia agents, anti-cholinergic drugs, conventional antipsychotics and bradycardia-inducing drugs. In clinical practice memantine shows a lower potential for pharmacodynamic drug-drug interactions (DDIs) compared to other drug classes. In conclusion, the concomitant use of anti-dementia drugs with other drugs can have variable clinical effects, making appropriate prescribing of these drugs very challenging. A simple and coherent way of presenting evidence on complex drug interaction information from heterogenous sources to clinicians is needed in order for the voluminous data available to have an impact on clinical practice.

  6. Children's knowledge of deceptive gaze cues and its relation to their actual lying behavior.

    PubMed

    McCarthy, Anjanie; Lee, Kang

    2009-06-01

    Eye gaze plays a pivotal role during communication. When interacting deceptively, it is commonly believed that the deceiver will break eye contact and look downward. We examined whether children's gaze behavior when lying is consistent with this belief. In our study, 7- to 15-year-olds and adults answered questions truthfully (Truth questions) or untruthfully (Lie questions) or answered questions that required thinking (Think questions). Younger participants (7- and 9-year-olds) broke eye contact significantly more when lying compared with other conditions. Also, their averted gaze when lying differed significantly from their gaze display in other conditions. In contrast, older participants did not differ in their durations of eye contact or averted gaze across conditions. Participants' knowledge about eye gaze and deception increased with age. This knowledge significantly predicted their actual gaze behavior when lying. These findings suggest that with increased age, participants became increasingly sophisticated in their use of display rule knowledge to conceal their deception.

  7. Tutorial on Actual Space Environmental Hazards For Space Systems (Invited)

    NASA Astrophysics Data System (ADS)

    Mazur, J. E.; Fennell, J. F.; Guild, T. B.; O'Brien, T. P.

    2013-12-01

    It has become common in the space science community to conduct research on diverse physical phenomena because they are thought to contribute to space weather. However, satellites contend with only three primary environmental hazards: single event effects, vehicle charging, and total dose, and not every physical phenomenon that occurs in space contributes in substantial ways to create these hazards. One consequence of the mismatch between actual threats and all-encompassing research is the often-described gap between research and operations; another is the creation of forecasts that provide no actionable information for design engineers or spacecraft operators. An example of the latter is the physics of magnetic field emergence on the Sun; the phenomenon is relevant to the formation and launch of coronal mass ejections and is also causally related to the solar energetic particles that may get accelerated in the interplanetary shock. Unfortunately for the research community, the engineering community mitigates the space weather threat (single-event effects from heavy ions above ~50 MeV/nucleon) with a worst-case specification of the environment and not with a prediction. Worst-case definition requires data mining of past events, while predictions involve large-scale systems science from the Sun to the Earth that is compelling for scientists and their funding agencies but not actionable for design or for most operations. Differing priorities among different space-faring organizations only compounds the confusion over what science research is relevant. Solar particle impacts to human crew arise mainly from the total ionizing dose from the solar protons, so the priority for prediction in the human spaceflight community is therefore much different than in the unmanned satellite community, while both communities refer to the fundamental phenomenon as space weather. Our goal in this paper is the presentation of a brief tutorial on the primary space environmental phenomena

  8. Toward standardized reporting of drug interactions: the READI checklist for anecdotal reports.

    PubMed

    Aronson, Jeffrey K

    2015-01-01

    Anecdotal reports contribute 30% of the literature on adverse drug reactions and interactions. However, the quality of such reports has not been uniformly high. Standardized reporting of clinical studies is of increasing interest, including the CARE guidelines on reporting anecdotal cases in general. Although there are guidelines on evaluating and managing drug-drug interactions, there are none recommending methods for reporting suspected drug interactions. Here, based on published guidelines for reporting suspected adverse drug reactions, I propose a checklist for reporting details of suspected drug interactions, the REporting Anecdotal Drug Interactions (READI) checklist, hoping to stimulate discussion and improve reporting of suspected drug interactions. The checklist includes items relating, among others, to the patient affected, the drugs involved, and the outcome.

  9. Perceived vs. Actual Strategy Use across Three Oral Communication Tasks

    ERIC Educational Resources Information Center

    Khan, Sarah; Victori, Mia

    2011-01-01

    This study sought to explore differences in strategy use across three oral communication tasks. Twenty-two intermediate level university students carried out three tasks in pairs at three different time periods. After each task, which varied in terms of cognitive, interactional and learner factors (Robinson, "International Review of Applied…

  10. Condensation heat transfer of actual flue gas on horizontal tubes

    SciTech Connect

    Osakabe, Masahiro; Itoh, Tugue; Yagi, Kiyoyuki

    1999-07-01

    In order to improve the boiler efficiency, latent heat recovery from an exhaust flue gas is a very important concept. Condensation heat transfer on horizontal stainless steel tubes was investigated experimentally using an actual flue gas from a natural gas boiler. The experiment was conducted at different air ratios and steam mass concentrations of the flue gas, and in a wide range of tube wall temperature. The condensation pattern was similar to the dropwise condensation near the dew point. As the wall temperature was decreased, the wall region covered with a thin liquid film increased. The heat and mass transfer behavior were well predicted with the simple analogy correlation in the high wall temperature region. But in the low wall temperature region, the total heat transfer rate was higher than that predicted by the simple analogy correlation. At a high steam mass concentration artificially generated with steam injection, the total heat transfer rate was higher than that predicted by the simple analogy correlation. The analogy correlation using the modified Sherwood number taking account of the mass absorption effect was proposed. The modified correlation gave a good prediction of the heat flux at the high steam mass concentration.

  11. A taxometric analysis of actual Internet sports gambling behavior.

    PubMed

    Braverman, Julia; LaBrie, Richard A; Shaffer, Howard J

    2011-03-01

    This article presents findings from the first taxometric study of actual gambling behavior to determine whether we can represent the characteristics of extreme gambling as qualitatively distinct (i.e., taxonic) or as a point along a dimension. We analyzed the bets made during a 24-month study period by the 4,595 most involved gamblers among a cohort of 48,114 people using an Internet service to gamble on sporting events. We applied two taxometric procedures (i.e., MAMBAC and MAXCOV) to three indicators of betting behavior: total money lost, total number of bets, and total money wagered. The results fail to provide support for the view that the most involved Internet sports gamblers include a distinct category of gamblers. More research is necessary to clarify the similar features of recreational and extreme gamblers and the dimensions that scientists can use to measure these behaviors. Finally, we discuss the implications of these findings for clinical, research, and public policy activities.

  12. Alternate corrections for estimating actual wetland evapotranspiration from potential evapotranspiration

    USGS Publications Warehouse

    Barclay, Shoemaker W.; Sumner, D.M.

    2006-01-01

    Corrections can be used to estimate actual wetland evapotranspiration (AET) from potential evapotranspiration (PET) as a means to define the hydrology of wetland areas. Many alternate parameterizations for correction coefficients for three PET equations are presented, covering a wide range of possible data-availability scenarios. At nine sites in the wetland Everglades of south Florida, USA, the relatively complex PET Penman equation was corrected to daily total AET with smaller standard errors than the PET simple and Priestley-Taylor equations. The simpler equations, however, required less data (and thus less funding for instrumentation), with the possibility of being corrected to AET with slightly larger, comparable, or even smaller standard errors. Air temperature generally corrected PET simple most effectively to wetland AET, while wetland stage and humidity generally corrected PET Priestley-Taylor and Penman most effectively to wetland AET. Stage was identified for PET Priestley-Taylor and Penman as the data type with the most correction ability at sites that are dry part of each year or dry part of some years. Finally, although surface water generally was readily available at each monitoring site, AET was not occurring at potential rates, as conceptually expected under well-watered conditions. Apparently, factors other than water availability, such as atmospheric and stomata resistances to vapor transport, also were limiting the PET rate. ?? 2006, The Society of Wetland Scientists.

  13. Actual development of the chenier coast of suriname (South America)

    NASA Astrophysics Data System (ADS)

    Augustinus, Pieter G. E. F.

    1980-04-01

    The Holocene coastal plain of Suriname is a chenier plain. Its actual sedimentological development has been studied during three field-work periods (1966, 1967/1968, 1972). Clay is the predominant sediment in this low- to medium-energy environment. It accumulates in extensive shoreface-attached mudflats (sometimes considered as giant mudwaves), which migrate continuously to the west due to deposition of slingmud at their west side and simultaneous erosion of the east side. In between the mudflats cheniers may develop. Thin-section analysis of the clay deposits revealed that they are built up of an alternation of thick clayey laminae and thin laminae of silt and fine sand. The clayey laminae chiefly show a unistrial plasmic fabric. Disturbaces in the upper zone are caused by bioturbation. Two types of cheniers can be distinguished. One type contains fine sand which has been winnowed out of the pelite deposits. Since this sand is brought from the shelf the chenier formation begins at approximately mean low-water level. Longshore bars are formed and these are driven shoreward by wave action. The other type is built up of medium to coarse sand supplied by a local river. It is transported westward by beachdrift in a narrow zone around the mean high-water line. These cheniers develop therefore at or just above the mean high-tide level. The sedimentary structures of both types of cheniers have many characteristics in common. However, each type also has its own distinct features.

  14. Reconciling actual and perceived rates of predation by domestic cats.

    PubMed

    McDonald, Jennifer L; Maclean, Mairead; Evans, Matthew R; Hodgson, Dave J

    2015-07-01

    The predation of wildlife by domestic cats (Felis catus) is a complex problem: Cats are popular companion animals in modern society but are also acknowledged predators of birds, herpetofauna, invertebrates, and small mammals. A comprehensive understanding of this conservation issue demands an understanding of both the ecological consequence of owning a domestic cat and the attitudes of cat owners. Here, we determine whether cat owners are aware of the predatory behavior of their cats, using data collected from 86 cats in two UK villages. We examine whether the amount of prey their cat returns influences the attitudes of 45 cat owners toward the broader issue of domestic cat predation. We also contribute to the wider understanding of physiological, spatial, and behavioral drivers of prey returns among cats. We find an association between actual prey returns and owner predictions at the coarse scale of predatory/nonpredatory behavior, but no correlation between the observed and predicted prey-return rates among predatory cats. Cat owners generally disagreed with the statement that cats are harmful to wildlife, and disfavored all mitigation options apart from neutering. These attitudes were uncorrelated with the predatory behavior of their cats. Cat owners failed to perceive the magnitude of their cats' impacts on wildlife and were not influenced by ecological information. Management options for the mitigation of cat predation appear unlikely to work if they focus on "predation awareness" campaigns or restrictions of cat freedom.

  15. Reconciling actual and perceived rates of predation by domestic cats

    PubMed Central

    McDonald, Jennifer L; Maclean, Mairead; Evans, Matthew R; Hodgson, Dave J

    2015-01-01

    The predation of wildlife by domestic cats (Felis catus) is a complex problem: Cats are popular companion animals in modern society but are also acknowledged predators of birds, herpetofauna, invertebrates, and small mammals. A comprehensive understanding of this conservation issue demands an understanding of both the ecological consequence of owning a domestic cat and the attitudes of cat owners. Here, we determine whether cat owners are aware of the predatory behavior of their cats, using data collected from 86 cats in two UK villages. We examine whether the amount of prey their cat returns influences the attitudes of 45 cat owners toward the broader issue of domestic cat predation. We also contribute to the wider understanding of physiological, spatial, and behavioral drivers of prey returns among cats. We find an association between actual prey returns and owner predictions at the coarse scale of predatory/nonpredatory behavior, but no correlation between the observed and predicted prey-return rates among predatory cats. Cat owners generally disagreed with the statement that cats are harmful to wildlife, and disfavored all mitigation options apart from neutering. These attitudes were uncorrelated with the predatory behavior of their cats. Cat owners failed to perceive the magnitude of their cats’ impacts on wildlife and were not influenced by ecological information. Management options for the mitigation of cat predation appear unlikely to work if they focus on “predation awareness” campaigns or restrictions of cat freedom. PMID:26306163

  16. Remotely sensed actual evapotranspiration: implications for groundwater management in Botswana.

    NASA Astrophysics Data System (ADS)

    Timmermans, W. J.; Meijerink, A. M. J.

    In order to determine evapotranspiration losses from the groundwater of an aquifer in Botswana during the dry season, the multi-step Surface Energy Balance Algorithm for Land (SEBAL) was applied using sequential Landsat TM and NOAA-AVHRR data. During satellite overpasses, continuous data on surface temperatures and soil moisture were available from a meteorological tower and field observations for calibration and partial validation of the results. The SEBAL method yielded high actual evapotranspiration (E a) rates (1.5 - 3 mm/d), if relatively dense savannah vegetation was present, even when the water-table was over 30 m deep, as is the case in the upper part of the aquifer. No relationship between Ea and depth to water-table was found, except in the valleys, where riverine forests are fed by a system of discharging groundwater flow. The patterns on a vegetation map, based on a supervised classification using TM data, including thermal bands, showed similarity with the E a patterns. The spatial distributions of vegetation types and of E a have been interpreted as important uptake of water by deep roots; this is supported by increasing evidence from other parts of the world. Sap flow was measured in tall bushes near the tower site. The upper part (2 m) of the soil was dry. The results have implications for the groundwater recharge mechanism and the management of groundwater. Further validation studies have been initiated.

  17. Virtual reality as telemedicine tool: technology, ergonomics and actual applications.

    PubMed

    Riva, G; Gamberini, L

    2000-01-01

    This paper surveys the state of the art in telemedicine applications of virtual environments (VEs) and related technologies for health care. The possible use of VEs as telemedicine tool has attracted much interest in medicine. Actually this technology is commonly used in remote or augmented surgery, and surgical training, which are critically dependent upon eye-hand coordination. Recently, however, different researchers have tried to use VEs in anatomic learning and for the assessment and rehabilitation in neuro-psychology. To date, such applications have improved the quality of health care, and later they will lead to substantial cost savings. Tools that respond to the needs of present VE systems are being refined or developed. However, the possible use of VEs in telemedicine is not linked to the solution of technical problems only. In fact telemedicine is not simply a technology but a complex process whose successful exploitation needs significant attention to ergonomics, human factors and organizational changes in the structure of the relevant health service.

  18. Beaked Whales Respond to Simulated and Actual Navy Sonar

    PubMed Central

    Tyack, Peter L.; Zimmer, Walter M. X.; Moretti, David; Southall, Brandon L.; Claridge, Diane E.; Durban, John W.; Clark, Christopher W.; D'Amico, Angela; DiMarzio, Nancy; Jarvis, Susan; McCarthy, Elena; Morrissey, Ronald; Ward, Jessica; Boyd, Ian L.

    2011-01-01

    Beaked whales have mass stranded during some naval sonar exercises, but the cause is unknown. They are difficult to sight but can reliably be detected by listening for echolocation clicks produced during deep foraging dives. Listening for these clicks, we documented Blainville's beaked whales, Mesoplodon densirostris, in a naval underwater range where sonars are in regular use near Andros Island, Bahamas. An array of bottom-mounted hydrophones can detect beaked whales when they click anywhere within the range. We used two complementary methods to investigate behavioral responses of beaked whales to sonar: an opportunistic approach that monitored whale responses to multi-day naval exercises involving tactical mid-frequency sonars, and an experimental approach using playbacks of simulated sonar and control sounds to whales tagged with a device that records sound, movement, and orientation. Here we show that in both exposure conditions beaked whales stopped echolocating during deep foraging dives and moved away. During actual sonar exercises, beaked whales were primarily detected near the periphery of the range, on average 16 km away from the sonar transmissions. Once the exercise stopped, beaked whales gradually filled in the center of the range over 2–3 days. A satellite tagged whale moved outside the range during an exercise, returning over 2–3 days post-exercise. The experimental approach used tags to measure acoustic exposure and behavioral reactions of beaked whales to one controlled exposure each of simulated military sonar, killer whale calls, and band-limited noise. The beaked whales reacted to these three sound playbacks at sound pressure levels below 142 dB re 1 µPa by stopping echolocation followed by unusually long and slow ascents from their foraging dives. The combined results indicate similar disruption of foraging behavior and avoidance by beaked whales in the two different contexts, at exposures well below those used by regulators to define

  19. Establishing seasonal chronicles of actual evapotranspiration under sloping conditions

    NASA Astrophysics Data System (ADS)

    Zitouna Chebbi, R.; Prévot, L.; Jacob, F.; Voltz, M.

    2012-04-01

    Estimation of daily and seasonal actual evapotranspiration (ETa) is strongly needed for hydrological and agricultural purposes. Although the eddy covariance method is well suited for such estimation of land surface fluxes, this method suffers from limitations when establishing long time series. Missing data are often encountered, resulting from bad meteorological conditions, rejection by quality control tests, power failures… Numerous gap fill techniques have been proposed in the literature but there applicability in sloping conditions is not well known. In order to estimate ETa over long periods (agricultural cycle) on crops cultivated in sloping areas, a pluri-annual experiment was conducted in the Kamech catchment, located in North-eastern Tunisia. This Mediterranean site is characterized by a large heterogeneity in topography, soils and crops. Land surface fluxes were measured using eddy covariance systems. Measurements were collected on the two opposite sides of the Kamech V-shaped catchment, within small fields having slopes steeper than 5%. During three different years, four crops were studied: durum wheat, oat, fava bean and pasture. The topography of the catchment and the wind regime induced upslope and downslope flows over the study fields. In this study, we showed that gap filling of the turbulent fluxes (sensible and latent heat) can be obtained through linear regressions against net radiation. To account for the effect of the topography, linear regressions were calibrated by distinguishing upslope and downslope flows. This significantly improved the quality of the reconstructed data over 30 minute intervals. This gap filling technique also improved the energy balance closure at the daily time scale. As a result, seasonal chronicles of daily ETa throughout the growth cycle of the study crops in the Kamech watershed were established, thus providing useful information about the water use of annual crops in a semi-arid rainfed and hilly area.

  20. Using lysimeters to test the Penman Monteith actual evapotranspiration.

    NASA Astrophysics Data System (ADS)

    Ben Asher, Jiftah; Volinski, Roman; Zilberman, Arkadi; Bar Yosef, Beni; Silber, Avner

    2015-04-01

    Differences in actual transpiration (ETa) of banana plants were quantified in a lysimeter experiment. ETA was computed using instantaneous data from two weighing lysimeters and compared to PM (Penman-Monteith) model for ETa. Two critical problems were faced in this test. A) Estimating canopy and aerodynamic resistances ("rc" and "ra" respectively ) and B) converting the lysimeter changes in water volume ( LYv cm3 ) to ETa length units ( cm ). The two unknowns " rc" and "ra" were obtained from continuous measurements of the differences between canopy and air temperature (Tc - Ta). This difference was established by means of the infrared thermometry which was followed by numerical and analytical calculation of ETa using the modification suggested by R. Jackson to the PM model. The conversion of lysimeter volumetric units (LYv) to ETa length units was derived from the slope of cumulative LYv/ETa. This relationship was significantly linear (r2=0.97and 0.98.). Its slope was interpreted as "evaporating leaf area" which accounted for 1.8E4 cm2 in lysimeter 1 and 2.3E4 cm2.in lysimeter 2 . The comparison between LYv and PM model was acceptable even under very low ETa. The average of two lysimeters was 1.1mm/day (1.4 mm/day , LYv 1 and 0.8 LYv 2) while ETa calculated on the basis of PM model was 1.2 mm/day. It was concluded that although lysimeters are most accurate systems to measure ETa one of its disadvantages ( beside the high cost) is the volumetric output that in many cases should be supported by a one dimensional energy balance system. The PM model was found to be a reliable complementary tool to convert lysimeters volumetric output into conventional length units of ETa.

  1. Beaked whales respond to simulated and actual navy sonar.

    PubMed

    Tyack, Peter L; Zimmer, Walter M X; Moretti, David; Southall, Brandon L; Claridge, Diane E; Durban, John W; Clark, Christopher W; D'Amico, Angela; DiMarzio, Nancy; Jarvis, Susan; McCarthy, Elena; Morrissey, Ronald; Ward, Jessica; Boyd, Ian L

    2011-03-14

    Beaked whales have mass stranded during some naval sonar exercises, but the cause is unknown. They are difficult to sight but can reliably be detected by listening for echolocation clicks produced during deep foraging dives. Listening for these clicks, we documented Blainville's beaked whales, Mesoplodon densirostris, in a naval underwater range where sonars are in regular use near Andros Island, Bahamas. An array of bottom-mounted hydrophones can detect beaked whales when they click anywhere within the range. We used two complementary methods to investigate behavioral responses of beaked whales to sonar: an opportunistic approach that monitored whale responses to multi-day naval exercises involving tactical mid-frequency sonars, and an experimental approach using playbacks of simulated sonar and control sounds to whales tagged with a device that records sound, movement, and orientation. Here we show that in both exposure conditions beaked whales stopped echolocating during deep foraging dives and moved away. During actual sonar exercises, beaked whales were primarily detected near the periphery of the range, on average 16 km away from the sonar transmissions. Once the exercise stopped, beaked whales gradually filled in the center of the range over 2-3 days. A satellite tagged whale moved outside the range during an exercise, returning over 2-3 days post-exercise. The experimental approach used tags to measure acoustic exposure and behavioral reactions of beaked whales to one controlled exposure each of simulated military sonar, killer whale calls, and band-limited noise. The beaked whales reacted to these three sound playbacks at sound pressure levels below 142 dB re 1 µPa by stopping echolocation followed by unusually long and slow ascents from their foraging dives. The combined results indicate similar disruption of foraging behavior and avoidance by beaked whales in the two different contexts, at exposures well below those used by regulators to define

  2. A case of a probable drug interaction between lurasidone and atazanavir-based antiretroviral therapy.

    PubMed

    Naccarato, Mark; Hall, Elise; Wai, Alan; Ostrowski, Mario; Carvalhal, Adriana

    2016-01-01

    The cytochrome P450 isoform that is primarily involved in the metabolism of the antipsychotic lurasidone is CYP3A4. Drugs that inhibit or induce this enzyme would then be expected to increase or decrease serum concentrations of lurasidone, respectively. Atazanavir, an HIV-1 protease inhibitor, has demonstrated to be an inhibitor of CYP3A4 and would be expected to increase the exposure of any drug metabolized by this enzyme. We report a case of an atazanavir-precipitated drug-drug interaction that led to elevated serum concentrations of lurasidone and associated clinical symptoms of drug toxicity.

  3. Construction and Validation of a Scale to Measure Maslow's Concept of Self-Actualization

    ERIC Educational Resources Information Center

    Jones, Kenneth Melvin; Randolph, Daniel Lee

    1978-01-01

    Designed to measure self-actualization as defined by Abraham Maslow, the Jones Self Actualizing Scale, as assessed in this study, possesses content validity, reliability, and a number of other positive characteristics. (JC)

  4. Biology of PXR: role in drug-hormone interactions

    PubMed Central

    Wang, Jing; Dai, Shu; Guo, Yan; Xie, Wen; Zhai, Yonggong

    2014-01-01

    Hormonal homeostasis is essential for a variety of physiological and pathological processes. Elimination and detoxification of xenobiotics, such as drugs introduced into the human body, could disrupt the balance of hormones due to the induction of drug metabolizing enzymes (DMEs) and transporters. Pregnane X receptor (PXR, NR1I2) functions as a master xenobiotic receptor involved in drug metabolism and drug-drug interactions by its coordinated transcriptional regulation of phase I and phase II DMEs and transporters. Recently, increasing evidences indicate that PXR can also mediate the endocrine disruptor function and thus impact the integrity of the endocrine system. This review focuses primarily on the recent advances in our understanding of the function of PXR in glucocorticoid, mineralocorticoid, androgen and estrogen homeostasis. The elucidation of PXR-mediated drug-hormone interactions might have important therapeutic implications in dealing with hormone-dependent diseases and safety assessment of drugs. PMID:26417296

  5. Management of drug and food interactions with azole antifungal agents in transplant recipients.

    PubMed

    Dodds-Ashley, Elizabeth

    2010-08-01

    Azole antifungal agents are frequently used in hematopoietic stem cell and solid organ transplant recipients for prevention or treatment of invasive fungal infections. However, because of metabolism by or substrate activity for various isoenzymes of the cytochrome P450 system and/or P-glycoprotein, azole antifungals have the potential to interact with many of the drugs commonly used in these patient populations. Thus, to identify drug interactions that may result between azole antifungals and other drugs, we conducted a literature search of the MEDLINE database (1966-December 2009) for English-language articles on drug interaction studies involving the azole antifungal agents fluconazole, itraconazole, voriconazole, and posaconazole. Another literature search between each of the azoles and the immunosuppressants cyclosporine, tacrolimus, and sirolimus, as well as the corticosteroids methylprednisolone, dexamethasone, prednisolone, and prednisone, was also conducted. Concomitant administration of azoles and immunosuppressive agents may cause clinically significant drug interactions resulting in extreme immunosuppression or toxicity. The magnitude and duration of an interaction between azoles and immunosuppressants are not class effects of the azoles, but differ between drug combinations and are subject to interpatient variability. Drug interactions in the transplant recipient receiving azole therapy may also occur with antibiotics, chemotherapeutic agents, and acid-suppressive therapies, among other drugs. Initiation of an azole antifungal in transplant recipients nearly ensures a drug-drug interaction, but often these drugs are required. Management of these interactions first involves knowledge of the potential drug interaction, appropriate dosage adjustments when necessary, and therapeutic or clinical monitoring at an appropriate point in therapy to assess the drug-drug interaction (e.g., immunosuppressive drug concentrations, signs and symptoms of toxicity

  6. Relationship between Burnout Syndrome Symptoms and Self-Actualization Scores in Critical-Care Nurses.

    DTIC Science & Technology

    1985-01-01

    opportunities, satisfactory supervision, and self-actualization. One study indicated that nursing education promotes self-actualization at least to... nursing education achieved in burnout syndrome symptoms? 8. Is there a difference by level of nursing education achieved in self-actualization...level of nursing education achieved in the burnout scores or the self-actualization scores. The exception was that the associate degree nurses scored

  7. Pharmacokinetic Drug Interactions of Antimicrobial Drugs: A Systematic Review on Oxazolidinones, Rifamycines, Macrolides, Fluoroquinolones, and Beta-Lactams

    PubMed Central

    Bolhuis, Mathieu S.; Panday, Prashant N.; Pranger, Arianna D.; Kosterink, Jos G. W.; Alffenaar, Jan-Willem C.

    2011-01-01

    Like any other drug, antimicrobial drugs are prone to pharmacokinetic drug interactions. These drug interactions are a major concern in clinical practice as they may have an effect on efficacy and toxicity. This article provides an overview of all published pharmacokinetic studies on drug interactions of the commonly prescribed antimicrobial drugs oxazolidinones, rifamycines, macrolides, fluoroquinolones, and beta-lactams, focusing on systematic research. We describe drug-food and drug-drug interaction studies in humans, affecting antimicrobial drugs as well as concomitantly administered drugs. Since knowledge about mechanisms is of paramount importance for adequate management of drug interactions, the most plausible underlying mechanism of the drug interaction is provided when available. This overview can be used in daily practice to support the management of pharmacokinetic drug interactions of antimicrobial drugs. PMID:24309312

  8. Pharmacokinetic Drug Interactions of Antimicrobial Drugs: A Systematic Review on Oxazolidinones, Rifamycines, Macrolides, Fluoroquinolones, and Beta-Lactams.

    PubMed

    Bolhuis, Mathieu S; Panday, Prashant N; Pranger, Arianna D; Kosterink, Jos G W; Alffenaar, Jan-Willem C

    2011-11-18

    Like any other drug, antimicrobial drugs are prone to pharmacokinetic drug interactions. These drug interactions are a major concern in clinical practice as they may have an effect on efficacy and toxicity. This article provides an overview of all published pharmacokinetic studies on drug interactions of the commonly prescribed antimicrobial drugs oxazolidinones, rifamycines, macrolides, fluoroquinolones, and beta-lactams, focusing on systematic research. We describe drug-food and drug-drug interaction studies in humans, affecting antimicrobial drugs as well as concomitantly administered drugs. Since knowledge about mechanisms is of paramount importance for adequate management of drug interactions, the most plausible underlying mechanism of the drug interaction is provided when available. This overview can be used in daily practice to support the management of pharmacokinetic drug interactions of antimicrobial drugs.

  9. 25 CFR 39.201 - Does ISEF reflect the actual cost of school operations?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false Does ISEF reflect the actual cost of school operations... Does ISEF reflect the actual cost of school operations? ISEF does not attempt to assess the actual cost of school operations either at the local school level or in the aggregate nationally. ISEF is...

  10. 25 CFR 39.101 - Does ISEF assess the actual cost of school operations?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false Does ISEF assess the actual cost of school operations? 39... SCHOOL EQUALIZATION PROGRAM Indian School Equalization Formula § 39.101 Does ISEF assess the actual cost of school operations? No. ISEF does not attempt to assess the actual cost of school operations...

  11. Self-Actualization in a Marathon Growth Group: Do the Strong Get Stronger?

    ERIC Educational Resources Information Center

    Kimball, Ronald; Gelso, Charles J.

    This study examined the effects of a weekend marathon on the level of self-actualization of college students one and four weeks following their group experience. It also studied the relationship between ego strength and extent of change in self-actualization during a marathon. Generally, the group experience did increase self-actualization and the…

  12. 7 CFR 400.51 - Availability of actual production history program.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 6 2010-01-01 2010-01-01 false Availability of actual production history program. 400.51 Section 400.51 Agriculture Regulations of the Department of Agriculture (Continued) FEDERAL CROP... History § 400.51 Availability of actual production history program. An Actual Production History...

  13. 7 CFR 400.51 - Availability of actual production history program.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 6 2014-01-01 2014-01-01 false Availability of actual production history program. 400.51 Section 400.51 Agriculture Regulations of the Department of Agriculture (Continued) FEDERAL CROP... History § 400.51 Availability of actual production history program. An Actual Production History...

  14. 7 CFR 400.51 - Availability of actual production history program.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 6 2013-01-01 2013-01-01 false Availability of actual production history program. 400.51 Section 400.51 Agriculture Regulations of the Department of Agriculture (Continued) FEDERAL CROP... History § 400.51 Availability of actual production history program. An Actual Production History...

  15. On the downscaling of actual evapotranspiration maps based on combination of MODIS and landsat-based actual evapotranspiration estimates

    USGS Publications Warehouse

    Singh, Ramesh K.; Senay, Gabriel B.; Velpuri, Naga Manohar; Bohms, Stefanie; Verdin, James P.

    2014-01-01

     Downscaling is one of the important ways of utilizing the combined benefits of the high temporal resolution of Moderate Resolution Imaging Spectroradiometer (MODIS) images and fine spatial resolution of Landsat images. We have evaluated the output regression with intercept method and developed the Linear with Zero Intercept (LinZI) method for downscaling MODIS-based monthly actual evapotranspiration (AET) maps to the Landsat-scale monthly AET maps for the Colorado River Basin for 2010. We used the 8-day MODIS land surface temperature product (MOD11A2) and 328 cloud-free Landsat images for computing AET maps and downscaling. The regression with intercept method does have limitations in downscaling if the slope and intercept are computed over a large area. A good agreement was obtained between downscaled monthly AET using the LinZI method and the eddy covariance measurements from seven flux sites within the Colorado River Basin. The mean bias ranged from −16 mm (underestimation) to 22 mm (overestimation) per month, and the coefficient of determination varied from 0.52 to 0.88. Some discrepancies between measured and downscaled monthly AET at two flux sites were found to be due to the prevailing flux footprint. A reasonable comparison was also obtained between downscaled monthly AET using LinZI method and the gridded FLUXNET dataset. The downscaled monthly AET nicely captured the temporal variation in sampled land cover classes. The proposed LinZI method can be used at finer temporal resolution (such as 8 days) with further evaluation. The proposed downscaling method will be very useful in advancing the application of remotely sensed images in water resources planning and management.

  16. Potential of Drug Interactions among Hospitalized Cancer Patients in a Developing Country

    PubMed Central

    Tavakoli-Ardakani, Maria; Kazemian, Kaveh; Salamzadeh, Jamshid; Mehdizadeh, Mahshid

    2013-01-01

    Cancer patients are more susceptible to adverse drug-drug interactions (DDIs) due to receiving multiple medications especially chemotherapy medications, hormonal agents and supportive care drugs. The aim of this study is to describe the prevalence of potential DDIs and to identify risk factors for these potential interactions in hospitalized cancer patients in a developing country. A cross-sectional study conducted by reviewing charts of 224 consecutive in hospitalized patients in hematology-oncology ward of a teaching hospital in Tehran, during a 12 month period from July 2009 to July 2010. “Drug Interaction Facts 2008, 2009: The Authority on Drug Interactions” was used for screening the potential drug-drug interactions. Potential interactions were classified by levels of severity and documentation. The median age of patients was 50 years, the length of hospital stay for patient was 5 days and the number of drugs per patient was 8 drugs. Two hundred and twenty-eight potential interactions were detected. Nearly 14% of the interactions were major and 60% were moderate. Approximately 9% and 10% potential interactions were graded as established and probable. In multivariate analysis, being older than 61 years old, suffering from hematologic cancer, source of cancer in different specific organs (esophagus, testis and cervices more than other sources), and number of ordered drugs for patients were independent predictors of having at least one potential DDI in hospital order. Suffering from hematologic cancer, source of cancer in different organs, length of hospital stay and number of ordered drugs for patients were independent predictors for number of interactions per patients. Having a DDI seems to be more likely to occur in patients older than 61 years old. Hematologic cancers, having more medications in physician’s order, longer length of hospital stay, esophageal cancer, testicular cancer and cervical cancer have related to having a DDI and also having more

  17. [Actualities in extrinsic allergic alveolities or hypersensitivity pneumonitis].

    PubMed

    Ndiaye, M; Soumah, M; Sow, M L

    2007-01-01

    Significant advances have been noticed in the pathogenesis and the diagnosis of extrinsic allergic alveolitis during the last few years. Indeed the immune mechanism and the enabling conditions have been more precisely defined, the clinical stages and the diagnosis criterias clearly defined, new antigens incriminated and some etiological agents have been reclassified. The present pathogenic explanation insists on the type IV hypersensitivity reaction with sensitization of T lymphocytes, activation macrophages, the formation of IgG type antibodies and immune complexes, activation of complement and secretion of cytokines. The involvement of certain HLA classes (HLA2, DR3, DRB1, DQB1), interaction of genetics and environments factors, the role of infections agents and smoking have been demonstrated in several studies. The development of news clinical and biological diagnosis criteria have led the discovery of new extrinsic allergic alveolitis in the work places, a better knowledge of the prognostic elements and an appropriate adaptation of prevention measures.

  18. A Review of the Toxicity of HIV Medications II: Interactions with Drugs and Complementary and Alternative Medicine Products.

    PubMed

    Stolbach, Andrew; Paziana, Karolina; Heverling, Harry; Pham, Paul

    2015-09-01

    For many patients today, HIV has become a chronic disease. For those patients who have access to and adhere to lifelong antiretroviral (ARV) therapy, the potential for drug-drug interactions has become a real and life-threatening concern. It is known that most ARV drug interactions occur through the cytochrome P450 (CYP) pathway. Medications for comorbid medical conditions, holistic supplements, and illicit drugs can be affected by CYP inhibitors and inducers and have the potential to cause harm and toxicity. Protease inhibitors (PIs) tend to inhibit CYP3A4, while most non-nucleoside reverse transcriptase inhibitors (NNRTIs) tend to induce the enzyme. As such, failure to adjust the dose of co-administered medications, such as statins and steroids, may lead to serious complications including rhabdomyolysis and hypercortisolism, respectively. Similarly, gastric acid blockers can decrease several ARV absorption, and warfarin doses may need to be adjusted to maintain therapeutic concentrations. Illicit drugs such as methylenedioxymethamphetamine (MDMA, "ecstasy") in combination with PIs lead to increased toxicity, while the concomitant administration of sedative drugs such as midazolam and alprazolam in patients taking PIs can result in prolonged sedation, delayed recovery, and increased length of stay. Even supplements like St. John's Wort can alter PI concentrations. In theory, any drug that is metabolized by CYP has potential for a pharmacokinetic drug-drug interaction with all PIs, cobicistat, and most NNRTIs. When adding a new medication to an ARV regimen, use of a drug-drug interaction software and/or consultation with a clinical pharmacist/pharmacologist or HIV specialist is recommended.

  19. Towards an Operational Monitoring of Actual Evapotranspiration With Modis Imagery

    NASA Astrophysics Data System (ADS)

    Timmermans, W.; Gieske, A.; Bastiaanssen, W.; Holtslag, B.; Wolski, P.; Arneth, A.; Wohland, P.

    2002-12-01

    as daily rates of ET. They are compared with ground-based energy flux measurements using a meteorological flux tower, situated at a homogeneous site in the savannah. The model returns estimates of sensible and soil heat fluxes that agree well with the tower measurements, but net radiation and latent heat flux show deviations. The net radiation is slightly low and mostly due to differences between modeled and actual albedo. Latent heat fluxes are overestimated by about 35 Wm-2, if compared to the eddy measurements. However, if the energy closure gap is due entirely to errors in the towers latent heat fluxes, which is done in the remote sensing approach, they are underestimated by about 30 Wm-2. In other words, further improvement of the model is hampered by possible errors in the validation data. Using this model output, a regional estimate of daily ET can be retrieved, assuming a constant daytime evaporative fraction. Typical values that emerge are 6 mm for the swamps, 2 for the grasslands and 1 mm for the savannah.

  20. Application of Caco-2 Cell Line in Herb-Drug Interaction Studies: Current Approaches and Challenges

    PubMed Central

    Awortwe, C.; Fasinu, P.S.; Rosenkranz, B.

    2015-01-01

    The Caco-2 model is employed in pre-clinical investigations to predict the likely gastrointestinal permeability of drugs because it expresses cytochrome P450 enzymes, transporters, microvilli and enterocytes of identical characteristics to the human small intestine. The FDA recommends this model as integral component of the Biopharmaceutics Classification System (BCS). Most dedicated laboratories use the Caco-2 cell line to screen new chemical entities through prediction of its solubility, bioavailability and the possibility of drug-drug or herb-drug interactions in the gut lumen. However, challenges in the inherent characteristics of Caco-2 cell and inter-laboratory protocol variations have resulted to generation of irreproducible data. These limitations affect the extrapolation of data from pre-clinical research to clinical studies involving drug-drug and herb-drug interactions. This review addresses some of these caveats and enumerates the plausible current and future approaches to reduce the anomalies associated with Caco-2 cell line investigations focusing on its application in herb-drug interactions. PMID:24735758

  1. Perceived and actual social discrimination: the case of overweight and social inclusion.

    PubMed

    Hartung, Freda-Marie; Renner, Britta

    2013-01-01

    The present study examined the correspondence between perceived and actual social discrimination of overweight people. In total, 77 first-year students provided self-ratings about their height, weight, and perceived social inclusion. To capture actual social inclusion, each participant nominated those fellow students (a) she/he likes and dislikes and (b) about whom she/he is likely to hear social news. Students with lower Body Mass Index (BMI) felt socially included, irrespective of their actual social inclusion. In contrast, students with higher BMI felt socially included depending on the degree of their actual social inclusion. Specifically, their felt social inclusion accurately reflected whether they were actually liked/disliked, but only when they were part of social news. When not part of social news, they also showed insensitivity to their actual social inclusion status. Thus, students with a lower BMI tended to be insensitive, while students with a higher BMI showed a differential sensitivity to actual social discrimination.

  2. Motor imagery of locomotion with an additional load: actual load experience does not affect differences between physical and mental durations.

    PubMed

    Munzert, Jörn; Blischke, Klaus; Krüger, Britta

    2015-03-01

    Motor imagery relies strongly on motor representations. Currently, it is widely accepted that both the imagery and execution of actions share the same neural representations (Jeannerod, Neuroimage 14:S103-S109, 2001). Comparing mental with actual movement durations opens a window through which to examine motor representations and how they relate to cognitive motor processes. The present experiment examined mental durations reported by participants standing upright who imagined walking either with or without an additional load while actually carrying or not carrying that same load. Results showed a robust effect of longer durations when imagining the additional load during mental walking, whereas physical walking with an additional load did not extend movement durations accordingly. However, experiencing an actual load during imagery did not influence mental durations substantially. This dissociation of load-related effects can be interpreted as being due to an interaction of motor processes and their cognitive representation along with a reduction in neural activity in vestibular and somatosensory areas during imagery of locomotion. It is argued that this effect might be specific to locomotion and not generalize to a broader range of movements.

  3. Actual fusion efficiency in the lipid mixing assay - Comparison between nanodiscs and liposomes

    PubMed Central

    François-Martin, Claire; Pincet, Frédéric

    2017-01-01

    Lipid exchange occurs between membranes during fusion or active lipid transfer. These processes are necessary in vivo for the homeostasis of the cell at the level of the membranes, the organelles and the cell itself. They are also used by the cell to interact with the surrounding medium. Several assays have been developed to characterize in vitro these processes on model systems. The most common one, relying on fluorescence dequenching, measures lipid mixing between small membranes such as liposomes or nanodiscs in bulk. Usually, relative comparisons of the rate of lipid exchange are made between measurements performed in parallel. Here, we establish a quantitative standardization of this assay to avoid any bias resulting from the temperatures, the chosen fluorescent lipid fractions and from the various detergents used to normalize the measurements. We used this standardization to quantitatively compare the efficiency of SNARE-induced fusion in liposome-liposome and liposome-nanodisc configurations having similar collision frequency. We found that the initial yield of fusion is comparable in both cases, 1 per 2–3 million collisions in spite of a much larger dequenching signal with nanodiscs. Also, the long-term actual fusion rate is slightly lower with nanodiscs than in the liposome-liposome assay. PMID:28266607

  4. Extinction paradox and actual power scattered in light beam scattering: a two-dimensional study.

    PubMed

    Lai, H M; Wong, W Y; Wong, W H

    2004-12-01

    The extinction paradox is examined by applying partial-wave analysis to a two-dimensional light beam interacting with a long transverse cylinder without absorption, assuming always short wavelengths. We show that the (conventional) power scattered, Psca, except for a very narrow beam hitting a transparent cylinder on axis, is always double the power directly intercepted by the scatterer, Pitc, including a zero result for Psca when the incident beam is basically off the material surface. This contradicts the interpretation that attributes one half of Psca to edge diffraction by the scatterer. Furthermore, we identify the shadow-forming wave (SFW) from the partial-wave sum in the forward direction and show that the actual power scattered or, equivalently, the power depleted from the incident beam is equal to one unit of Pitc for a narrow beam, gets larger for a broader beam, and approaches 2Pitc for a very broad beam. The larger value in the latter cases is due to the extent of divergence of the SFW beam out of the incident beam at distances well beyond the Rayleigh range.

  5. Children’s knowledge of deceptive gaze cues and its relation to their actual lying behavior

    PubMed Central

    McCarthy, Anjanie; Lee, Kang

    2012-01-01

    Eye gaze plays a pivotal role during communication. When interacting deceptively, it is commonly believed that the deceiver will break eye contact and look downward. We examined whether children’s gaze behavior when lying is consistent with this belief. In our study, 7- to 15-year-olds and adults answered questions truthfully (Truth questions) or untruthfully (Lie questions) or answered questions that required thinking (Think questions). Younger participants (7- and 9-year-olds) broke eye contact significantly more when lying compared with other conditions. Also, their averted gaze when lying differed significantly from their gaze display in other conditions. In contrast, older participants did not differ in their durations of eye contact or averted gaze across conditions. Participants’ knowledge about eye gaze and deception increased with age. This knowledge significantly predicted their actual gaze behavior when lying. These findings suggest that with increased age, participants became increasingly sophisticated in their use of display rule knowledge to conceal their deception. PMID:18678376

  6. Actual fusion efficiency in the lipid mixing assay - Comparison between nanodiscs and liposomes

    NASA Astrophysics Data System (ADS)

    François-Martin, Claire; Pincet, Frédéric

    2017-03-01

    Lipid exchange occurs between membranes during fusion or active lipid transfer. These processes are necessary in vivo for the homeostasis of the cell at the level of the membranes, the organelles and the cell itself. They are also used by the cell to interact with the surrounding medium. Several assays have been developed to characterize in vitro these processes on model systems. The most common one, relying on fluorescence dequenching, measures lipid mixing between small membranes such as liposomes or nanodiscs in bulk. Usually, relative comparisons of the rate of lipid exchange are made between measurements performed in parallel. Here, we establish a quantitative standardization of this assay to avoid any bias resulting from the temperatures, the chosen fluorescent lipid fractions and from the various detergents used to normalize the measurements. We used this standardization to quantitatively compare the efficiency of SNARE-induced fusion in liposome-liposome and liposome-nanodisc configurations having similar collision frequency. We found that the initial yield of fusion is comparable in both cases, 1 per 2–3 million collisions in spite of a much larger dequenching signal with nanodiscs. Also, the long-term actual fusion rate is slightly lower with nanodiscs than in the liposome-liposome assay.

  7. [Actuality of Wallon's emotional model: toward a "body-psychosocial" model of emotions].

    PubMed

    Santiago Delefosse, M

    2000-01-01

    Author focuses on qualitative approach of emotions with their human function. She postulates that emotions would be one of the way of the mind's body-inscription. A short presentation of the actual discussion, within psychoneurology and cognitive psychology, shows the lack of a developmental perspective. From the Wallon's emotions theory, the author presents a model that allows to go beyond this limit and to redefine the primary function of emotions: the "body-psycho-social Wallon's model" of emotions. Wallon's emotional model focuses on the interaction between body-image and psycho-social construction. This model: a) fixes the emotions into automatisms, but these automatisms are already in link with the social world (through the sense of the mother's language), b) establishes the integrative function of antagonisms (between mind and automatisms, between emotions and mind, between emotions and automatisms). This model shows that emotion's function cannot be reduce to the adaptative response to an unpredictable situation (cognitive or motor). The initial function of emotions concerns the communication system, or better, the first function of emotions is a search for action on family circle, by means of mimicry with ambient and emotional contagion. This emotional system is completely dependent (addicted) on the environment. It gives a "tool" to put in coordination with its environment: a) it favours the setting up of an instant empathy within infant and family circle, b) it makes easier the mind and motor accommodation, c) it put in the necessary plasticity for the emergence of the consciousness.

  8. Does medical students’ clinical performance affect their actual performance during medical internship?

    PubMed Central

    Han, Eui-Ryoung; Chung, Eun-Kyung

    2016-01-01

    INTRODUCTION This study examines the relationship between the clinical performance of medical students and their performance as doctors during their internships. METHODS This retrospective study involved 63 applicants of a residency programme conducted at Chonnam National University Hospital, South Korea, in November 2012. We compared the performance of the applicants during their internship with their clinical performance during their fourth year of medical school. The performance of the applicants as interns was periodically evaluated by the faculty of each department, while their clinical performance as fourth-year medical students was assessed using the Clinical Performance Examination (CPX) and the Objective Structured Clinical Examination (OSCE). RESULTS The performance of the applicants as interns was positively correlated with their clinical performance as fourth-year medical students, as measured by the CPX and OSCE. The performance of the applicants as interns was moderately correlated with the patient-physician interaction items addressing communication and interpersonal skills in the CPX. CONCLUSION The clinical performance of medical students during their fourth year in medical school was related to their performance as medical interns. Medical students should be trained to develop good clinical skills through actual encounters with patients or simulated encounters using manikins, to enable them to become more competent doctors. PMID:26768172

  9. Er:YAG laser for dentistry: basics, actual questions, and perspectives

    NASA Astrophysics Data System (ADS)

    Hibst, Raimund; Keller, Ulrich

    1994-12-01

    In recent years the dental use of the Er:YAG has found increasing interest. Most of the papers published so far concentrate on in vitro studies on cavity preparation, including the determination of ablation rates, measurements of temperature increase, microscopical analysis, and studies on the effect of water spray. The results are qualitatively in agreement and reveal a combination of high ablation efficiency and small side effects superior to other laser systems. Quantitative results, however, e.g., on ablation threshold or crater depths, sometimes differ. Some of these differences now can be explained and related to laser parameters or experimental conditions. Besides increasing the understanding on laser tissue interaction, the actual research enlarges the potential applications of the Er:YAG laser, such as for condition of enamel or dentin surfaces to enhance the bonding of composites. With the use of fibers, additional perspectives are given in periodontics and endodontics, e.g., for concrement removal or root canal preparation or sterilization.

  10. Tomato fruit carotenoid biosynthesis is adjusted to actual ripening progression by a light-dependent mechanism.

    PubMed

    Llorente, Briardo; D'Andrea, Lucio; Ruiz-Sola, M Aguila; Botterweg, Esther; Pulido, Pablo; Andilla, Jordi; Loza-Alvarez, Pablo; Rodriguez-Concepcion, Manuel

    2016-01-01

    Carotenoids are isoprenoid compounds that are essential for plants to protect the photosynthetic apparatus against excess light. They also function as health-promoting natural pigments that provide colors to ripe fruit, promoting seed dispersal by animals. Work in Arabidopsis thaliana unveiled that transcription factors of the phytochrome-interacting factor (PIF) family regulate carotenoid gene expression in response to environmental signals (i.e. light and temperature), including those created when sunlight reflects from or passes though nearby vegetation or canopy (referred to as shade). Here we show that PIFs use a virtually identical mechanism to modulate carotenoid biosynthesis during fruit ripening in tomato (Solanum lycopersicum). However, instead of integrating environmental information, PIF-mediated signaling pathways appear to fulfill a completely new function in the fruit. As tomatoes ripen, they turn from green to red due to chlorophyll breakdown and carotenoid accumulation. When sunlight passes through the flesh of green fruit, a self-shading effect within the tissue maintains high levels of PIFs that directly repress the master gene of the fruit carotenoid pathway, preventing undue production of carotenoids. This effect is attenuated as chlorophyll degrades, causing degradation of PIF proteins and boosting carotenoid biosynthesis as ripening progresses. Thus, shade signaling components may have been co-opted in tomato fruit to provide information on the actual stage of ripening (based on the pigment profile of the fruit at each moment) and thus finely coordinate fruit color change. We show how this mechanism may be manipulated to obtain carotenoid-enriched fruits.

  11. Cosmic Interactions

    NASA Astrophysics Data System (ADS)

    2008-01-01

    An image based on data taken with ESO's Very Large Telescope reveals a triplet of galaxies intertwined in a cosmic dance. ESO PR Photo 02/08 ESO PR Photo 02/08 NGC 7173, 7174, and 7176 The three galaxies, catalogued as NGC 7173 (top), 7174 (bottom right) and 7176 (bottom left), are located 106 million light-years away towards the constellation of Piscis Austrinus (the 'Southern Fish'). NGC 7173 and 7176 are elliptical galaxies, while NGC 7174 is a spiral galaxy with quite disturbed dust lanes and a long, twisted tail. This seems to indicate that the two bottom galaxies - whose combined shape bears some resemblance to that of a sleeping baby - are currently interacting, with NGC 7176 providing fresh material to NGC 7174. Matter present in great quantity around the triplet's members also points to the fact that NGC 7176 and NGC 7173 have interacted in the past. Astronomers have suggested that the three galaxies will finally merge into a giant 'island universe', tens to hundreds of times as massive as our own Milky Way. ESO PR Photo 02/08 ESO PR Photo 02b/08 NGC 7173, 7174, and 7176 The triplet is part of a so-called 'Compact Group', as compiled by Canadian astronomer Paul Hickson in the early 1980s. The group, which is the 90th entry in the catalogue and is therefore known as HCG 90, actually contains four major members. One of them - NGC 7192 - lies above the trio, outside of this image, and is another peculiar spiral galaxy. Compact groups are small, relatively isolated, systems of typically four to ten galaxies in close proximity to one another. Another striking example is Robert's Quartet. Compact groups are excellent laboratories for the study of galaxy interactions and their effects, in particular the formation of stars. As the striking image reveals, there are many other galaxies in the field. Some are distant ones, while others seem to be part of the family. Studies made with other telescopes have indeed revealed that the HCG 90 group contains 16 members

  12. Let's not, and say we would: imagined and actual responses to witnessing homophobia.

    PubMed

    Crosby, Jennifer Randall; Wilson, Johannes

    2015-01-01

    We compared imagined versus actual affective and behavioral responses to witnessing a homophobic slur. Participants (N = 72) witnessed a confederate using a homophobic slur, imagined the same scenario, or were not exposed to the slur. Those who imagined hearing the slur reported significantly higher levels of negative affect than those who actually witnessed the slur, and nearly one half of them reported that they would confront the slur, whereas no participants who actually heard the slur confronted it. These findings reveal a discrepancy between imagined and real responses to homophobic remarks, and they have implications for the likelihood that heterosexuals will actually confront homophobic remarks.

  13. The interactive brain hypothesis

    PubMed Central

    Di Paolo, Ezequiel; De Jaegher, Hanne

    2012-01-01

    Enactive approaches foreground the role of interpersonal interaction in explanations of social understanding. This motivates, in combination with a recent interest in neuroscientific studies involving actual interactions, the question of how interactive processes relate to neural mechanisms involved in social understanding. We introduce the Interactive Brain Hypothesis (IBH) in order to help map the spectrum of possible relations between social interaction and neural processes. The hypothesis states that interactive experience and skills play enabling roles in both the development and current function of social brain mechanisms, even in cases where social understanding happens in the absence of immediate interaction. We examine the plausibility of this hypothesis against developmental and neurobiological evidence and contrast it with the widespread assumption that mindreading is crucial to all social cognition. We describe the elements of social interaction that bear most directly on this hypothesis and discuss the empirical possibilities open to social neuroscience. We propose that the link between coordination dynamics and social understanding can be best grasped by studying transitions between states of coordination. These transitions form part of the self-organization of interaction processes that characterize the dynamics of social engagement. The patterns and synergies of this self-organization help explain how individuals understand each other. Various possibilities for role-taking emerge during interaction, determining a spectrum of participation. This view contrasts sharply with the observational stance that has guided research in social neuroscience until recently. We also introduce the concept of readiness to interact to describe the practices and dispositions that are summoned in situations of social significance (even if not interactive). This latter idea links interactive factors to more classical observational scenarios. PMID:22701412

  14. Iatrogenic Cushing Syndrome Secondary to Ritonavir-Epidural Triamcinolone Interaction: An Illustrative Case and Review

    PubMed Central

    Berg, Melody L.

    2014-01-01

    HIV positive patients on ritonavir-containing antiretroviral therapy (ART) can develop iatrogenic Cushing syndrome (IACS) and adrenal insufficiency as a result of drug-drug interactions with inhaled or intranasal glucocorticoid therapy. Reports related to epidural triamcinolone injections are relatively uncommon but increasingly reported. We describe a 48-year-old woman with immunologically and virologically well-controlled HIV on ritonavir-based ART, who developed headache, dizziness, and candida and herpes simplex virus (HSV) ulcerative esophagitis 7 days after receiving an epidural triamcinolone injection for cervical radicular pain. Iatrogenic Cushing syndrome and relative adrenal insufficiency were suspected and proven. The patient's ART was changed to a non-HIV protease inhibitor- (PI-) containing program, her symptoms improved, and she did not require hydrocortisone replacement. In this paper, we review the literature on IACS and relative secondary adrenal insufficiency from epidural triamcinolone injections in HIV patients on ritonavir-containing ART regimens. A high index of clinical suspicion is needed for diagnosis. Prevention of drug-drug interactions by taking a thorough medication history for patients on ritonavir-containing ART regimens before prescribing any form of corticosteroid is crucial and effective and sustained interdisciplinary communication in the care of such patients. PMID:24895495

  15. The inequality of water scarcity events: who is actually being affected?

    NASA Astrophysics Data System (ADS)

    Veldkamp, Ted I. E.; Wada, Yoshihide; Kummu, Matti; Aerts, Jeroen C. J. H.; Ward, Philip J.

    2015-04-01

    Over the past decades, changing hydro-climatic and socioeconomic conditions increased regional and global water scarcity problems. In the near future, projected changes in human water use and population growth - in combination with climate change - are expected to aggravate water scarcity conditions and its associated impacts on our society. Whilst a wide range of studies have modelled past and future regional and global patterns of change in population or land area impacted by water scarcity conditions, less attention is paid on who is actually affected and how vulnerable this share of the population is to water scarcity conditions. The actual impact of water scarcity events, however, not only depends on the numbers being affected, but merely on how sensitive this population is to water scarcity conditions, how quick and efficient governments can deal with the problems induced by water scarcity, and how many (financial and infrastructural) resources are available to cope with water scarce conditions. Only few studies have investigated the above mentioned interactions between societal composition and water scarcity conditions (e.g. by means of the social water scarcity index and the water poverty index) and, up to our knowledge, a comprehensive global analysis including different water scarcity indicators and multiple climate and socioeconomic scenarios is missing. To address this issue, we assess in this contribution the adaptive capacity of a society to water scarcity conditions, evaluate how this may be driven by different societal factors, and discuss how enhanced knowledge on this topic could be of interest for water managers in their design of adaptation strategies coping with water scarcity events. For that purpose, we couple spatial information on water scarcity conditions with different components from, among others, the Human Development Index and the Worldwide Governance Indicators, such as: the share of the population with an income below the poverty

  16. PREFACE: XVII International Youth Scientific School on Actual Problems of Magnetic Resonance and its Applications

    NASA Astrophysics Data System (ADS)

    2014-11-01

    Editors: M.S.Tagirov, V.V.Semashko, A.S.Nizamutdinov Kazan is the motherland of Electronic Paramagnetic Resonance (EPR) which was discovered in Kazan State University in 1944 by prof. E.K.Zavojskii. Since the Young Scientist School of Magnetic Resonance run by professor G.V.Skrotskii from MIPT stopped its work, Kazan took up the activity under the initiative of academician A.S.Borovik-Romanov. Nowadays this school is rejuvenated and the International Youth Scientific School studying "Actual problems of the magnetic resonance and its application" is developing. Traditionally the main subjects of the School meetings are: Magnetic Resonance in Solids, Chemistry, Geology, Biology and Medicine. The unchallenged organizers of that school are Kazan Federal University and Kazan E. K. Zavoisky Physical-Technical Institute. The rector of the School is professor Murat Tagirov, vice-rector - professor Valentine Zhikharev. Since 1997 more than 100 famous scientists from Germany, France, Switzerland, USA, Japan, Russia, Ukraine, Moldavia, Georgia provided plenary lecture presentations. Almost 700 young scientists have had an opportunity to participate in discussions of the latest scientific developments, to make their oral reports and to improve their knowledge and skills. To enhance competition among the young scientists, reports take place every year and the Program Committee members name the best reports, the authors of which are invited to prepare full-scale scientific papers. Since 2013 the International Youth Scientific School "Actual problems of the magnetic resonance and its application", following the tendency for comprehensive studies of matter properties and its interaction with electromagnetic fields, expanded "the field of interest" and opened the new section: Coherent Optics and Optical Spectroscopy. Many young people have submitted interesting reports on photonics, quantum electronics, laser physics, quantum optics, traditional optical and laser spectroscopy, non

  17. Oseltamivir-warfarin interaction in hypoplastic left heart syndrome: case report and review.

    PubMed

    Wagner, Jonathan; Abdel-Rahman, Susan M

    2015-05-01

    An 8-year-old boy with hypoplastic left heart syndrome with a previous history of thrombosis within the inferior vena cava receiving stable warfarin dosing for anticoagulation was diagnosed with influenza B. He was subsequently placed on oseltamivir therapy according to the Centers for Disease Control and Prevention clinical practice guidelines. During the hospitalization, his international normalized ratio steadily increased to supratherapeutic levels and returned to baseline after discontinuation of oseltamivir therapy. This case represents a drug-drug interaction that has not been previously reported in children or adolescents. An extensive review of the pharmacokinetic and pharmacodynamic literature did not uncover a definitive etiology for this interaction. However, several undefined aspects in each drug's disposition pathway need further elucidation. Until this interaction is understood, caution is warranted, and close monitoring of the international normalized ratio should be performed in all patients prescribed oseltamivir concomitantly with warfarin.

  18. From VET School to the Labour Market in Bosnia and Herzegovina: Expected versus Actual Wages

    ERIC Educational Resources Information Center

    Brankovic, Nina; Oruc, Nermin

    2016-01-01

    This article analyses the differences between expected and actual wages of VET students and graduates. It uses a survey of VET students enrolled in schools in Bosnia and Herzegovina, and data about employed VET graduates from the Labour Force Survey. The model of determinants of wages, expected or actual, estimated separately on each dataset,…

  19. 40 CFR Appendix C to Part 72 - Actual 1985 Yearly SO2 Emissions Calculation

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 17 2013-07-01 2013-07-01 false Actual 1985 Yearly SO2 Emissions Calculation C Appendix C to Part 72 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PERMITS REGULATION Pt. 72, App. C Appendix C to Part 72—Actual 1985 Yearly...

  20. Interpersonal Communication Behaviors and Self-Actualizing Values: A Conceptual Framework.

    ERIC Educational Resources Information Center

    Macklin, Thomas

    This report addresses the relationship between self-actualizing values and interpersonal communication behaviors. After a discussion of behavioristic and humanistic frameworks for social science research, the paper explains Abraham Maslow's and Carl Roger's concepts of self-actualization as the tendency toward completing and perfecting one's…

  1. 49 CFR 24.301 - Payment for actual reasonable moving and related expenses.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 1 2012-10-01 2012-10-01 false Payment for actual reasonable moving and related... ASSISTANCE AND REAL PROPERTY ACQUISITION FOR FEDERAL AND FEDERALLY-ASSISTED PROGRAMS Payments for Moving and Related Expenses § 24.301 Payment for actual reasonable moving and related expenses. (a) General. (1)...

  2. 49 CFR 24.301 - Payment for actual reasonable moving and related expenses.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 1 2014-10-01 2014-10-01 false Payment for actual reasonable moving and related... ASSISTANCE AND REAL PROPERTY ACQUISITION FOR FEDERAL AND FEDERALLY-ASSISTED PROGRAMS Payments for Moving and Related Expenses § 24.301 Payment for actual reasonable moving and related expenses. (a) General. (1)...

  3. 49 CFR 24.301 - Payment for actual reasonable moving and related expenses.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 1 2010-10-01 2010-10-01 false Payment for actual reasonable moving and related... ASSISTANCE AND REAL PROPERTY ACQUISITION FOR FEDERAL AND FEDERALLY-ASSISTED PROGRAMS Payments for Moving and Related Expenses § 24.301 Payment for actual reasonable moving and related expenses. (a) General. (1)...

  4. 7 CFR 400.51 - Availability of actual production history program.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ....51 Section 400.51 Agriculture Regulations of the Department of Agriculture (Continued) FEDERAL CROP... History § 400.51 Availability of actual production history program. An Actual Production History (APH... identified in this section in those areas where the Actuarial Table provides coverage. Except when...

  5. 7 CFR 400.51 - Availability of actual production history program.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ....51 Section 400.51 Agriculture Regulations of the Department of Agriculture (Continued) FEDERAL CROP... History § 400.51 Availability of actual production history program. An Actual Production History (APH... identified in this section in those areas where the Actuarial Table provides coverage. Except when...

  6. 40 CFR Appendix C to Part 72 - Actual 1985 Yearly SO2 Emissions Calculation

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 16 2010-07-01 2010-07-01 false Actual 1985 Yearly SO2 Emissions Calculation C Appendix C to Part 72 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PERMITS REGULATION Pt. 72, App. C Appendix C to Part 72—Actual 1985 Yearly...

  7. 77 FR 13328 - Federal Acquisition Regulation; Information Collection; Davis Bacon Act-Price Adjustment (Actual...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-06

    ... Regulation; Information Collection; Davis Bacon Act--Price Adjustment (Actual Method) AGENCY: Department of... previously approved information collection requirement concerning the Davis-Bacon Act price adjustment... comments identified by Information Collection 9000- 0154, Davis Bacon Act--Price Adjustment (Actual...

  8. 30 CFR 1206.180 - How do I determine an actual processing allowance?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 3 2014-07-01 2014-07-01 false How do I determine an actual processing... THE INTERIOR NATURAL RESOURCES REVENUE PRODUCT VALUATION Indian Gas Processing Allowances § 1206.180 How do I determine an actual processing allowance? (a) Determining a processing allowance if you...

  9. 75 FR 28059 - Actual Effects of the Free Trade Agreements With Chile, Australia, and Singapore

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-19

    ... COMMISSION Actual Effects of the Free Trade Agreements With Chile, Australia, and Singapore AGENCY: United...) instituted investigation No. 332-515, Actual Effects of the Free Trade Agreements with Chile, Australia, and...) concluded with Chile, Singapore, and Australia. In its report the Commission will-- (1) With respect to...

  10. A comparison of actual and perceived residential proximity to toxic waste sites.

    PubMed

    Howe, H L

    1988-01-01

    Studies of Memphis and Three Mile Island have noted a positive association between actual residential distance and public concern about exposure to the potential of contamination, whereas none was found at Love Canal. In this study, concern about environmental contamination and exposure was examined in relation to both perceived and actual proximity to a toxic waste disposal site (TWDS). It was hypothesized that perceived residential proximity would better predict concern levels that would actual residential distance. The data were abstracted from a New York State, excluding New York City, survey using all respondents (N = 317) from one county known to have a large number of TWDSs. Using linear regression, the variance explained in concern scores was 22 times higher with perceived distance than for actual distance. Perceived residential distance was a significant predictor of concern scores, while actual distance was not. However, perceived distance explained less than 5% of the variance in concern scores.

  11. Response to actual and simulated recordings of conventional takeoff and landing jet aircraft

    NASA Technical Reports Server (NTRS)

    Mabry, J. E.; Sullivan, B. M.

    1978-01-01

    Comparability between noise characteristics of synthesized recordings of aircraft in flight and actual recordings were investigated. Although the synthesized recordings were more smoothly time-varying than the actual recordings and the synthesizer could not produce a comb-filter effect that was present in the actual recordings, results supported the conclusion that annoyance response is comparable to the synthesized and actual recordings. A correction for duration markedly improved the validity of engineering calculation procedures designed to measure noise annoyance. Results led to the conclusion that the magnitude estimation psychophysical method was a highly reliable approach for evaluating engineering calculation procedures designed to measure noise annoyance. For repeated presentations of pairs of actual recordings, differences between judgment results for identical signals ranged from 0.0 to 0.5 db.

  12. Intention to use and actual use of electronic information resources: further exploring Technology Acceptance Model (TAM).

    PubMed

    Tao, Donghua

    2009-11-14

    Following up a previous study that examined public health students' intention to use e-resources for completing research paper assignments, the present study proposed two models to investigate whether or not public health students actually used the e-resources they intended to use and whether or not the determinants of intention to use predict actual use of e-resources. Focus groups and pre- and post-questionnaires were used to collect data. Descriptive analysis, data screening, and Structural Equation Modeling (SEM) techniques were used for data analysis. The study found that the determinants of intention-to-use significantly predict actual use behavior. Direct impact of perceived usefulness and indirect impact of perceived ease of use to both behavior intention and actual behavior indicated the importance of ease of use at the early stage of technology acceptance. Non-significant intention-behavior relationship prompted thoughts on the measurement of actual behavior and multidimensional characteristics of the intention construct.

  13. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models

    NASA Astrophysics Data System (ADS)

    Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

    2016-05-01

    Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com.

  14. Involvement of breast cancer resistance protein (BCRP/ABCG2) in the secretion of danofloxacin into milk: interaction with ivermectin.

    PubMed

    Real, R; Egido, E; Pérez, M; González-Lobato, L; Barrera, B; Prieto, J G; Alvarez, A I; Merino, G

    2011-08-01

    Danofloxacin, a veterinary fluoroquinolone antimicrobial drug, is actively secreted into milk by an as yet unknown mechanism. One of the main determinants of active drug secretion into milk is the transporter (BCRP/ABCG2). The main purpose was to determine whether danofloxacin is an in vitro substrate for Bcrp1/BCRP and to assess its involvement in danofloxacin secretion into milk. In addition, the role of potential drug-drug interactions in this process was assessed using ivermectin. Danofloxacin was transported in vitro by Bcrp1/BCRP, and ivermectin efficiently blocked this transport. Experiments with Bcrp1(-/-) mice showed no evidence of the involvement of Bcrp1 in plasma pharmacokinetics of danofloxacin. However, the milk concentration and milk-to-plasma ratio of danofloxacin were almost twofold higher in wild-type compared with Bcrp1(-/-) mice. The in vivo interaction with ivermectin was studied in sheep after co-administration of danofloxacin (1.25 mg/kg, i.m.) and ivermectin (0.2 mg/kg, s.c.). Ivermectin had no significant effect on the plasma levels of danofloxacin but significantly decreased danofloxacin concentrations in milk by almost 40%. Concomitant administration of multiple drugs, often used in veterinary therapy, may not only affect their pharmacological activity but also their secretion into milk, because of potential drug-drug interactions mediated by BCRP.

  15. Nuclear Receptors in Drug Metabolism, Drug Response and Drug Interactions

    PubMed Central

    Prakash, Chandra; Zuniga, Baltazar; Song, Chung Seog; Jiang, Shoulei; Cropper, Jodie; Park, Sulgi; Chatterjee, Bandana

    2016-01-01

    Orally delivered small-molecule therapeutics are metabolized in the liver and intestine by phase I and phase II drug-metabolizing enzymes (DMEs), and transport proteins coordinate drug influx (phase 0) and drug/drug-metabolite efflux (phase III). Genes involved in drug metabolism and disposition are induced by xenobiotic-activated nuclear receptors (NRs), i.e. PXR (pregnane X receptor) and CAR (constitutive androstane receptor), and by the 1α, 25-dihydroxy vitamin D3-activated vitamin D receptor (VDR), due to transactivation of xenobiotic-response elements (XREs) present in phase 0-III genes. Additional NRs, like HNF4-α, FXR, LXR-α play important roles in drug metabolism in certain settings, such as in relation to cholesterol and bile acid metabolism. The phase I enzymes CYP3A4/A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, CYP1A2, CYP2C8, CYP2A6, CYP2J2, and CYP2E1 metabolize >90% of all prescription drugs, and phase II conjugation of hydrophilic functional groups (with/without phase I modification) facilitates drug clearance. The conjugation step is mediated by broad-specificity transferases like UGTs, SULTs, GSTs. This review delves into our current understanding of PXR/CAR/VDR-mediated regulation of DME and transporter expression, as well as effects of single nucleotide polymorphism (SNP) and epigenome (specified by promoter methylation, histone modification, microRNAs, long non coding RNAs) on the expression of PXR/CAR/VDR and phase 0-III mediators, and their impacts on variable drug response. Therapeutic agents that target epigenetic regulation and the molecular basis and consequences (overdosing, underdosing, or beneficial outcome) of drug-drug/drug-food/drug-herb interactions are also discussed. Precision medicine requires understanding of a drug’s impact on DME and transporter activity and their NR-regulated expression in order to achieve optimal drug efficacy without adverse drug reactions. In future drug screening, new tools such as humanized mouse models and

  16. Nuclear Receptors in Drug Metabolism, Drug Response and Drug Interactions.

    PubMed

    Prakash, Chandra; Zuniga, Baltazar; Song, Chung Seog; Jiang, Shoulei; Cropper, Jodie; Park, Sulgi; Chatterjee, Bandana

    Orally delivered small-molecule therapeutics are metabolized in the liver and intestine by phase I and phase II drug-metabolizing enzymes (DMEs), and transport proteins coordinate drug influx (phase 0) and drug/drug-metabolite efflux (phase III). Genes involved in drug metabolism and disposition are induced by xenobiotic-activated nuclear receptors (NRs), i.e. PXR (pregnane X receptor) and CAR (constitutive androstane receptor), and by the 1α, 25-dihydroxy vitamin D3-activated vitamin D receptor (VDR), due to transactivation of xenobiotic-response elements (XREs) present in phase 0-III genes. Additional NRs, like HNF4-α, FXR, LXR-α play important roles in drug metabolism in certain settings, such as in relation to cholesterol and bile acid metabolism. The phase I enzymes CYP3A4/A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, CYP1A2, CYP2C8, CYP2A6, CYP2J2, and CYP2E1 metabolize >90% of all prescription drugs, and phase II conjugation of hydrophilic functional groups (with/without phase I modification) facilitates drug clearance. The conjugation step is mediated by broad-specificity transferases like UGTs, SULTs, GSTs. This review delves into our current understanding of PXR/CAR/VDR-mediated regulation of DME and transporter expression, as well as effects of single nucleotide polymorphism (SNP) and epigenome (specified by promoter methylation, histone modification, microRNAs, long non coding RNAs) on the expression of PXR/CAR/VDR and phase 0-III mediators, and their impacts on variable drug response. Therapeutic agents that target epigenetic regulation and the molecular basis and consequences (overdosing, underdosing, or beneficial outcome) of drug-drug/drug-food/drug-herb interactions are also discussed. Precision medicine requires understanding of a drug's impact on DME and transporter activity and their NR-regulated expression in order to achieve optimal drug efficacy without adverse drug reactions. In future drug screening, new tools such as humanized mouse models and

  17. An Empirical Analysis of Interactivity in Teleconference.

    ERIC Educational Resources Information Center

    Mishra, Sanjaya

    1999-01-01

    Reports on the nature of interaction during one-way video and two-way audio teleconference sessions at the Indira Gandhi National Open University (IGNOU) based on recording of actual interaction and participants' reactions. Suggests a design for an ideal teleconference session, based on findings of the study. Includes seven tables. (AEF)

  18. Variation in actual relationship as a consequence of Mendelian sampling and linkage

    PubMed Central

    HILL, W.G.; WEIR, B.S.

    2011-01-01

    Summary Although the expected relationship or proportion of genome shared by pairs of relatives can be obtained from their pedigrees, the actual quantities deviate as a consequence of Mendelian sampling and depend on the number of chromosomes and map length. Formulae have been published previously for the variance of actual relationship for a number of specific types of relatives but no general formula for non-inbred individuals is available. We provide here a unified framework that enables the variances for distant relatives to be easily computed, showing, for example, how the variance of sharing for great grandparent–great grandchild, great uncle–great nephew, half uncle–nephew and first cousins differ, even though they have the same expected relationship. Results are extended in order to include differences in map length between sexes, no recombination in males and sex linkage. We derive the magnitude of skew in the proportion shared, showing the skew becomes increasingly large the more distant the relationship. The results obtained for variation in actual relationship apply directly to the variation in actual inbreeding as both are functions of genomic coancestry, and we show how to partition the variation in actual inbreeding between and within families. Although the variance of actual relationship falls as individuals become more distant, its coefficient of variation rises, and so, exacerbated by the skewness, it becomes increasingly difficult to distinguish different pedigree relationships from the actual fraction of the genome shared. PMID:21226974

  19. Deep-Learning-Based Drug-Target Interaction Prediction.

    PubMed

    Wen, Ming; Zhang, Zhimin; Niu, Shaoyu; Sha, Haozhi; Yang, Ruihan; Yun, Yonghuan; Lu, Hongmei

    2017-04-07

    Identifying interactions between known drugs and targets is a major challenge in drug repositioning. In silico prediction of drug-target interaction (DTI) can speed up the expensive and time-consuming experimental work by providing the most potent DTIs. In silico prediction of DTI can also provide insights about the potential drug-drug interaction and promote the exploration of drug side effects. Traditionally, the performance of DTI prediction depends heavily on the descriptors used to represent the drugs and the target proteins. In this paper, to accurately predict new DTIs between approved drugs and targets without separating the targets into different classes, we developed a deep-learning-based algorithmic framework named DeepDTIs. It first abstracts representations from raw input descriptors using unsupervised pretraining and then applies known label pairs of interaction to build a classification model. Compared with other methods, it is found that DeepDTIs reaches or outperforms other state-of-the-art methods. The DeepDTIs can be further used to predict whether a new drug targets to some existing targets or whether a new target interacts with some existing drugs.

  20. Measuring Peer Socialization for Adolescent Substance Use: A Comparison of Perceived and Actual Friends’ Substance Use Effects

    PubMed Central

    Deutsch, Arielle R.; Chernyavskiy, Pavel; Steinley, Douglas; Slutske, Wendy S.

    2015-01-01

    Objective: There has been an increase in the use of social network analysis in studies of peer socialization effects on adolescent substance use. Some researchers argue that social network analyses provide more accurate measures of peer substance use, that the alternate strategy of assessing perceptions of friends’ drug use is biased, and that perceptions of peer use and actual peer use represent different constructs. However, there has been little research directly comparing the two effects, and little is known about the extent to which the measures differ in the magnitude of their influence on adolescent substance use, as well as how these two effects may be redundant or separate constructs. Method: Using Waves I and II of the National Longitudinal Study of Adolescent Health (Add Health) saturated subsample, we directly compared effects of perception of friends’ use (PFU) and actual friends’ use (AFU) on alcohol, cigarette, and marijuana initiation and persistence of use 1 year later. We also examined potential moderating effects of friendship quality and individual use on the relationship between perceived and actual friends’ substance use and outcomes. Results: Results indicated that, overall, PFU effects were larger than AFU effects; however, these effects did not significantly differ in magnitude for most models. In addition, interaction effects differed for different substances and usage outcomes, indicating the meaning of PFU and AFU constructs (and thus, different types of peer socialization) may change based on substance and type of use. Conclusions: These results highlight the multifaceted nature of peer influence on substance use and the importance of assessing multiple aspects of peer socialization while accounting for distinct contexts related to specific substances and use outcomes. PMID:25785802

  1. The interaction of visual and proprioceptive inputs in pointing to actual and remembered targets in Parkinson's disease.

    PubMed

    Adamovich, S V; Berkinblit, M B; Hening, W; Sage, J; Poizner, H

    2001-01-01

    We previously reported that Parkinson's disease patients could point with their eyes closed as accurately as normal subjects to targets in three-dimensional space that were initially presented with full vision. We have now further restricted visual information in order to more closely examine the individual and combined influences of visual information, proprioceptive feedback, and spatial working memory on the accuracy of Parkinson's disease patients. All trials were performed in the dark. A robot arm presented a target illuminated by a light-emitting diode at one of five randomly selected points composing a pyramidal array. Subjects attempted to "touch" the target location with their right finger in one smooth movement in three conditions: dark, no illumination of arm or target during movement; movement was to the remembered target location after the robot arm retracted; finger, a light-emitting diode on the pointing fingertip was visible during the movement but the target was extinguished; again, movement was to the remembered target location; and target, the target light-emitting diode remained in place and visible throughout the trial but there was no vision of the arm. In the finger condition, there is no need to use visual-proprioceptive integration, since the continuously visualized fingertip position can be compared to the remembered location of the visual target. In the target condition, the subject must integrate the current visible target with arm proprioception, while in the dark condition, the subject must integrate current proprioception from the arm with the remembered visual target. Parkinson's disease patients were significantly less accurate than controls in both the dark and target conditions, but as accurate as controls in the finger condition. Parkinson's disease patients, therefore, were selectively impaired in those conditions (target and dark) which required integration of visual and proprioceptive information in order to achieve accurate movements. In contrast, the patients' normal accuracy in the finger condition indicates that they had no substantial deficits in their relevant spatial working memory. Final arm configurations were significantly different in the two subject groups in all three conditions, even in the finger condition where mean movement endpoints were not significantly different. Variability of the movement endpoints was uniformly increased in Parkinson's disease patients across all three conditions. The current study supports an important role for the basal ganglia in the integration of proprioceptive signals with concurrent or remembered visual information that is needed to guide movements. This role can explain much of the patients' dependence on visual information for accuracy in targeted movements. It also underlines what may be an essential contribution of the basal ganglia to movement, the integration of afferent information that is initially processed through multiple, discrete modality-specific pathways, but which must be combined into a unified and continuously updated spatial model for effective, accurate movement.

  2. Double-blind photo lineups using actual eyewitnesses: an experimental test of a sequential versus simultaneous lineup procedure.

    PubMed

    Wells, Gary L; Steblay, Nancy K; Dysart, Jennifer E

    2015-02-01

    Eyewitnesses (494) to actual crimes in 4 police jurisdictions were randomly assigned to view simultaneous or sequential photo lineups using laptop computers and double-blind administration. The sequential procedure used in the field experiment mimicked how it is conducted in actual practice (e.g., using a continuation rule, witness does not know how many photos are to be viewed, witnesses resolve any multiple identifications), which is not how most lab experiments have tested the sequential lineup. No significant differences emerged in rates of identifying lineup suspects (25% overall) but the sequential procedure produced a significantly lower rate (11%) of identifying known-innocent lineup fillers than did the simultaneous procedure (18%). The simultaneous/sequential pattern did not significantly interact with estimator variables and no lineup-position effects were observed for either the simultaneous or sequential procedures. Rates of nonidentification were not significantly different for simultaneous and sequential but nonidentifiers from the sequential procedure were more likely to use the "not sure" response option than were nonidentifiers from the simultaneous procedure. Among witnesses who made an identification, 36% (41% of simultaneous and 32% of sequential) identified a known-innocent filler rather than a suspect, indicating that eyewitness performance overall was very poor. The results suggest that the sequential procedure that is used in the field reduces the identification of known-innocent fillers, but the differences are relatively small.

  3. Quantifying actual and theoretical ethanol yields for switchgrass strains using NIRS analyses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Quantifying actual and theoretical ethanol yields from biomass conversion processes such as simultanteous saccharification and fermentation (SSF) requires expensive, complex fermentation assays and extensive compositional analyses of the biomass sample. Near infrared reflectance spectroscopy (NIRS...

  4. Prediction of Self-Actualization in Male Participants in a Group Conducted by Female Leaders

    ERIC Educational Resources Information Center

    Follingstad, Diane R.; And Others

    1976-01-01

    Attempts to predict which male Ss (high or low authoritarian personality) would reflect higher self-actualization scores when exposed to a 16-hour marathon group conducted by female leaders. (Author/RK)

  5. Effect of Supervisor Actually Writing Performance Reports, Sex, and Communication between Workers on Organizational Effectiveness.

    DTIC Science & Technology

    1981-09-01

    SUPERVISOR ACTUALLY WRITING PERFORMANCE AU-APIT-LS Technical REPORTS, SEX, AND COMUNICATION BETWEEN WORKERS Report ON ORGANIZATIONAL EFFECTIVENESS 6...Technolcy (ATC Interpersonal comunication flterwfl A L 4.... Supervisory performance evalaution 20. ABSTRACT (Continue an reverse aide It necesry and

  6. An Analysis of Reenlistment Intention and Actual Reenlistment of Army Male Second-Term Enlisted Personnel

    DTIC Science & Technology

    1991-12-01

    satisfaction with work environment , and satisfaction with pecuniary benefits. The result indicates that there were significant differences in the factors...affecting the intended and actual reenlistment decisions. Black, YOS, Medical, Probability of Alternative, Satisfaction with Work Environment , and...Satisfaction with Pecuniary Benefits were significant in explaining intentions while Single/Wo/Dep., Married/Wo/Dep., YOS, Admin/Supply, and Satisfaction with Work Environment were significant in explaining actual reenlistment.

  7. Comparison of Intent-to-Leave with Actual Turnover within the FAA

    DTIC Science & Technology

    2006-12-01

    Incentives for early retirement (e.g., “buy-outs”) were offered in 1997 throughout the federal government as part of the shrinking of the federal...workforce under the Clinton administration (National Performance Review, 1993). It is possible that incentives for early retirement inflated the expressed...buy-out” as the primary reason. The FAA did not offer incentives for early retirement in 2000 through 2004. Actual turnover The actual turnover rate

  8. Correlation of parents' religious behavior with family's emotional relations and students' self-actualization.

    PubMed

    Poorsheikhali, Fatemah; Alavi, Hamid Reza

    2015-02-01

    The main goal of this research is to study the relationship between parents' religious behavior, emotional relations inside family, and self-actualization of male and female high school students of district 2 in Kerman city. Research method is descriptive and of correlative type. Questionnaires of parent's religious behavior, emotional relations inside family, and students' self-actualization were used in the research. After collecting questionnaires, data were analyzed by SPSS, MINITAB, and EXCEL software. The sample volume in the research has been 309 students and their parents, and the sampling method was in the form of classification and then in the form of cluster in two stages. 1.29 % of students had a low self-actualization, 17.15 % had average, and 81.55 % of them had high self-actualization. Also the results showed that 9.4 % of emotional relations in families were undesirable, 55.3 % were relatively desirable, and 35.3 % were desirable. Moreover, 2.27 % of parents' religious behavior was inappropriate, 29.13 % was relatively appropriate, and 68.61 % was appropriate. The main results of the research are as follows: (1) There is a significant positive correlation between parents' religious behavior and emotional relations inside students' family. (2) There is not any significant correlational between parents' religious behavior and students' self-actualization. (3) There is a significant positive correlation between emotional relations inside family and students' self-actualization.

  9. From preferred to actual mate characteristics: the case of human body shape.

    PubMed

    Courtiol, Alexandre; Picq, Sandrine; Godelle, Bernard; Raymond, Michel; Ferdy, Jean-Baptiste

    2010-09-27

    The way individuals pair to produce reproductive units is a major factor determining evolution. This process is complex because it is determined not only by individual mating preferences, but also by numerous other factors such as competition between mates. Consequently, preferred and actual characteristics of mates obtained should differ, but this has rarely been addressed. We simultaneously measured mating preferences for stature, body mass, and body mass index, and recorded corresponding actual partner's characteristics for 116 human couples from France. Results show that preferred and actual partner's characteristics differ for male judges, but not for females. In addition, while the correlation between all preferred and actual partner's characteristics appeared to be weak for female judges, it was strong for males: while men prefer women slimmer than their actual partner, those who prefer the slimmest women also have partners who are slimmer than average. This study therefore suggests that the influences of preferences on pair formation can be sex-specific. It also illustrates that this process can lead to unexpected results on the real influences of mating preferences: traits considered as highly influencing attractiveness do not necessarily have a strong influence on the actual pairing, the reverse being also possible.

  10. Interactions between Transporters and Herbal Medicines/Drugs: A Focus on Hepatoprotective Compounds.

    PubMed

    Zhang, Aijie; Li, Quansheng; He, Xin; Si, Duanyun; Liu, Changxiao

    2015-01-01

    Many herbal medicines and drugs are available in the clinic as potent hepatoprotective agents for the treatment of commonly occurring liver diseases. Recently, herbal medicines such as silymarin and curcumin have gained more attention and popularity for the treatment of various liver diseases because of their safety and efficacy profiles. Some of them are related to transporters for drug disposition processes, therapeutic efficacy and/or adverse drug reactions. Currently, herbal medicines and diet supplements made from natural products are widely used in patients who are being treated with conventional prescription medicines, which are related to an increasing risk of herbal-drug interactions (HDIs) and/or drug-drug interactions (DDIs). The purpose of present review is to summarize the contemporary knowledge of transporter-mediated HDIs or DDIs for herbal medicines/drugs focusing on hepatoprotective compounds. Several herbal medicines/drugs are discussed in detail in this review.

  11. Comparison of actual tidal volume in neonatal lung model volume control ventilation using three ventilators.

    PubMed

    Toyama, H; Endo, Y; Ejima, Y; Matsubara, M; Kurosawa, S

    2011-07-01

    In neonates, small changes in tidal volumes (V(T)) may lead to complications. Previous studies have shown a significant difference between ventilator-measured tidal volume and tidal volume delivered (actual V(T)). We evaluated the accuracy of three different ventilators to deliver small V(T) during volume-controlled ventilation. We tested Servo 300, 840 ventilator and Evita 4 Neoflow ventilators with lung models simulating normal and injured neonatal lung compliance models. Gas volume delivered from the ventilator into the test circuit (V(TV)) and actual V(T) to the test lung were measured using Ventrak respiration monitors at set V(T) (30 ml). The gas volume increase of the breathing circuit was then calculated. Tidal volumes of the SV300 and PB840 in both lung models were similar to the set V(T) and the actual tidal volumes in the injured model (20.7 ml and 19.8 ml, respectively) were significantly less than that in the normal model (27.4 ml and 23.4 ml). PB840 with circuit compliance compensation could not improve the actual V(T). V(TV) of the EV4N in the normal and the injured models (37.8 ml and 46.6 ml) were markedly increased compared with set V(T), and actual V(T) were similar to set V(T) in the normal and injured model (30.2 ml and 31.9 ml, respectively). EV4N measuring V(T) close to the lung could match actual V(T) to almost the same value as the set V(T) however the gas volume of the breathing circuit was increased. If an accurate value for the patient's actual V(T) is needed, this V(T) must be measured by a sensor located between the Y-piece and the tracheal tube.

  12. A clinically significant drug interaction between warfarin and amoxicillin resulting in persistent postoperative bleeding in a dental patient.

    PubMed

    Goodchild, Jason H; Donaldson, Mark

    2013-07-01

    One of the few cases reported in the literature, this article reviews the case of a 66-year-old man who developed an elevated international normalized ratio and sustained clinically significant bleeding as a result of a drug-drug interaction between warfarin and amoxicillin. Given the popularity of these medications, it is surprising that these reports are not more commonplace, and there is a concern that the lack of reports may result in practitioners overlooking the significance of this possible complication. Although the mechanism for this interaction is not fully known, it is suspected that a decrease in vitamin K-producing gut flora, with resulting vitamin K deficiency, is the most likely contributing factor. An objective causality assessment revealed that this adverse drug event, secondary to the warfarin and amoxicillin interaction, was probable.

  13. Adolescents' explicit and implicit evaluations of hypothetical and actual peers with different bullying participant roles.

    PubMed

    Pouwels, J Loes; Lansu, Tessa A M; Cillessen, Antonius H N

    2017-03-15

    This study examined how adolescents evaluate bullying at three levels of specificity: (a) the general concept of bullying, (b) hypothetical peers in different bullying participant roles, and (c) actual peers in different bullying participant roles. Participants were 163 predominantly ethnic majority adolescents in The Netherlands (58% girls; Mage=16.34years, SD=0.79). For the hypothetical peers, we examined adolescents' explicit evaluations as well as their implicit evaluations. Adolescents evaluated the general concept of bullying negatively. Adolescents' explicit evaluations of hypothetical and actual peers in the bullying roles depended on their own role, but adolescents' implicit evaluations of hypothetical peers did not. Adolescents' explicit evaluations of hypothetical peers and actual peers were different. Hypothetical bullies were evaluated negatively by all classmates, whereas hypothetical victims were evaluated relatively positively compared with the other roles. However, when adolescents evaluated their actual classmates, the differences between bullies and the other roles were smaller, whereas victims were evaluated the most negatively of all roles. Further research should take into account that adolescents' evaluations of hypothetical peers differ from their evaluations of actual peers.

  14. Actual and perceived sleep: associations with daytime functioning among postpartum women.

    PubMed

    Insana, Salvatore P; Stacom, Elizabeth E; Montgomery-Downs, Hawley E

    2011-02-01

    Sleep and wake have a homeostatic relation that influences most aspects of physiology and waking behavior. Sleep disturbance has a detrimental effect on sleepiness and psychomotor vigilance. The purpose of this study was to identify which actual or perceived sleep characteristics accounted for the most variance in daytime functioning among postpartum mothers. Seventy first-time postpartum mothers' actual sleep (actigraphically estimated: total sleep time, number of wake bouts, length of nocturnal wake, and sleep efficiency) and perceived sleep (self-reported: number of awakenings, wake time, and sleep quality) were measured along with their daytime functioning (Stanford Sleepiness Scale [SSS], Epworth Sleepiness Scale [ESS], Visual Analogue of Fatigue Scale [VAFS], and morning Psychomotor Vigilance Test [PVT]). Data were repeatedly collected from the same sample during postpartum weeks 2, 7, and 13. Four stepwise linear regressions were calculated for each postpartum week to examine which objective and/or subjective variable(s) accounted for the most variance in daytime functioning. The SSS and VAFS were both most consistently associated with perceived sleep quality. The ESS was most consistently associated with actual total sleep time. PVT performance was most consistently associated with estimates of actual and perceived sleep efficiency. Actual and perceived sleep profiles were differentially associated with specific daytime functions. These results from postpartum mothers may indicate that populations who experience specific forms of sleep disturbance (e.g. fragmentation and/or deprivation) may also experience specific daytime conditions.

  15. Observation results of actual phase defects using micro coherent EUV scatterometry microscope

    NASA Astrophysics Data System (ADS)

    Hashimoto, Hiraku; Harada, Tetsuo; Watanabe, Takeo

    2016-10-01

    One of the critical issue of EUV lithography is fabrication of defect-free mask. The origin of the defect is a particle inside the multilayer and bump or pit on glass substrate. This type of defect is called a phase defect. If there is a phase defect, the reflection phase is disordered. As a result, the phase structure is printed as a defect on a wafer. Thus, we have developed micro coherent EUV scatterometry microscope (we called micro-CSM) for phase defect characterization. Micro-CSM records scattering signal from a defect directly exposed by focused coherent EUV having a spot size of φ140-nm in diameter. An off-axis-type Fresnel zone plate was employed as a focusing optics. Phase distribution of the defect is reconstructed with the scattering image by the coherent-diffraction-imaging method. We observed actual phase defects in this work. Actual phase defects were on a mask blanks which was the same grade of the pre-production mask of the semiconductor devices. The positions of actual phase defects have been already inspected by the actinic blank inspection tool. And, the actual phase defects have been already observed using an atomic force microscope. A purpose of this work is observation of these actual defects using micro-CSM and comparison of the results.

  16. Relative contribution of effects included in contemporary groups for adjusted and actual 120-day and 210-day weights in Nelore cattle in Brazil

    PubMed Central

    Pascoa, Lillian; de los Reyes, Arcadio; Elzo, Mauricio A.; Ferreira, Jorge L.; Bezerra, Luiz A.F.; Lôbo, Raysildo B.

    2011-01-01

    The objective of this research was to estimate the relative magnitude of effects included in contemporary groups (CG) and their interactions with adjusted and actual 120 d and 210 d weights in 72,731 male and female Nelore calves born from 1985 to 2005 in 40 herds from PMGRN (Genetic Improvement Program of Nelore). Ten models with different CG structures were compared. The analyses were done using the general linear models (GLM) procedure run in SAS software. All of the effects included in the CG for each model were significant (p < 0.001) for the four traits analyzed. Inclusion of semester or trimester of birth as part of a CG was more appropriate than its use as an independent effect in the model because it accounted for interactions with the other effects in the CG. Calf sex (CS) and dam age at calving (DAC) had similar effects across the models, which suggested independence from other effects in these models. The corresponding age deviation effect had a larger impact on actual weight at 120 d than any other effect in all of the models tested. The use of actual weights in models with no CS effect in CG provides an alternative that would allow better genetic connectedness among CGs and greater accuracy in genetic evaluations. PMID:22215959

  17. Actual and Simulated Weightlessness Inhibit Osteogenesis in Long Bone Metaphysis by Different Mechanisms

    NASA Technical Reports Server (NTRS)

    Roberts, W. E.

    1985-01-01

    Weightlessness and simulated weightlessness inhibit the rate of periosteal bone formation in long bones. Formation of preosteoblasts is suppressed in periodontal ligament (PDL) of maxillary molars, which suggests a generalized block in osteoblast histogenesis. Growth in length of long bones is decreased by simulated weightlessness, but there are no reliable data on the influence of actual weightlessness on metaphyseal growth. The nuclear size assay for assessing relative numbers of osteoblast precursor cells was utilized in the primary spongiosa of growing long bones subjected to actual and simulated weightlessness. It is found that: (1) Actual weightlessness decreases total number of osteogenic cells and inhibits differentiation of osteoblast precursor cells, (2) Simulated weightlessness suppresses only osteoblast differentation; and (3) The nuclear morphometric assay is an effective means of assessing osteogenic activity in the growing metaphysis or long bones.

  18. `PROBABILISTIC Knowledge' as `OBJECTIVE Knowledge' in Quantum Mechanics: Potential Immanent Powers Instead of Actual Properties

    NASA Astrophysics Data System (ADS)

    Ronde, Christian De

    In classical physics, probabilistic or statistical knowledge has been always related to ignorance or inaccurate subjective knowledge about an actual state of affairs. This idea has been extended to quantum mechanics through a completely incoherent interpretation of the Fermi-Dirac and Bose-Einstein statistics in terms of "strange" quantum particles. This interpretation, naturalized through a widespread "way of speaking" in the physics community, contradicts Born's physical account of Ψ as a "probability wave" which provides statistical information about outcomes that, in fact, cannot be interpreted in terms of `ignorance about an actual state of affairs'. In the present paper we discuss how the metaphysics of actuality has played an essential role in limiting the possibilities of understating things differently. We propose instead a metaphysical scheme in terms of immanent powers with definite potentia which allows us to consider quantum probability in a new light, namely, as providing objective knowledge about a potential state of affairs.

  19. Discrepancy between actual and ideal body images; Impact on eating and exercise behaviors.

    PubMed

    Anton, S D; Perri, M G; Riley, J R

    2000-12-01

    This study examined how discrepancies between actual and ideal body images are related to eating and exercise patterns. A total of 115 college-age women completed the Body Discrepancy Scale (BDS, a measure of the discrepancy between one's "actual" vs. "ideal" weight and size), a leisure-time physical activity survey, and questionnaires assessing the intake of fat and fiber (i.e., fruits and vegetables), as well as measures of maladaptive eating attitudes and behaviors. Partial correlations (controlling for Body Mass Index, BMI) showed that scores on the BDS were significantly (P's<.05) associated with low levels of physical activity (r=-.28), with low levels of fruit and vegetable consumption (r=-.19), and with high levels of body image dissatisfaction (r=.32) and binge eating (r=.32). Collectively, these findings suggest that discrepancies between actual and ideal body images are associated with maladaptive eating and exercise patterns.

  20. Remote Sensing of Actual Evapotranspiration at Basin Scale in the Northern Tibetan Plateau Area

    NASA Astrophysics Data System (ADS)

    Zhong, Lei; Zou, Mijun; Ma, Yaoming; Su, Zhongbo; Ma, Weiqiang; Hu, Yuanyuan; Han, Cunbo; Wang, Binbin

    2016-08-01

    Evapotranspiration(ET), as one of the most uncertain components of the water cycle, was derived in the Nagqu river basin of the northern Tibetan Plateau based on multi-sensor remote sensing data and field observations under clear-sky condition. Improved land surface albedo, improved downward shortwave radiation flux and reconstructed normalized difference vegetation index (NDVI) were coupled into the topographical enhanced surface energy balance system (TESEBS) model to estimate actual ET. The model-estimated results were compared with those determined by the combinatory method which were treated as actual ET. The results indicated that the model-estimated ET agreed well with actual ET with correlation coefficient, mean bias error and root mean square error of 0.836, 0.087 and 0.140 respectively.

  1. Differences in science students' view of ideal and actual role behavior according to success and gender

    NASA Astrophysics Data System (ADS)

    Kauchak, Don; Peterson, Ken

    Information about how success and gender affect students' views of ideal and actual classroom role behavior can help both researchers and teachers better understand classroom components such as achievement and curriculum. A 20-item double Q sort was used to measure differences in perceptions of high school science students according to letter grades and gender. Individual Q sort item rankings of 160 students were tested for significant differences according to letter grade received; item ratings were compared according to gender for 215 students. Differences in perception according to success were found for both ideal and actual behavior; 8 and 5 items, respectively, out of each 20-item sort were found to be significant at the p = < 0.05 level. No such overall patterns of difference in view were found between boys and girls, although three ideal student items and one actual self-report item were found to be significantly different at the p = < 0.05 level.

  2. Differences between actual and expected leisure activities after total knee arthroplasty for osteoarthritis.

    PubMed

    Jones, Dina L; Bhanegaonkar, Abhijeet J; Billings, Anthony A; Kriska, Andrea M; Irrgang, James J; Crossett, Lawrence S; Kwoh, C Kent

    2012-08-01

    This prospective cohort study determined the type, frequency, intensity, and duration of actual vs expected leisure activity among a cohort undergoing total knee arthroplasty. Data on actual and expected participation in 36 leisure activities were collected preoperatively and at 12 months in 90 patients with knee osteoarthritis. Despite high expectations, there were statistically and clinically significant differences between actual and expected activity at 12 months suggesting that expectations may not have been fulfilled. The differences were equivalent to walking 14 less miles per week than expected, which is more than the amount of activity recommended in national physical activity guidelines. Perhaps an educational intervention could be implemented to help patients establish appropriate and realistic leisure activity expectations before surgery.

  3. Term Familiarity to indicate Perceived and Actual Difficulty of Text in Medical Digital Libraries.

    PubMed

    Leroy, Gondy; Endicott, James E

    2011-10-01

    With increasing text digitization, digital libraries can personalize materials for individuals with different education levels and language skills. To this end, documents need meta-information describing their difficulty level. Previous attempts at such labeling used readability formulas but the formulas have not been validated with modern texts and their outcome is seldom associated with actual difficulty. We focus on medical texts and are developing new, evidence-based meta-tags that are associated with perceived and actual text difficulty. This work describes a first tag, term familiarity , which is based on term frequency in the Google corpus. We evaluated its feasibility to serve as a tag by looking at a document corpus (N=1,073) and found that terms in blogs or journal articles displayed unexpected but significantly different scores. Term familiarity was then applied to texts and results from a previous user study (N=86) and could better explain differences for perceived and actual difficulty.

  4. Power and Control in Kathmandu: A Comparison of Attempted Power, Actual Power, and Achieved Power.

    PubMed

    Emery, Clifton R; Thapa, Sirjana; Wu, Shali

    2016-05-05

    We argue that the concept of power has been inadvertently sidelined in recent theory and research on husband violence. Three types of relationship power may matter with respect to husband violence: attempted power, actual power, and achieved power. Analyses of a randomly selected representative sample of 270 married or partnered women in Kathmandu showed that actual power was related to husband violence prevalence, severity, and injury. Achieved power was related to husband violence prevalence and severity, and attempted power was related to husband violence injury. Implications are discussed.

  5. Correlation of ideal and actual shear strengths of metals with their friction properties

    NASA Technical Reports Server (NTRS)

    Miyoshi, K.; Buckley, D. H.

    1981-01-01

    The relation between the ideal and actual shear strengths and friction properties of clean metals in contact with clean diamond, boron nitride, silicon carbide, manganese-zinc ferrite, and the metals themselves in vacuum is discussed. An estimate of the ideal shear strength for metals is obtained from the shear modulus, the repeat distance of atoms in the direction of shear of the metal, and the interplanar spacing of the shearing planes. The coefficient of friction for metals is shown to be correlated with both the ideal and actual shear strength of metals. The higher the strength of the metal, the lower the coefficient of friction occurs.

  6. Rifampin-sirolimus-voriconazole interaction in a hematopoietic cell transplant recipient.

    PubMed

    Wasko, Justin A; Westholder, James S; Jacobson, Pamala A

    2017-01-01

    Purpose Patients undergoing hematopoietic cell transplantation are treated with multiple medications, potentially complicated by drug-drug interactions. Drug interactions with sirolimus, voriconazole, and rifampin are particularly difficult because of the complex and simultaneous enzyme inhibition and induction mechanisms. We report a hematopoietic cell transplantation patient receiving sirolimus and voriconazole who was given rifampin while being treated for presumed methicillin-resistant Staphylococcus aureus meningitis. Summary A 31 year-old female received a nonmyeloablative allogeneic umbilical cord hematopoietic cell transplantation for myelodysplastic syndrome transformed to acute myeloid leukemia (AML). Her graft versus host disease and antifungal prophylaxis included sirolimus and voriconazole, respectively. Therapeutic drug monitoring prior to admission revealed a stable outpatient sirolimus regimen of 0.4 mg orally daily (trough goal 3-12 mcg/L). She was admitted to the inpatient hematopoietic cell transplantation service and diagnosed with methicillin-resistant Staphylococcus aureus bacteremia and presumed bacterial meningitis 217 days after transplant. Intravenous rifampin and vancomycin were initiated and voriconazole was changed to micafungin. Sirolimus trough concentrations were undetectable two days after starting rifampin. Therapeutic sirolimus concentrations were achieved four days later, at a sirolimus dose of 16-18 mg orally daily. Rifampin was discontinued after nine days and the sirolimus dose was adjusted accordingly, maintaining therapeutic levels throughout follow-up. The patient suffered a flare of chronic skin graft versus host disease requiring etanercept, high-dose systemic steroids, and topical steroids. Conclusion To the best of our knowledge, this is the first report describing the management of sirolimus during the transition from voriconazole inhibition to rifampin induction. Clinicians should be aware of potential drug-drug

  7. Possible interaction between letrozole and long-acting injectable zuclopenthixol.

    PubMed

    Lertxundi, Unax; Hernandez, Rafael; Albeniz, Juan Medrano; Echaburu, Saioa Domingo; Ruiz, Borja; García, Montserrat García; Aguirre, Carmelo

    2015-01-01

    Mrs A, a 68-year-old woman with paranoid schizophrenia, was on long-term psychiatric treatment with long-acting intramuscular zuclopenthixol, quetiapine and alprazolam when, in April 2012, she was diagnosed with right breast infiltrating ductal carcinoma. After starting treatment with letrozole on 4 July, Mrs A progressively developed extrapyramidal symptoms and these were particularly evident after each zuclopenthixol administration. On 9 January, both quetiapine and alprazolam were stopped due to excessive lethargy. After the administration of the last dose of zuclopenthixol on 26 January, she presented with sedation, sialorrhea, festinant gait, axial dystonia and dysphagia, all of which were severe. The introduction of letrozole was the only change that had been made to her pharmacotherapeutic regimen in that period. The rest of the findings on neurological examination were normal. Renal function was adequate. Slow symptom onset and progressive worsening until full-blown clinical presentation after 6 months, and the dramatic improvement in the clinical picture achieved 2 days after treatment with biperiden, suggests a long-term insidious interaction leading to zuclopenthixol accumulation. To the best of our knowledge, this is the first report of a possible interaction between letrozole and zuclopenthixol. We consider that it warrants further investigation. In the meanwhile, physicians should be aware of the occurrence of this potentially serious drug-drug interaction.

  8. How Are Mate Preferences Linked with Actual Mate Selection? Tests of Mate Preference Integration Algorithms Using Computer Simulations and Actual Mating Couples

    PubMed Central

    Conroy-Beam, Daniel; Buss, David M.

    2016-01-01

    Prior mate preference research has focused on the content of mate preferences. Yet in real life, people must select mates among potentials who vary along myriad dimensions. How do people incorporate information on many different mate preferences in order to choose which partner to pursue? Here, in Study 1, we compare seven candidate algorithms for integrating multiple mate preferences in a competitive agent-based model of human mate choice evolution. This model shows that a Euclidean algorithm is the most evolvable solution to the problem of selecting fitness-beneficial mates. Next, across three studies of actual couples (Study 2: n = 214; Study 3: n = 259; Study 4: n = 294) we apply the Euclidean algorithm toward predicting mate preference fulfillment overall and preference fulfillment as a function of mate value. Consistent with the hypothesis that mate preferences are integrated according to a Euclidean algorithm, we find that actual mates lie close in multidimensional preference space to the preferences of their partners. Moreover, this Euclidean preference fulfillment is greater for people who are higher in mate value, highlighting theoretically-predictable individual differences in who gets what they want. These new Euclidean tools have important implications for understanding real-world dynamics of mate selection. PMID:27276030

  9. Exaggerated Claims for Interactive Stories

    NASA Astrophysics Data System (ADS)

    Thue, David; Bulitko, Vadim; Spetch, Marcia; Webb, Michael

    As advertising becomes more crucial to video games' success, developers risk promoting their products beyond the features that they can actually include. For features of interactive storytelling, the effects of making such exaggerations are not well known, as reports from industry have been anecdotal at best. In this paper, we explore the effects of making exaggerated claims for interactive stories, in the context of the theory of advertising. Results from a human user study show that female players find linear and branching stories to be significantly less enjoyable when they are advertised with exaggerated claims.

  10. Divergence of actual and reference evapotranspiration observations for irrigated sugarcane with windy tropical conditions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Standardized reference evapotranspiration (ET) and ecosystem-specific vegetation coefficients are frequently used to estimate actual ET. However, equations for calculating reference ET have not been well validated in more humid environments. We measured ET (ETEC) using Eddy Covariance (EC) towers a...

  11. 29 CFR 776.10 - Employees participating in the actual movement of commerce.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 3 2010-07-01 2010-07-01 false Employees participating in the actual movement of commerce... commerce. (a) Under the principles stated in § 776.9, the wage and hours provisions of the Act apply... instrumentalities and channels of interstate and foreign commerce. Similarly, employees of such businesses...

  12. The Lived-Experience of Novice Nurse's Actualizing Clinical Reasoning in Academic Simulation

    ERIC Educational Resources Information Center

    Brinker, Mary Catherine

    2016-01-01

    The purpose of this existential-phenomenological study was to address the first-person perspective of what it is like to experience clinical reasoning during a simulation. It was not known how a novice nurse would describe the experience of actualizing clinical reasoning during the academic simulation experience. In order to maintain the…

  13. Writing at the Graduate Level: What Tasks Do Professors Actually Require?

    ERIC Educational Resources Information Center

    Cooper, Amy; Bikowski, Dawn

    2007-01-01

    This paper presents a case study of writing tasks in graduate courses at a large, American university. The study investigates writing tasks across the curriculum and draws implications for curriculum design in English for Academic Purposes (EAP). Using actual course syllabi for task analysis, the researchers analyzed 200 course syllabi from 20…

  14. The On-Site Mentor of Counseling Interns: Perceptions of Ideal Role and Actual Role Performance

    ERIC Educational Resources Information Center

    Lazovsky, Rivka; Shimoni, Aviva

    2007-01-01

    This study examined the role of the ideal on-site mentor and the actual mentor's role performance, as perceived by 158 mentor counselors and 171 school counseling interns. Results indicated that the ideal mentor's professional traits were given priority by both groups and that the teacher role was the most salient among role domains. In the actual…

  15. The Role of Non-Actuality Implicatures in Processing Elided Constituents

    ERIC Educational Resources Information Center

    Grant, Margaret; Clifton, Charles, Jr.; Frazier, Lyn

    2012-01-01

    When an elided constituent and its antecedent do not match syntactically, the presence of a word implying the non-actuality of the state of affairs described in the antecedent seems to improve the example. ("This information should be released but Gorbachev didn't." vs. "This information was released but Gorbachev didn't.") We model this effect in…

  16. 41 CFR 301-11.300 - When is actual expense reimbursement warranted?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 41 Public Contracts and Property Management 4 2010-07-01 2010-07-01 false When is actual expense reimbursement warranted? 301-11.300 Section 301-11.300 Public Contracts and Property Management Federal Travel... meals are procured at a prearranged place such as a hotel where a meeting, conference or...

  17. Using Actual Patients in the Classroom To Develop Positive Student Attitudes Toward Pharmaceutical Care.

    ERIC Educational Resources Information Center

    Chisholm, Marie A.; Wade, William E.

    1999-01-01

    Evaluates the use of actual patients in a required clinical applications course at the University of Georgia College of Pharmacy. Patients discuss their illness and how it affects their lives with the first-year students. On 12 of 13 items, students scored significantly higher on an attitude survey following the first patient presentation than…

  18. Sexualization of Awareness: Catchy, but Does It Actually Increase Knowledge of Breast Cancer?

    ERIC Educational Resources Information Center

    Burgess, Melinda C. R.; Murray, Ashley B.

    2014-01-01

    Currently, in the United States, there exist numerous public awareness campaigns about breast cancer. Many of these campaigns are highly sexualized, focusing on the breasts as an object of fun, as opposed to focusing on information about prevention/diagnosis/treatment. In spite of their popularity, it is unknown what effect they actually have on…

  19. Relative Proximity Theory: Measuring the Gap between Actual and Ideal Online Course Delivery

    ERIC Educational Resources Information Center

    Swart, William; MacLeod, Kenneth; Paul, Ravi; Zhang, Aixiu; Gagulic, Mario

    2014-01-01

    Based on the Theory of Transactional Distance and Needs Assessment, this article reports a procedure for quantitatively measuring how close the actual delivery of a course was to ideal, as perceived by students. It extends Zhang's instrument and prescribes the computational steps to calculate relative proximity at the element and construct…

  20. Forest Landowner Education Interests and Delivery Preferences: A Retrospective Look at Survey Results and Actual Participation

    ERIC Educational Resources Information Center

    Zobrist, Kevin W.; Rozance, Mary Ann

    2015-01-01

    This article presents survey data on education interests and delivery preferences of small forest landowners in Washington and compares it to actual program participation over 6 years. The survey was conducted in late 2007 to guide development and implementation of a Extension forestry program. The survey found broad interest across many topics…

  1. 12 CFR 408.5 - Ensuring environmental documents are actually considered in Agency decision-making.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... considered in Agency decision-making. 408.5 Section 408.5 Banks and Banking EXPORT-IMPORT BANK OF THE UNITED... Procedures § 408.5 Ensuring environmental documents are actually considered in Agency decision-making... environmental documents in agency decision-making. To implement these requirements, Eximbank officials will:...

  2. 12 CFR 408.5 - Ensuring environmental documents are actually considered in Agency decision-making.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... considered in Agency decision-making. 408.5 Section 408.5 Banks and Banking EXPORT-IMPORT BANK OF THE UNITED... Procedures § 408.5 Ensuring environmental documents are actually considered in Agency decision-making... environmental documents in agency decision-making. To implement these requirements, Eximbank officials will:...

  3. 12 CFR 408.5 - Ensuring environmental documents are actually considered in Agency decision-making.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... considered in Agency decision-making. 408.5 Section 408.5 Banks and Banking EXPORT-IMPORT BANK OF THE UNITED... Procedures § 408.5 Ensuring environmental documents are actually considered in Agency decision-making... environmental documents in agency decision-making. To implement these requirements, Eximbank officials will:...

  4. 12 CFR 408.5 - Ensuring environmental documents are actually considered in Agency decision-making.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... considered in Agency decision-making. 408.5 Section 408.5 Banks and Banking EXPORT-IMPORT BANK OF THE UNITED... Procedures § 408.5 Ensuring environmental documents are actually considered in Agency decision-making... environmental documents in agency decision-making. To implement these requirements, Eximbank officials will:...

  5. 12 CFR 408.5 - Ensuring environmental documents are actually considered in Agency decision-making.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... considered in Agency decision-making. 408.5 Section 408.5 Banks and Banking EXPORT-IMPORT BANK OF THE UNITED... Procedures § 408.5 Ensuring environmental documents are actually considered in Agency decision-making... environmental documents in agency decision-making. To implement these requirements, Eximbank officials will:...

  6. The Actual and Desired Role of Local Vocational Directors: A Comparison of Perceptions.

    ERIC Educational Resources Information Center

    Moore, Gary E.; And Others

    The current and desired role of local vocational directors (LVDs) in North Carolina was assessed through a survey of superintendents, principals, vocational teachers, and LVDs. A literature review indicated differences in various groups' perceptions regarding the actual and ideal role of LVDs. The instrument required respondents to reply 2 times…

  7. Actual and Prescribed Energy and Protein Intakes for Very Low Birth Weight Infants: An Observational Study

    ERIC Educational Resources Information Center

    Abel, Deborah Marie

    2012-01-01

    Objectives: To determine (1) whether prescribed and delivered energy and protein intakes during the first two weeks of life met Ziegler's estimated requirements for Very Low Birth Weight (VLBW) infants, (2) if actual energy during the first week of life correlated with time to regain birth weight and reach full enteral nutrition (EN) defined as…

  8. Salient Key Features of Actual English Instructional Practices in Saudi Arabia

    ERIC Educational Resources Information Center

    Al-Seghayer, Khalid

    2015-01-01

    This is a comprehensive review of the salient key features of the actual English instructional practices in Saudi Arabia. The goal of this work is to gain insights into the practices and pedagogic approaches to English as a foreign language (EFL) teaching currently employed in this country. In particular, we identify the following central features…

  9. Certification Change versus Actual Behavior Change in Teenage Suicide Rates, 1955-1979.

    ERIC Educational Resources Information Center

    Gist, Richard; Welch, Q. B.

    1989-01-01

    Examined national data on firearm suicides and accidental deaths for 15- through 19-year-olds from 1955-1979. Considered improved accuracy in determination and certification of suicide in equivocal firearm deaths, actual increases in rate of firearm suicides, or combination. Data support hypothesis of certification changes as primary factor…

  10. Discrepancies between Official Science Curriculum and Actual Classroom Practice: The Nigerian Experience.

    ERIC Educational Resources Information Center

    Olorundare, Solomon A.

    1990-01-01

    This paper was based on an investigation of how an officially prescribed science curriculum was interpreted and translated by teachers into actual classroom practice in Nigerian primary schools. Mismatches between official and hidden curricula were rampant and often beyond teachers' control. The teacher's role was "policy broker," not…

  11. 40 CFR 63.5335 - How do I determine the actual HAP loss?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... process operation type. (2) Chemical Inventory Mass Balance. Determine the actual monthly HAP loss from... mass balance must be based on a detailed inventory of stored chemicals at the beginning and end of each month, and business purchasing records to indicate additions to the inventory of chemical supplies....

  12. 45 CFR 149.335 - Documentation of costs of actual claims involved.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Documentation of costs of actual claims involved. 149.335 Section 149.335 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES REQUIREMENTS RELATING TO HEALTH CARE ACCESS REQUIREMENTS FOR THE EARLY RETIREE REINSURANCE PROGRAM Reimbursement...

  13. Testing two temporal upscaling schemes for the estimation of the time variability of the actual evapotranspiration

    NASA Astrophysics Data System (ADS)

    Maltese, A.; Capodici, F.; Ciraolo, G.; La Loggia, G.

    2015-10-01

    Temporal availability of grapes actual evapotranspiration is an emerging issue since vineyards farms are more and more converted from rainfed to irrigated agricultural systems. The manuscript aims to verify the accuracy of the actual evapotranspiration retrieval coupling a single source energy balance approach and two different temporal upscaling schemes. The first scheme tests the temporal upscaling of the main input variables, namely the NDVI, albedo and LST; the second scheme tests the temporal upscaling of the energy balance output, the actual evapotranspiration. The temporal upscaling schemes were implemented on: i) airborne remote sensing data acquired monthly during a whole irrigation season over a Sicilian vineyard; ii) low resolution MODIS products released daily or weekly; iii) meteorological data acquired by standard gauge stations. Daily MODIS LST products (MOD11A1) were disaggregated using the DisTrad model, 8-days black and white sky albedo products (MCD43A) allowed modeling the total albedo, and 8-days NDVI products (MOD13Q1) were modeled using the Fisher approach. Results were validated both in time and space. The temporal validation was carried out using the actual evapotranspiration measured in situ using data collected by a flux tower through the eddy covariance technique. The spatial validation involved airborne images acquired at different times from June to September 2008. Results aim to test whether the upscaling of the energy balance input or output data performed better.

  14. Actual versus perceived peer sexual risk behavior in online youth social networks.

    PubMed

    Black, Sandra R; Schmiege, Sarah; Bull, Sheana

    2013-09-01

    Perception of peer behaviors is an important predictor of actual risk behaviors among youth. However, we lack understanding of peer influence through social media and of actual and perceived peer behavior concordance. The purpose of this research is to document the relationship between individual perception of and actual peer sexual risk behavior using online social networks. The data are a result of a secondary analysis of baseline self-reported and peer-reported sexual risk behavior from a cluster randomized trial including 1,029 persons from 162 virtual networks. Individuals (seeds) recruited up to three friends who then recruited additional friends, extending three waves from the seed. ANOVA models compared network means of actual participant behavior across categories of perceived behavior. Concordance varied between reported and perceived behavior, with higher concordance between perceived and reported condom use, multiple partners, concurrent partners, sexual pressure, and drug and alcohol use during sex. Individuals significantly over-reported risk and under-reported protective peer behaviors related to sex.

  15. 29 CFR 776.10 - Employees participating in the actual movement of commerce.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... typically, but not exclusively, to employees such, as those in the telephone, 29 telegraph, 30 television, radio, 31 transportation and shipping 32 industries, since these industries serve as the actual instrumentalities and channels of interstate and foreign commerce. Similarly, employees of such businesses...

  16. 29 CFR 776.10 - Employees participating in the actual movement of commerce.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... typically, but not exclusively, to employees such, as those in the telephone, 29 telegraph, 30 television, radio, 31 transportation and shipping 32 industries, since these industries serve as the actual instrumentalities and channels of interstate and foreign commerce. Similarly, employees of such businesses...

  17. 29 CFR 776.10 - Employees participating in the actual movement of commerce.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... typically, but not exclusively, to employees such, as those in the telephone, 29 telegraph, 30 television, radio, 31 transportation and shipping 32 industries, since these industries serve as the actual instrumentalities and channels of interstate and foreign commerce. Similarly, employees of such businesses...

  18. 41 CFR 302-10.101 - Must I furnish actual odometer readings on the travel claim?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... odometer readings on the travel claim? 302-10.101 Section 302-10.101 Public Contracts and Property... § 302-10.101 Must I furnish actual odometer readings on the travel claim? No, you do not need to furnish odometer readings on the travel claim but you must indicate the total miles traveled. Any deviation...

  19. 41 CFR 302-10.101 - Must I furnish actual odometer readings on the travel claim?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... odometer readings on the travel claim? 302-10.101 Section 302-10.101 Public Contracts and Property... § 302-10.101 Must I furnish actual odometer readings on the travel claim? No, you do not need to furnish odometer readings on the travel claim but you must indicate the total miles traveled. Any deviation...

  20. 41 CFR 302-10.101 - Must I furnish actual odometer readings on the travel claim?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... odometer readings on the travel claim? 302-10.101 Section 302-10.101 Public Contracts and Property... § 302-10.101 Must I furnish actual odometer readings on the travel claim? No, you do not need to furnish odometer readings on the travel claim but you must indicate the total miles traveled. Any deviation...

  1. 41 CFR 302-10.101 - Must I furnish actual odometer readings on the travel claim?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... odometer readings on the travel claim? 302-10.101 Section 302-10.101 Public Contracts and Property... § 302-10.101 Must I furnish actual odometer readings on the travel claim? No, you do not need to furnish odometer readings on the travel claim but you must indicate the total miles traveled. Any deviation...

  2. 41 CFR 302-10.101 - Must I furnish actual odometer readings on the travel claim?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... odometer readings on the travel claim? 302-10.101 Section 302-10.101 Public Contracts and Property... § 302-10.101 Must I furnish actual odometer readings on the travel claim? No, you do not need to furnish odometer readings on the travel claim but you must indicate the total miles traveled. Any deviation...

  3. The Role of Non-Actuality Implicatures in Processing Elided Constituents

    PubMed Central

    Grant, Margaret; Clifton, Charles; Frazier, Lyn

    2011-01-01

    When an elided constituent and its antecedent do not match syntactically, the presence of a word implying the non-actuality of the state of affairs described in the antecedent seems to improve the example (This information should be released but Gorbachev didn’t. vs This information was released but Gorbachev didn’t.) We model this effect in terms of Non-Actuality Implicatures (NAIs) conveyed by non-epistemic modals like should and other words such as want to and be eager to that imply non-actuality. We report three studies. A rating and interpretation study showed that such implicatures are drawn and that they improve the acceptability of mismatch ellipsis examples. An interpretation study showed that adding a NAI trigger to ambiguous examples increases the likelihood of choosing an antecedent from the NAI clause. An eye movement study shows that a NAI trigger also speeds online reading of the ellipsis clause. By introducing alternatives (the desired state of affairs vs. the actual state of affairs), the NAI trigger introduces a potential Question Under Discussion (QUD). Processing an ellipsis clause is easier, the processor is more confident of its analysis, when the ellipsis clause comments on the QUD. PMID:22247589

  4. The Challenge to Cumulative Learning: Do Introductory Courses Actually Benefit Advanced Students?

    ERIC Educational Resources Information Center

    Nathanson, Craig; Paulhus, Delroy L.; Williams, Kevin M.

    2004-01-01

    Previous research has questioned the educational value of taking introductory courses in psychology. Study 1 confirmed the usual null to negative associations between taking introductory psychology and performance in a subsequent psychology course. Study 2 showed that, after controlling for IQ, there was actually a positive association between…

  5. A Comparison of Actual and Preferred Classroom Environments as Perceived by Middle School Students

    ERIC Educational Resources Information Center

    Lai, Hsiang-Ru; Chou, Wei-Lun; Miao, Nae-Fang; Wu, Yu-Ping; Lee, Pi-Hsia; Jwo, Jiunn-Chern

    2015-01-01

    Background: A good classroom environment can promote students' learning motivation and affect their academic efficacy and adaptation. This study compares the perceptions of Taiwanese middle school students regarding actual and preferred classroom environments and explores the association with sex and grade level. Methods: Data were collected using…

  6. 30 CFR 206.180 - How do I determine an actual processing allowance?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 2 2010-07-01 2010-07-01 false How do I determine an actual processing allowance? 206.180 Section 206.180 Mineral Resources MINERALS MANAGEMENT SERVICE, DEPARTMENT OF THE INTERIOR MINERALS REVENUE MANAGEMENT PRODUCT VALUATION Indian Gas Processing Allowances § 206.180 How do I...

  7. Comparison between Computer-Controlled Troposcatter Simulation and an Actual Link.

    DTIC Science & Technology

    The purpose of this report is to compare a computer-controlled troposcatter simulation with data obtained over an actual troposcatter test link. Parameters compared are fade rate, signal amplitude, and fade duration and correlation coefficient distributions, as well as error rates obtained with various high speed digital modems. (Author)

  8. 12 CFR Appendix M2 to Part 226 - Actual Repayment Disclosures

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 3 2010-01-01 2010-01-01 false Actual Repayment Disclosures M2 Appendix M2 to Part 226 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE... nearest whole year if the estimate contains a fractional year less than 0.5, and rounded up to the...

  9. 25 CFR 700.153 - Actual reasonable moving and related expenses-residential moves.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 25 Indians 2 2014-04-01 2014-04-01 false Actual reasonable moving and related expenses-residential moves. 700.153 Section 700.153 Indians THE OFFICE OF NAVAJO AND HOPI INDIAN RELOCATION COMMISSION OPERATIONS AND RELOCATION PROCEDURES Moving and Related Expenses, Temporary Emergency Moves § 700.153...

  10. 25 CFR 700.157 - Actual reasonable moving and related expenses-nonresidential moves.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 25 Indians 2 2013-04-01 2013-04-01 false Actual reasonable moving and related expenses-nonresidential moves. 700.157 Section 700.157 Indians THE OFFICE OF NAVAJO AND HOPI INDIAN RELOCATION COMMISSION OPERATIONS AND RELOCATION PROCEDURES Moving and Related Expenses, Temporary Emergency Moves § 700.157...

  11. 25 CFR 700.157 - Actual reasonable moving and related expenses-nonresidential moves.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 25 Indians 2 2014-04-01 2014-04-01 false Actual reasonable moving and related expenses-nonresidential moves. 700.157 Section 700.157 Indians THE OFFICE OF NAVAJO AND HOPI INDIAN RELOCATION COMMISSION OPERATIONS AND RELOCATION PROCEDURES Moving and Related Expenses, Temporary Emergency Moves § 700.157...

  12. 25 CFR 700.153 - Actual reasonable moving and related expenses-residential moves.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 25 Indians 2 2010-04-01 2010-04-01 false Actual reasonable moving and related expenses-residential moves. 700.153 Section 700.153 Indians THE OFFICE OF NAVAJO AND HOPI INDIAN RELOCATION COMMISSION OPERATIONS AND RELOCATION PROCEDURES Moving and Related Expenses, Temporary Emergency Moves § 700.153...

  13. 25 CFR 700.153 - Actual reasonable moving and related expenses-residential moves.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 25 Indians 2 2012-04-01 2012-04-01 false Actual reasonable moving and related expenses-residential moves. 700.153 Section 700.153 Indians THE OFFICE OF NAVAJO AND HOPI INDIAN RELOCATION COMMISSION OPERATIONS AND RELOCATION PROCEDURES Moving and Related Expenses, Temporary Emergency Moves § 700.153...

  14. 25 CFR 700.157 - Actual reasonable moving and related expenses-nonresidential moves.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 25 Indians 2 2012-04-01 2012-04-01 false Actual reasonable moving and related expenses-nonresidential moves. 700.157 Section 700.157 Indians THE OFFICE OF NAVAJO AND HOPI INDIAN RELOCATION COMMISSION OPERATIONS AND RELOCATION PROCEDURES Moving and Related Expenses, Temporary Emergency Moves § 700.157...

  15. 25 CFR 700.153 - Actual reasonable moving and related expenses-residential moves.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 25 Indians 2 2011-04-01 2011-04-01 false Actual reasonable moving and related expenses-residential moves. 700.153 Section 700.153 Indians THE OFFICE OF NAVAJO AND HOPI INDIAN RELOCATION COMMISSION OPERATIONS AND RELOCATION PROCEDURES Moving and Related Expenses, Temporary Emergency Moves § 700.153...

  16. 25 CFR 700.153 - Actual reasonable moving and related expenses-residential moves.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 25 Indians 2 2013-04-01 2013-04-01 false Actual reasonable moving and related expenses-residential moves. 700.153 Section 700.153 Indians THE OFFICE OF NAVAJO AND HOPI INDIAN RELOCATION COMMISSION OPERATIONS AND RELOCATION PROCEDURES Moving and Related Expenses, Temporary Emergency Moves § 700.153...

  17. From FBA to Implementation: A Look at What Is Actually Being Delivered

    ERIC Educational Resources Information Center

    Blood, Erika; Neel, Richard S.

    2007-01-01

    This study looks at the utilization of assessments on developing behavior intervention plans (BIPs) and their use in designing actual implementation for the children (elementary through high school) labeled EBD in a mid-sized district in eastern Washington. Files were reviewed to determine the types of assessments used, FBA components addressed,…

  18. Teachers' Perceptions of Their Working Conditions: How Predictive of Planned and Actual Teacher Movement?

    ERIC Educational Resources Information Center

    Ladd, Helen F.

    2011-01-01

    This quantitative study examines the relationship between teachers' perceptions of their working conditions and their intended and actual departures from schools. Based on rich administrative data for North Carolina combined with a 2006 statewide survey administered to all teachers in the state, the study documents that working conditions are…

  19. 29 CFR 778.312 - Pay for task without regard to actual hours.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... LABOR STATEMENTS OF GENERAL POLICY OR INTERPRETATION NOT DIRECTLY RELATED TO REGULATIONS OVERTIME COMPENSATION Special Problems âtaskâ Basis of Payment § 778.312 Pay for task without regard to actual hours. (a... compensation for work in excess of 40 hours is paid at an established hourly rate for the first 40 of...

  20. The Relationship between EFL Teachers' Beliefs and Actual Practices of Classroom Management

    ERIC Educational Resources Information Center

    Aliakbari, Mohammad; Heidarzad, Mohsen

    2015-01-01

    This study aimed at analyzing Iranian EFL teachers' beliefs toward classroom management and the relationship between teachers' beliefs and their actual practices of classroom management in regard with individual variables such as gender, education degree, and teaching experience. The data were collected using a behavior and instructional…

  1. Affective Education: A Teacher's Manual to Promote Student Self-Actualization and Human Relations Skills.

    ERIC Educational Resources Information Center

    Snyder, Thomas R.

    This teacher's manual presents affective education as a program to promote student self-actualization and human relations skills. Abraham Maslow's hierarchy of needs and Erik Erikson's life stages of psychosocial development form the conceptual base for this program. The goals and objectives of this manual are concerned with problem-solving…

  2. 40 CFR 63.5335 - How do I determine the actual HAP loss?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... process operation type. (2) Chemical Inventory Mass Balance. Determine the actual monthly HAP loss from... mass balance must be based on a detailed inventory of stored chemicals at the beginning and end of each month, and business purchasing records to indicate additions to the inventory of chemical supplies....

  3. Effect of Knowledge About Self-Actualization on Faking the Personal Orientation Inventory

    ERIC Educational Resources Information Center

    Goldman, Jeffrey A.; Olczak, Paul V.

    1976-01-01

    The study factorially manipulated instructions (fake bad, be honest again control, fake good) and knowledge of self-actualization (naive, knowledgeable) to determine whether knowledge affects ability to create poor impressions or create good impressions in comparison with appropriate controls on the Personal Orientation Inventory (POI). (Author)

  4. Actual and simulated injury of Creontiades signatus (Heteroptera: Miridae) feeding on cotton bolls

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The actual feeding injury of Creontiades signatus (Distant) was compared to a simulated technique for study years 2005, 2006 and 2008 by injecting varying dilutions of pectinase into cotton bolls at different boll sizes (ages) in an effort to determine if such a technique could be used to reduce the...

  5. Determinants of Tracking Intentions, and Actual Education Choices among Junior High School Students in Rural China

    ERIC Educational Resources Information Center

    Song, Yingquan; Loyalka, Prashant; Wei, Jianguo

    2013-01-01

    This article analyzes rural middle school students' tracking intentions (academic high school, vocational high school, or going to work), actual education choices, and the factors affecting them, using a random sampled baseline survey and follow-up survey of 2,216 second-year students residing outside of county seats in forty-one impoverished…

  6. Parent-Child Discrepancies in Educational Expectations: Differential Effects of Actual versus Perceived Discrepancies

    ERIC Educational Resources Information Center

    Wang, Yijie; Benner, Aprile D.

    2014-01-01

    This study explored how discrepancies between parents' and adolescents' educational expectations influenced adolescents' achievement using a nationally representative, longitudinal sample of 14,041 students (14 years old at baseline). "Actual" discrepancies (i.e., those between parents' and adolescents' actual…

  7. 42 CFR 414.48 - Limits on actual charges of nonparticipating suppliers.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... suppliers. 414.48 Section 414.48 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF... SERVICES Physicians and Other Practitioners § 414.48 Limits on actual charges of nonparticipating suppliers. (a) General rule. A supplier, as defined in § 400.202 of this chapter, who is nonparticipating...

  8. Thesis and Dissertation Writing: An Examination of Published Advice and Actual Practice.

    ERIC Educational Resources Information Center

    Paltridge, Brian

    2002-01-01

    Explores the extent to which published advice on the organization and structure of theses and dissertations concurs with what happens in actual practice. Examines guides and handbooks that focus on thesis and dissertation writing and postgraduate research. Found that only a few books devoted a substantial amount of space to this topic. Discusses…

  9. Measuring the Disparities between Biology Undergraduates' Perceptions and Their Actual Knowledge of Scientific Literature with Clickers

    ERIC Educational Resources Information Center

    Bandyopadhyay, Aditi

    2013-01-01

    This article demonstrates an innovative method used to determine the need for information literacy among science undergraduate students at Adelphi University. Using clickers technology, this study measured the disconnect between biology undergraduates' perceived and actual knowledge of scientific literature. The quantitative data collected in the…

  10. 41 CFR 301-74.23 - Is the conference lodging allowance an actual expense reimbursement?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 41 Public Contracts and Property Management 4 2013-07-01 2012-07-01 true Is the conference lodging... Management Federal Travel Regulation System TEMPORARY DUTY (TDY) TRAVEL ALLOWANCES AGENCY RESPONSIBILITIES 74-CONFERENCE PLANNING Conference Attendees § 301-74.23 Is the conference lodging allowance an actual...

  11. 41 CFR 301-74.22 - When should actual expense reimbursement be authorized for conference attendees?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... expense reimbursement be authorized for conference attendees? 301-74.22 Section 301-74.22 Public Contracts and Property Management Federal Travel Regulation System TEMPORARY DUTY (TDY) TRAVEL ALLOWANCES AGENCY RESPONSIBILITIES 74-CONFERENCE PLANNING Conference Attendees § 301-74.22 When should actual expense...

  12. 41 CFR 301-74.24 - When should actual expense reimbursement be authorized for conference attendees?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... expense reimbursement be authorized for conference attendees? 301-74.24 Section 301-74.24 Public Contracts and Property Management Federal Travel Regulation System TEMPORARY DUTY (TDY) TRAVEL ALLOWANCES AGENCY RESPONSIBILITIES 74-CONFERENCE PLANNING Conference Attendees § 301-74.24 When should actual expense...

  13. 41 CFR 301-74.24 - When should actual expense reimbursement be authorized for conference attendees?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... expense reimbursement be authorized for conference attendees? 301-74.24 Section 301-74.24 Public Contracts and Property Management Federal Travel Regulation System TEMPORARY DUTY (TDY) TRAVEL ALLOWANCES AGENCY RESPONSIBILITIES 74-CONFERENCE PLANNING Conference Attendees § 301-74.24 When should actual expense...

  14. 41 CFR 301-74.24 - When should actual expense reimbursement be authorized for conference attendees?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... expense reimbursement be authorized for conference attendees? 301-74.24 Section 301-74.24 Public Contracts and Property Management Federal Travel Regulation System TEMPORARY DUTY (TDY) TRAVEL ALLOWANCES AGENCY RESPONSIBILITIES 74-CONFERENCE PLANNING Conference Attendees § 301-74.24 When should actual expense...

  15. 41 CFR 301-74.24 - When should actual expense reimbursement be authorized for conference attendees?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... expense reimbursement be authorized for conference attendees? 301-74.24 Section 301-74.24 Public Contracts and Property Management Federal Travel Regulation System TEMPORARY DUTY (TDY) TRAVEL ALLOWANCES AGENCY RESPONSIBILITIES 74-CONFERENCE PLANNING Conference Attendees § 301-74.24 When should actual expense...

  16. Corrective Feedback in L2 Latvian Classrooms: Teacher Perceptions versus the Observed Actualities of Practice

    ERIC Educational Resources Information Center

    Dilans, Gatis

    2016-01-01

    This two-part study aims to investigate teacher perceptions about providing oral corrective feedback (CF) to minority students of Latvian as a second language and compare the perceptions to the actual provision of CF in L2 Latvian classrooms. The survey sample represents sixty-six L2 Latvian teachers while the classroom observations involved 13…

  17. 45 CFR 73.735-904 - Resolution of apparent or actual conflicts of interest.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... statements and shall monitor compliance with these statements on a regular basis. (b) Change of assignment is... under 18 U.S.C. 208(b) is an appropriate method for resolving apparent or actual conflicts of interest... adequately resolved by any of the methods set forth in paragraphs (a), (b), (c), and (d) of this section....

  18. 45 CFR 73.735-904 - Resolution of apparent or actual conflicts of interest.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... statements and shall monitor compliance with these statements on a regular basis. (b) Change of assignment is... under 18 U.S.C. 208(b) is an appropriate method for resolving apparent or actual conflicts of interest... adequately resolved by any of the methods set forth in paragraphs (a), (b), (c), and (d) of this section....

  19. 45 CFR 73.735-904 - Resolution of apparent or actual conflicts of interest.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... statements and shall monitor compliance with these statements on a regular basis. (b) Change of assignment is... under 18 U.S.C. 208(b) is an appropriate method for resolving apparent or actual conflicts of interest... adequately resolved by any of the methods set forth in paragraphs (a), (b), (c), and (d) of this section....

  20. 45 CFR 73.735-904 - Resolution of apparent or actual conflicts of interest.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... statements and shall monitor compliance with these statements on a regular basis. (b) Change of assignment is... under 18 U.S.C. 208(b) is an appropriate method for resolving apparent or actual conflicts of interest... adequately resolved by any of the methods set forth in paragraphs (a), (b), (c), and (d) of this section....