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Sample records for actual drug-drug interactions

  1. Aprepitant: drug-drug interactions in perspective.

    PubMed

    Aapro, M S; Walko, C M

    2010-12-01

    The implications of chemotherapeutic drug-drug interactions can be serious and thus need to be addressed. This review concerns the potential interactions of the antiemetic aprepitant, a neurokinin-1 receptor antagonist indicated for use (in Europe) in highly emetogenic chemotherapy and moderately emetogenic chemotherapy (MEC) in combination with a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist and corticosteroids and (in the United States) in combination with other antiemetic agents, for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy including high-dose cisplatin. When considering use of aprepitant for prevention of chemotherapy-induced nausea and vomiting, its potential drug-drug interaction profile as a moderate inhibitor of cytochrome P-450 isoenzyme 3A4 (CYP3A4) has been a source of concern for some physicians and other health care professionals. We explore in this paper how real those concerns are. Our conclusion is that either no interaction or no clinically relevant interaction exists with chemotherapeutic agents (intravenous cyclophosphamide, docetaxel, intravenous vinorelbine) or 5-HT3 antagonists (granisetron, ondansetron, palonosetron). For relevant interactions, appropriate measures, such as corticosteroid dose modifications and extended International Normalized Ratio monitoring of patients on warfarin therapy, can be taken to effectively manage them. Therefore, the concern of negative interactions remains largely theoretical but needs to be verified with new agents extensively metabolized through the 3A4 pathway. PMID:20488873

  2. [Drug-drug interactions in antirheumatic treatment].

    PubMed

    Krüger, K

    2012-04-01

    Clinically relevant drug-drug interactions contribute considerably to potentially dangerous drug side-effects and are frequently the reason for hospitalization. Nevertheless they are often overlooked in daily practice. For most antirheumatic drugs a vast number of interactions have been described but only a minority with clinical relevance. Several potentially important drug interactions exist for non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate, azathioprine, mycophenolate-mofetil and especially for cyclosporin A. Most importantly co-medication with methotrexate and sulfmethoxazole trimethoprim as well as azathioprine and allopurinol carries the risk of severe, sometimes life-threatening consequences. Nevertheless, besides these well-known high-risk combinations in each case of polypharmacy with antirheumatic drugs it is necessary to bear in mind the possibility of drug interactions. As polypharmacy is a common therapeutic practice in older patients with rheumatic diseases, they are at special risk. PMID:22527215

  3. Clinical Weighting of Drug-Drug Interactions in Hospitalized Elderly.

    PubMed

    Juárez-Cedillo, Teresa; Martinez-Hernández, Cynthia; Hernández-Constantino, Angel; Garcia-Cruz, Juan Carlos; Avalos-Mejia, Annia M; Sánchez-Hurtado, Luis A; Islas Perez, Valentin; Hansten, Philip D

    2016-04-01

    Adverse drug reactions impact on patient health, effectiveness of pharmacological therapy and increased health care costs. This investigation intended to detect the most critical drug-drug interactions in hospitalized elderly patients, weighting clinical risk. We conducted a cross-sectional study between January and April 2014; all patients 70 years or older, hospitalized for >24 hr and prescribed at least one medication were included in the study. Drug-drug interactions were estimated by combining Stockley's, Hansten and Tatro drug interactions. Drug-drug interactions were weighted using a risk-analysis method based on failure modes, effects and criticality analysis. We calculated a criticality index for each drug involved in the drug-drug interactions based on the severity of the interaction mechanism, the frequency the drug was involved in drug-drug interactions and the risk of drug-drug interactions in patients with impaired renal function. The average number of drugs consumed in the hospital was 6 ± 2.69, involving 160 active ingredients. The most frequent were as follows: Furosemide, followed by Enalapril. Of drug-drug interactions, 2% were classified as contraindicated, 14% advised against and 83% advised caution during the hospital stay. Thirty-four drug-drug interactions were assessed, of which 23 were pharmacodynamic drug-drug interactions and 12 were pharmacokinetic drug-drug interactions (1 was both). The clinical risk calculated for each drug-drug interaction included heparins + non-steroidal anti-inflammatory drugs (NSAIDs) or Digoxin + Calcium Gluconate, cases which are pharmacodynamic drug-drug interactions with agonist effect and clinical risk of bleeding, one of the most common clinical risks in the hospital. An index of clinical risk for drug-drug interactions can be calculated based on severity by the interaction mechanism, the frequency that the drug is involved in drug-drug interactions and the risk of drug-drug interactions in an

  4. The need for translational research on drug-drug interactions.

    PubMed

    Hennessy, S; Flockhart, D A

    2012-05-01

    Drug-drug interactions (DDIs) are an important clinical and public health concern. Although DDI screening now occurs during drug development, it is difficult to predict clinical importance based on in vitro experiments. Furthermore, older drugs that were not screened may have interactions that have not yet been identified. In this Commentary, we review the importance of DDIs and argue that a translational research approach is needed to produce clinically actionable information as well as generalizable biological knowledge. PMID:22513312

  5. Adverse drug reactions caused by drug-drug interactions reported to Croatian Agency for Medicinal Products and Medical Devices: a retrospective observational study

    PubMed Central

    Mirošević Skvrce, Nikica; Macolić Šarinić, Viola; Mucalo, Iva; Krnić, Darko; Božina, Nada; Tomić, Siniša

    2011-01-01

    Aim To analyze potential and actual drug-drug interactions reported to the Spontaneous Reporting Database of the Croatian Agency for Medicinal Products and Medical Devices (HALMED) and determine their incidence. Methods In this retrospective observational study performed from March 2005 to December 2008, we detected potential and actual drug-drug interactions using interaction programs and analyzed them. Results HALMED received 1209 reports involving at least two drugs. There were 468 (38.7%) reports on potential drug-drug interactions, 94 of which (7.8% of total reports) were actual drug-drug interactions. Among actual drug-drug interaction reports, the proportion of serious adverse drug reactions (53 out of 94) and the number of drugs (n = 4) was significantly higher (P < 0.001) than among the remaining reports (580 out of 1982; n = 2, respectively). Actual drug-drug interactions most frequently involved nervous system agents (34.0%), and interactions caused by antiplatelet, anticoagulant, and non-steroidal anti-inflammatory drugs were in most cases serious. In only 12 out of 94 reports, actual drug-drug interactions were recognized by the reporter. Conclusion The study confirmed that the Spontaneous Reporting Database was a valuable resource for detecting actual drug-drug interactions. Also, it identified drugs leading to serious adverse drug reactions and deaths, thus indicating the areas which should be in the focus of health care education. PMID:21990078

  6. 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. PMID:25991099

  7. 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. PMID:25707701

  8. Monitoring of drug-drug and drug-food interactions.

    PubMed

    Garabedian-Ruffalo, S M; Syrja-Farber, M; Lanius, P M; Plucinski, A

    1988-07-01

    A program for detecting and preventing potentially serious drug-drug and drug-food interactions is described. Two clinical pharmacists developed drug interaction alert (DIA) cards for each potential interaction to be monitored. The cards contain information about the proposed mechanism and potential result of the interaction, as well as information about how to monitor or circumvent the interaction. Staff pharmacists check for the occurrence of potential interactions daily as they verify the filling of the patient-medication cassettes; a poster of all the interactions that are included in the program is posted in each satellite pharmacy to serve as a quick reference for the pharmacists. When a pharmacist detects a potential interaction, he or she completes a DIA card and places it in the medication cassette drawer (if the notice is directed to the nurse) or on the front of the patient's chart (if the notice is directed to the physician). The program was introduced to hospital personnel through inservice education programs and departmental newsletters. The results of a quality assurance review indicated that 95 of 279 (34%) cards dispensed to nurses and 40 of 49 (82%) cards dispensed to physicians resulted in some form of action. The program to detect and prevent potentially serious drug-drug and drug-food interactions has been successful. PMID:3414718

  9. 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. PMID:26341013

  10. 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

  11. 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. PMID:26199424

  12. 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. PMID:23251210

  13. Prolonged Drug-Drug Interaction between Terbinafine and Perphenazine

    PubMed Central

    2012-01-01

    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. PMID:23251210

  14. 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

  15. Text Mining Driven Drug-Drug Interaction Detection

    PubMed Central

    Yan, Su; Jiang, Xiaoqian; Chen, Ying

    2014-01-01

    Identifying drug-drug interactions is an important and challenging problem in computational biology and healthcare research. There are accurate, structured but limited domain knowledge and noisy, unstructured but abundant textual information available for building predictive models. The difficulty lies in mining the true patterns embedded in text data and developing efficient and effective ways to combine heterogenous types of information. We demonstrate a novel approach of leveraging augmented text-mining features to build a logistic regression model with improved prediction performance (in terms of discrimination and calibration). Our model based on synthesized features significantly outperforms the model trained with only structured features (AUC: 96% vs. 91%, Sensitivity: 90% vs. 82% and Specificity: 88% vs. 81%). Along with the quantitative results, we also show learned “latent topics”, an intermediary result of our text mining module, and discuss their implications. PMID:25131635

  16. Text Mining Driven Drug-Drug Interaction Detection.

    PubMed

    Yan, Su; Jiang, Xiaoqian; Chen, Ying

    2013-01-01

    Identifying drug-drug interactions is an important and challenging problem in computational biology and healthcare research. There are accurate, structured but limited domain knowledge and noisy, unstructured but abundant textual information available for building predictive models. The difficulty lies in mining the true patterns embedded in text data and developing efficient and effective ways to combine heterogenous types of information. We demonstrate a novel approach of leveraging augmented text-mining features to build a logistic regression model with improved prediction performance (in terms of discrimination and calibration). Our model based on synthesized features significantly outperforms the model trained with only structured features (AUC: 96% vs. 91%, Sensitivity: 90% vs. 82% and Specificity: 88% vs. 81%). Along with the quantitative results, we also show learned "latent topics", an intermediary result of our text mining module, and discuss their implications. PMID:25131635

  17. Drug-Drug Interaction Extraction via Convolutional Neural Networks.

    PubMed

    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

  18. Statin drug-drug interactions in a Romanian community pharmacy

    PubMed Central

    BADIU, RALUCA; BUCSA, CAMELIA; MOGOSAN, CRISTINA; DUMITRASCU, DAN

    2016-01-01

    Background and aim Statins are frequently prescribed for patients with dyslipidemia and have a well-established safety profile. However, when associated with interacting dugs, the risk of adverse effects, especially muscular toxicity, is increased. The objective of this study was to identify, characterize and quantify the prevalence of the potential drug-drug interactions (pDDIs) of statins in reimbursed prescriptions from a community pharmacy in Bucharest. Methods We analyzed the reimbursed prescriptions including statins collected during one month in a community pharmacy. The online program Medscape Drug Interaction Checker was used for checking the drug interactions and their classification based on severity: Serious – Use alternative, Significant – Monitor closely and Minor. Results 132 prescriptions pertaining to 125 patients were included in the analysis. Our study showed that 25% of the patients who were prescribed statins were exposed to pDDIs: 37 Serious and Significant interactions in 31 of the statins prescriptions. The statins involved were atorvastatin, simvastatin and rosuvastatin. Conclusions Statin pDDIs have a high prevalence and patients should be monitored closely in order to prevent the development of adverse effects that result from statin interactions. PMID:27152080

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

    PubMed

    Samardzic, I; Bacic-Vrca, V

    2015-06-01

    In an effort to achieve normoglycemia more than one antidiabetic agent is usually needed. Diabetes is associated with several comorbidities and patients with diabetes are often treated with multiple medications. Therefore, patients with diabetes are especially exposed to drug-drug interactions (DDIs). The aim of this study was to analyse the incidence and type of potential DDIs of antidiabetic drugs in patients with diabetes. This retrospective study analyzed pharmacy record data of 225 patients with diabetes mellitus. Both type 1 and type 2 diabetic patients who were taking at least one antidiabetic agent during the period of six months were included. We investigated associated therapy in that period in order to identify potential DDIs with antidiabetic therapy. Potential interactions were identified by Lexicomp Lexi-Interat Online (Lexi-Comp, Inc., Hudson, USA) software which categorizes potential DDIs according to clinical significance in five types (A, B, C, D and X). Categories C, D and X are of clinical concern and always require medical attention (therapy monitoring, therapy modification or avoiding combination). We found that 80.9% of patients had at least one potential category C interaction while there were no D and X interactions. Most frequently encountered potential DDI (n = 176) included antidiabetic drugs and thiazide or thiazide like diuretics. Patients with diabetes are exposed to a large number of potential clinically significant DDIs that may require appropriate monitoring. Using databases of DDIs could be helpful in reducing the risk of potential clinically significant DDIs. PMID:26189304

  20. QSAR Modeling and Prediction of Drug-Drug Interactions.

    PubMed

    Zakharov, Alexey V; Varlamova, Ekaterina V; Lagunin, Alexey A; Dmitriev, Alexander V; Muratov, Eugene N; Fourches, Denis; Kuz'min, Victor E; Poroikov, Vladimir V; Tropsha, Alexander; Nicklaus, Marc C

    2016-02-01

    Severe adverse drug reactions (ADRs) are the fourth leading cause of fatality in the U.S. with more than 100,000 deaths per year. As up to 30% of all ADRs are believed to be caused by drug-drug interactions (DDIs), typically mediated by cytochrome P450s, possibilities to predict DDIs from existing knowledge are important. We collected data from public sources on 1485, 2628, 4371, and 27,966 possible DDIs mediated by four cytochrome P450 isoforms 1A2, 2C9, 2D6, and 3A4 for 55, 73, 94, and 237 drugs, respectively. For each of these data sets, we developed and validated QSAR models for the prediction of DDIs. As a unique feature of our approach, the interacting drug pairs were represented as binary chemical mixtures in a 1:1 ratio. We used two types of chemical descriptors: quantitative neighborhoods of atoms (QNA) and simplex descriptors. Radial basis functions with self-consistent regression (RBF-SCR) and random forest (RF) were utilized to build QSAR models predicting the likelihood of DDIs for any pair of drug molecules. Our models showed balanced accuracy of 72-79% for the external test sets with a coverage of 81.36-100% when a conservative threshold for the model's applicability domain was applied. We generated virtually all possible binary combinations of marketed drugs and employed our models to identify drug pairs predicted to be instances of DDI. More than 4500 of these predicted DDIs that were not found in our training sets were confirmed by data from the DrugBank database. PMID:26669717

  1. 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

  2. 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

  3. [Drug-drug interactions in the elderly : Which ones really matter?].

    PubMed

    Bitter, K; Schlender, J F; Woltersdorf, R

    2016-07-01

    Pharmacotherapy in the elderly is challenging due to age-related physiological changes, high interindividual variability, and increasing frequency of multimorbidity. The resulting polypharmacy increases the risk of drug-drug interactions and requires an individual risk assessment. Some drug-drug interactions are documented to be associated with harm in older adults including intoxication, gastrointestinal bleeding, or falls. Therefore, they are considered to be of special importance in the elderly. Moreover, frequent risk factors and continuous physiological alterations in the elderly should be taken into account during risk assessment. This review exemplifies clinically relevant drug-drug interactions and risk factors in the elderly. In addition, assessment tools as well as prevention and management strategies for clinical practice are presented. PMID:27294383

  4. Prevalence and Correlates of Drug-drug Interactions in the Regional Hospital of Gjilan, Kosovo

    PubMed Central

    Shabani, Driton; Tahiri, Zejdush; Bara, Petrit; Hudhra, Klejda; Malaj, Ledian; Jucja, Besnik; Bozalia, Adnan; Burazeri, Genc

    2014-01-01

    Aim: Our aim was to assess the prevalence and socioeconomic and clinical correlates of drug-drug interactions among the adult population of transitional Kosovo. Methods: A cross-sectional study was conducted including a representative sample of 1921 patients aged ≥18 years (mean age: 57.8±11.2 years; 50.3% women; overall response: 96%) from the regional hospital of Gjilan, Kosovo, during 2011-2013. Potential drug-drug-interactions were assessed and clinical data as well as demographic and socioeconomic information were collected. Binary logistic regression was used to assess the correlates of drug-drug interactions. Results: Upon multivariable adjustment for all the demographic and socioeconomic factors as well as the clinical characteristics, drug-drug interactions were positively and significantly related to older age (OR=2.1, 95%CI=1.3-2.8), a lower educational attainment (OR=1.4, 95%CI=1.1-1.9), a longer hospitalization period (OR=2.7, 95%CI=2.1-3.6), presence of three groups of diseases [infectious diseases (OR=1.7, 95%CI=1.3-2.4), cardiovascular diseases (OR=1.8, 95%CI=1.4-2.6), respiratory diseases (OR=1.6, 95%CI=1.2-2.5)], presence of comorbid conditions (OR=3.2, 95%CI=2.3-4.4) and an intake of at least four drugs (OR=5.9, 95%CI=4.6-7.1). Conclusions: Our study provides important evidence on the prevalence and socioeconomic and clinical correlates of drug-drug interactions among the hospitalized patients in the regional hospital of Gjilan, Kosovo. Findings from our study should raise the awareness of decision-makers and policy makers about the prevalence and determinants of drug-drug interactions in the adult population of post-war Kosovo. PMID:25395892

  5. Can drug-drug interactions be predicted from in vitro studies?

    PubMed

    Kremers, Pierre

    2002-03-19

    Potential drug-drug interactions as well as drug-xenobiotic interactions are a major source of clinical problems, sometimes with dramatic consequences. Investigation of drug-drug interactions during drug development is a major concern for the drug companies while developing new drugs. Our knowledge of the drug-metabolising enzymes, their mechanism of action, and their regulation has made considerable progress during the last decades. Various efficient in vitro approaches have been developed during recent years and powerful computer-based data handling is becoming widely available. All these tools allow us to initiate, early in the development of new chemical entities, large-scale studies on the interactions of drugs with selective cytochrome P-450 (CYP) isozymes, drug receptors, and other cellular entities. Standardisation and validation of these methodological approaches significantly improve the quality of the data generated and the reliability of their interpretation. The simplicity and the low costs associated with the use of in vitro techniques have made them a method of choice to investigate drug-drug interactions. Promising successes have been achieved in the extrapolation of in vitro data to the in vivo situation and in the prediction of drug-drug interaction. Nevertheless, linking in vitro and in vivo studies still remains fraught with difficulties and should be made with great caution. PMID:12806001

  6. 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

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

    PubMed

    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

  8. 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. PMID:23920643

  9. 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

  10. Impact of Participatory Design for Drug-Drug Interaction Alerts. A Comparison Study Between Two Interfaces.

    PubMed

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

    2016-01-01

    Decision support systems for alert drug-drug interactions have been shown as valid strategy to reduce medical error. Even so the use of these systems has not been as expected, probably due to the lack of a suitable design. This study compares two interfaces, one of them developed using participatory design techniques (based on user centered design processes). This work 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 with the system. PMID:27577343

  11. Impact of genetic polymorphisms and drug-drug interactions on clopidogrel and prasugrel response variability.

    PubMed

    Ancrenaz, V; Daali, Y; Fontana, P; Besson, M; Samer, C; Dayer, P; Desmeules, J

    2010-10-01

    Thienopyridine antiaggregating platelet agents (clopidogrel and prasugrel) act as irreversible P2Y12 receptor inhibitors. They are used with aspirin to prevent thrombotic complications after an acute coronary syndrome or percutaneous coronary intervention. A large interindividual variability in response to clopidogrel and to a lesser extent to prasugrel is observed and may be related to their metabolism. Clopidogrel and prasugrel are indeed prodrugs converted into their respective active metabolites by several cytochromes P450 (CYPs). Besides clopidogrel inactivation (85%) by esterases to the carboxylic acid, clopidogrel is metabolized by CYPs to 2-oxo-clopidogrel (15%) and further metabolized to an unstable but potent platelet-aggregating inhibitor. Prasugrel is more potent than clopidogrel with a better bioavailability and lower pharmacodynamic variability. Prasugrel is completely converted by esterases to an intermediate oxo-metabolite (R-95913) further bioactivated by CYPs. Numerous clinical studies have shown the influence of CYP2C19 polymorphism on clopidogrel antiplatelet activity. Moreover, unwanted drug-drug pharmacokinetic interactions influencing CYP2C19 activity and clopidogrel bioactivation such as with proton pump inhibitors remain a matter of intense controversy. Several studies have also demonstrated that CYP3A4/5 and CYP1A2 are important in clopidogrel bioactivation and should also be considered as potential targets for unwanted drug-drug interactions. Prasugrel bioactivation is mainly related to CYP3A4 and 2B6 activity and therefore the question of the effect of drug-drug interaction on its activity is open. The purpose of this review is to critically examine the current literature evaluating the influence of genetic and environmental factors such as unwanted drug-drug interaction affecting clopidogrel and prasugrel antiplatelet activity. PMID:20942779

  12. A screening study of drug-drug interactions in cerivastatin users: an adverse effect of clopidogrel.

    PubMed

    Floyd, J S; Kaspera, R; Marciante, K D; Weiss, N S; Heckbert, S R; Lumley, T; Wiggins, K L; Tamraz, B; Kwok, P-Y; Totah, R A; Psaty, B M

    2012-05-01

    An analysis of a case-control study of rhabdomyolysis was conducted to screen for previously unrecognized cytochrome P450 enzyme (CYP) 2C8 inhibitors that may cause other clinically important drug-drug interactions. Medication use in cases of rhabdomyolysis using cerivastatin (n = 72) was compared with that in controls using atorvastatin (n = 287) for the period 1998-2001. The use of clopidogrel was strongly associated with rhabdomyolysis (odds ratio (OR) 29.6; 95% confidence interval (CI), 6.1-143). In a replication effort that used the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS), it was found that clopidogrel was used more commonly in patients with rhabdomyolysis receiving cerivastatin (17%) than in those receiving atorvastatin (0%, OR infinity; 95% CI = 5.2-infinity). Several medications were tested in vitro for their potential to cause drug-drug interactions. Clopidogrel, rosiglitazone, and montelukast were the most potent inhibitors of cerivastatin metabolism. Clopidogrel and its metabolites also inhibited cerivastatin metabolism in human hepatocytes. These epidemiological and in vitro findings suggest that clopidogrel may cause clinically important, dose-dependent drug-drug interactions with other medications metabolized by CYP2C8. PMID:22419147

  13. Transporters and drug-drug interactions: important determinants of drug disposition and effects.

    PubMed

    König, Jörg; Müller, Fabian; Fromm, Martin F

    2013-07-01

    Uptake and efflux transporters determine plasma and tissue concentrations of a broad variety of drugs. They are localized in organs such as small intestine, liver, and kidney, which are critical for drug absorption and elimination. Moreover, they can be found in important blood-tissue barriers such as the blood-brain barrier. Inhibition or induction of drug transporters by coadministered drugs can alter pharmacokinetics and pharmacodynamics of the victim drugs. This review will summarize in particular clinically observed drug-drug interactions attributable to inhibition or induction of intestinal export transporters [P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)], to inhibition of hepatic uptake transporters [organic anion transporting polypeptides (OATPs)], or to inhibition of transporter-mediated [organic anion transporters (OATs), organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATEs), P-gp] renal secretion of xenobiotics. Available data on the impact of nutrition on transport processes as well as genotype-dependent, transporter-mediated drug-drug interactions will be discussed. We will also present and discuss data on the variable extent to which information on the impact of transporters on drug disposition is included in summaries of product characteristics of selected countries (SPCs). Further work is required regarding a better understanding of the role of the drug metabolism-drug transport interplay for drug-drug interactions and on the extrapolation of in vitro findings to the in vivo (human) situation. PMID:23686349

  14. Drug-Drug Interactions within Protein Cavities Probed by Triplet-Triplet Energy Transfer.

    PubMed

    Nuin, Edurne; Jiménez, M Consuelo; Sastre, Germán; Andreu, Inmaculada; Miranda, Miguel A

    2013-05-16

    A new direct and noninvasive methodology based on transient absorption spectroscopy has been developed to probe the feasibility of drug-drug interactions within a common protein binding site. The simultaneous presence of (R)-cinacalcet (CIN) and (S)-propranolol (PPN) within human or bovine α1-acid glycoproteins (AAGs) is revealed by detection of (3)CIN* as the only transient species after laser flash photolysis of CIN/PPN/AAG mixtures at 308 nm. This is the result of triplet-triplet energy transfer from (3)PPN* to CIN, which requires close contact between the two drugs within the same biological compartment. Similar results are obtained with nabumetone and CIN as donor/acceptor partners. This new methodology can, in principle, be extended to a variety of drug/drug/biomolecule combinations. PMID:26282966

  15. Intrapartum Magnesium Sulfate and the Potential for Cardiopulmonary Drug-Drug Interactions

    PubMed Central

    Campbell, Sarah C.; Stockmann, Chris; Balch, Alfred; Clark, Erin A.S.; Kamyar, Manijeh; Varner, Michael; Korgenski, E. Kent; Bonkowsky, Joshua L.; Spigarelli, Michael G.; Sherwin, Catherine M.T.

    2014-01-01

    Objective This study sought to determine the frequency of possible cardiopulmonary drug-drug interactions among pregnant women who received intrapartum magnesium sulfate (MgSO4). Methods Pregnant women admitted to an Intermountain Healthcare facility between January 2009 and October 2011 were studied if they received one or more doses of MgSO4. Concomitant medications were electronically queried from an electronic health records system. Adverse events were identified using administrative discharge codes. The frequency of cardiopulmonary drug-drug interactions was compared among women who did, and did not, receive aminoglycoside antibiotics, antacids / laxatives, calcium channel blockers, corticosteroids, diuretics, neuromuscular blocking agents, and vitamin D analogs, all of which are contraindicated for patients receiving MgSO4. Results Overall, 683 women received intrapartum MgSO4 during the study period. A total of 219 MgSO4 potentially interacting drugs were identified among 155 (23%) unique patients. The most commonly identified potentially interacting agents included calcium channel blockers (26%), diuretics (25%), and antacids / laxatives (19%). Longer hospital stays were significantly associated with increasing numbers of MgSO4 interacting drugs (P<0.001). Three of 53 (6%) women who received furosemide experienced a cardiac arrest, compared to 0 of 618 (0%) women who did not receive furosemide (Fisher’s Exact Test P<0.001). Conclusion Intrapartum administration of drugs that interact with MgSO4 is common and associated with prolonged hospital stays and potentially cardiopulmonary drug-drug interactions. Caution is warranted when prescribing MgSO4 in combination with known interacting medications. PMID:24487252

  16. Using Nonexperts for Annotating Pharmacokinetic Drug-Drug Interaction Mentions in Product Labeling: A Feasibility Study

    PubMed Central

    Ning, Yifan; Hernandez, Andres; Horn, John R; Jacobson, Rebecca; Boyce, Richard D

    2016-01-01

    Background Because vital details of potential pharmacokinetic drug-drug interactions are often described in free-text structured product labels, manual curation is a necessary but expensive step in the development of electronic drug-drug interaction information resources. The use of nonexperts to annotate potential drug-drug interaction (PDDI) mentions in drug product label annotation may be a means of lessening the burden of manual curation. Objective Our goal was to explore the practicality of using nonexpert participants to annotate drug-drug interaction descriptions from structured product labels. By presenting annotation tasks to both pharmacy experts and relatively naïve participants, we hoped to demonstrate the feasibility of using nonexpert annotators for drug-drug information annotation. We were also interested in exploring whether and to what extent natural language processing (NLP) preannotation helped improve task completion time, accuracy, and subjective satisfaction. Methods Two experts and 4 nonexperts were asked to annotate 208 structured product label sections under 4 conditions completed sequentially: (1) no NLP assistance, (2) preannotation of drug mentions, (3) preannotation of drug mentions and PDDIs, and (4) a repeat of the no-annotation condition. Results were evaluated within the 2 groups and relative to an existing gold standard. Participants were asked to provide reports on the time required to complete tasks and their perceptions of task difficulty. Results One of the experts and 3 of the nonexperts completed all tasks. Annotation results from the nonexpert group were relatively strong in every scenario and better than the performance of the NLP pipeline. The expert and 2 of the nonexperts were able to complete most tasks in less than 3 hours. Usability perceptions were generally positive (3.67 for expert, mean of 3.33 for nonexperts). Conclusions The results suggest that nonexpert annotation might be a feasible option for comprehensive

  17. 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

  18. The role of metabolites in predicting drug-drug interactions: Focus on irreversible P450 inhibition

    PubMed Central

    VandenBrink, Brooke M.; Isoherranen, Nina

    2010-01-01

    Irreversible inhibition of cytochrome P450 enzymes can cause significant drug-drug interactions (DDIs). Formation of metabolites is fundamental for the inactivation of P450 enzymes. Of the 19 inactivators with a known mechanism of inactivation, 10 have circulating metabolites that are known to be on path to inactive P450. The fact that inactivation usually requires multiple metabolic steps implies that predicting in vivo interactions may require complex models, and in vitro data generated from each metabolite. The data reviewed here suggest that circulating metabolites are much more important in in vivo P450 inhibition than is currently acknowledged. PMID:20047147

  19. Detection of Drug-Drug Interactions by Modeling Interaction Profile Fingerprints

    PubMed Central

    Vilar, Santiago; Uriarte, Eugenio; Santana, Lourdes; Tatonetti, Nicholas P.; Friedman, Carol

    2013-01-01

    Drug-drug interactions (DDIs) constitute an important problem in postmarketing pharmacovigilance and in the development of new drugs. The effectiveness or toxicity of a medication could be affected by the co-administration of other drugs that share pharmacokinetic or pharmacodynamic pathways. For this reason, a great effort is being made to develop new methodologies to detect and assess DDIs. In this article, we present a novel method based on drug interaction profile fingerprints (IPFs) with successful application to DDI detection. IPFs were generated based on the DrugBank database, which provided 9,454 well-established DDIs as a primary source of interaction data. The model uses IPFs to measure the similarity of pairs of drugs and generates new putative DDIs from the non-intersecting interactions of a pair. We described as part of our analysis the pharmacological and biological effects associated with the putative interactions; for example, the interaction between haloperidol and dicyclomine can cause increased risk of psychosis and tardive dyskinesia. First, we evaluated the method through hold-out validation and then by using four independent test sets that did not overlap with DrugBank. Precision for the test sets ranged from 0.4–0.5 with more than two fold enrichment factor enhancement. In conclusion, we demonstrated the usefulness of the method in pharmacovigilance as a DDI predictor, and created a dataset of potential DDIs, highlighting the etiology or pharmacological effect of the DDI, and providing an exploratory tool to facilitate decision support in DDI detection and patient safety. PMID:23520498

  20. 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

  1. 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. PMID:27013915

  2. 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

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

    PubMed

    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

  4. 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

  5. Computing with evidence Part II: An evidential approach to predicting metabolic drug-drug interactions.

    PubMed

    Boyce, Richard; Collins, Carol; Horn, John; Kalet, Ira

    2009-12-01

    We describe a novel experiment that we conducted with the Drug Interaction Knowledge-base (DIKB) to determine which combinations of evidence enable a rule-based theory of metabolic drug-drug interactions to make the most optimal set of predictions. The focus of the experiment was a group of 16 drugs including six members of the HMG-CoA-reductase inhibitor family (statins). The experiment helped identify evidence-use strategies that enabled the DIKB to predict significantly more interactions present in a validation set than the most rigorous strategy developed by drug experts with no loss of accuracy. The best-performing strategies included evidence types that would normally be of lesser predictive value but that are often more accessible than more rigorous types. Our experimental methods represent a new approach to leveraging the available scientific evidence within a domain where important evidence is often missing or of questionable value for supporting important assertions. PMID:19539050

  6. Polypharmacy, Drug-Drug Interactions, and Potentially Inappropriate Medications in Older HIV-Infected Adults

    PubMed Central

    Greene, Meredith; Steinman, Michael A.; McNicholl, Ian R.; Valcour, Victor

    2014-01-01

    Objectives To describe the frequency of medication-related problems in older HIV-infected adults Design Retrospective chart review Setting And Participants Community dwelling HIV-infected adults age 60 and older and age and sex-matched HIV-uninfected adults Measurements Total number of medications, potentially inappropriate medications as defined by the modified Beers criteria, anticholinergic drug burden as defined by the Anticholinergic Risk Scale, and drug-drug interactions using Lexi-Interact online drug interactions database. Results Of 89 HIV-infected participants, most were Caucasian (91%) and male (94%) with a median age of 64 (range 60-82). Common comorbidities included hyperlipidemia, hypertension, and depression. Participants were taking a median of 13 medications (range 2-38), of which only a median of 4 were antiretrovirals. At least one potentially inappropriate medication was prescribed in 46 participants (52%). Sixty-two (70%) participants had at least one Category D (consider therapy modification) drug-drug interaction and 10 (11%) had a Category X (avoid combination) interaction. One-third of these interactions were between two non-antiretroviral medications. We identified 15 participants (17%) with an anticholinergic risk scale score ≥3. In contrast, HIV-uninfected participants were taking a median of 6 medications, 29% had at least one potentially inappropriate medication, and 4% had an anticholinergic risk scale score ≥ 3 (p-value <0.05 for each comparison except p=0.07 for anticholinergic burden). Conclusion HIV-infected older adults have a high frequency of medication-related problems, of which a large portion is due to medications used to treat comorbid diseases. These medication issues were substantially higher than HIV-uninfected participants. Attention to the principles of geriatric prescribing is needed as this population ages in order to minimize complications from multiple medication use. PMID:24576251

  7. Assessment of the consistency among three drug compendia in listing and ranking of drug-drug interactions

    PubMed Central

    Nikolić, Božana S.; Ilić, Maja S.

    2013-01-01

    Inconsistent information about drug-drug interactions can cause variations in prescribing, and possibly increase the incidence of morbidity and mortality. The aim of this study was to assess whether there is an inconsistency in drug-drug interaction listing and ranking in three authoritative, freely accessible online drug information sources: The British National Formulary; The Compendium about Drugs Licensed for Use in the United Kingdom (the Electronic Medicines Compendium) and the Compendium about Drugs Licensed for Use in the United States (the DailyMed). Information on drug-drug interactions for thirty drugs which have a high or medium potential for interactions have been selected for analysis. In total, 1971 drug-drug interactions were listed in all three drug information sources, of these 992 were ranked as the interactions with the potential of clinical significance. Comparative analysis identified that 63.98% of interactions were listed in only one drug information source, and 66.63% of interactions were ranked in only one drug information source. Only 15.12% listed and 11.19% ranked interactions were identified in all three information sources. Intraclass correlation coefficient indicated a weak correlation among the three drug information sources in listing (0.366), as well as in ranking drug interactions (0.467). This study showed inconsistency of information on drug-drug interaction for the selected drugs in three authoritative, freely accessible online drug information sources. The application of a uniform methodology in assessment of information, and then the presentation of information in a standardized format is required to prevent and adequately manage drug-drug interactions. PMID:24289762

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

    PubMed Central

    Namazi, Soha; Pourhatami, Shiva; Borhani-Haghighi, Afshin; Roosta, Sareh

    2014-01-01

    Background: Reciprocal drug interactions are among the most common causes of adverse drug reactions. We investigated the incidence and related risk factors associated with mutual drug interactions in relation to prescriptions written in the neurology wards of two major teaching hospitals in Shiraz, southern Iran. Methods: Data was collected from hand-written prescriptions on a daily basis. Mutual drug interactions were identified using Lexi-Comp 2012 version 1.9.1. Type D and X drug interactions were considered as potential drug-drug interactions. The potential risk factors associated with drug-drug interactions included the patient’s age and gender, number of medications and orders, length of hospitalization and the type of neurological disorder. To determine potential drug-drug interactions, relevant interventions were suggested to the physicians or nurses and the outcome of the interventions were documented. Results: The study comprised 589 patients, of which 53% were males and 47% females, with a mean age of 56.65±18.19 SD years. A total of 4942 drug orders and 3784 medications were prescribed among which 4539 drug-drug interactions were detected, including 4118 type C, 403 type D, and 18 type X. Using a logistic regression model, the number of medications, length of hospitalization and non-vascular type of the neurological disorder were found to be significantly associated with potential drug-drug interactions. From the total interventions, 74.24% were accepted by physicians and nurses. Conclusion: Potentially hazardous reciprocal drug interactions are common among patients in neurology wards. Clinical pharmacists can play a critical role in the prevention of drug-drug interactions in hospitalized patients. PMID:25429173

  9. 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

  10. Albumin Supplement Affects the Metabolism and Metabolism-Related Drug-Drug Interaction of Fenoprofen Enantiomers.

    PubMed

    Wang, Nan; Wang, Feng; Meng, Yu; Yang, Guo-Hui; Chen, Ju-Wu; Wang, Jia-Xiang

    2015-07-01

    The influence of albumin towards the metabolism behavior of fenoprofen enantiomers and relevant drug-drug interaction was investigated in the present study. The metabolic behavior of fenoprofen enantiomers was compared in a phase II metabolic incubation system with and without bovine serum albumin (BSA). BSA supplement increased the binding affinity parameter (Km) of (R)-fenoprofen towards human liver microsomes (HLMs) from 148.3 to 214.4 μM. In contrast, BSA supplement decreased the Km of (S)-fenoprofen towards HLMs from 218.2 to 123.5 μM. For maximum reaction velocity (Vmax), the addition of BSA increased the Vmax of (R)-fenoprofen from 1.3 to 1.6 nmol/min/mg protein. In the contrast, BSA supplement decreased the Vmax value from 3.3 to 1.5 nmol/min/mg protein. Andrographolide-fenoprofen interaction was used as an example to investigate the influence of BSA supplement towards fenoprofen-relevant drug-drug interaction. The addition of 0.2% BSA in the incubation system significantly decreased the inhibition potential of andrographolide towards (R)-fenoprofen metabolism (P < 0.001). Different from (R)-fenoprofen, the addition of BSA significantly increased the inhibition potential of andrographolide towards the metabolism of (S)-fenoprofen. BSA supplement also changed the inhibition kinetic type and parameter of andrographolide towards the metabolism of (S)-fenoprofen. In conclusion, albumin supplement changes the metabolic behavior of fenoprofen enantiomers and the fenoprofen-andrographolide interaction. PMID:26037509

  11. 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

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

    PubMed

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

    2015-02-01

    Little is known about clinically significant drug-drug interactions (DDIs) in respiratory settings. DDIs are more likely to occur in critically ill patients due to complex pharmacotherapy regimens and organ dysfunctions. The aim of this study was to identify the pattern of potential DDIs (pDDIs) occurring in cardiothoracic intensive care unit (ICU) of a pulmonary hospital. A prospective observational study was conducted for 6 months. All pDDIs for admitted patients in cardiothoracic ICU were identified with Lexi-Interact program and assessed by a clinical pharmacologist. The interacting drugs, reliability, mechanisms, potential outcomes, and clinical management were evaluated for severe and contraindicated interactions. The study included 195 patients. Lung cancer (14.9%) was the most common diagnosis followed by tracheal stenosis (14.3%). The rate of pDDIs was 720.5/100 patients. Interactions were more commonly observed in transplant patients. 17.7% of pDDIs were considered as severe and contraindicated interactions. Metabolism (54.8%) and additive (24.2%) interactions were the most frequent mechanisms leading to pDDIs, and azole antifungals and fluoroquinolones were the main drug classes involved. The pattern of pDDIs in cardiothoracic ICU differs from other ICU settings. Specialized epidemiological knowledge of drug interactions may help clinical practitioners to reduce the risk of adverse drug events. PMID:25369984

  13. A Successful Model and Visual Design for Creating Context-Aware Drug-Drug Interaction Alerts

    PubMed Central

    Duke, Jon D.; Bolchini, Davide

    2011-01-01

    Evaluating the potential harm of a drug-drug interaction (DDI) requires knowledge of a patient’s relevant co-morbidities and risk factors. Current DDI alerts lack such patient-specific contextual data. In this paper, we present an efficient model for integrating pertinent patient data into DDI alerts. This framework is designed to be interoperable across multiple drug knowledge bases and clinical information systems. To evaluate the model, we generated a set of contextual DDI data using our local drug knowledge base then conducted an evaluation study of a prototype contextual alert design. The alert received favorable ratings from study subjects, who agreed it was an improvement over traditional alerts and was likely to support clinical management and save physician time. This framework may ultimately help reduce alert fatigue through the dynamic display of DDI alerts based on patient risk. PMID:22195086

  14. 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

  15. Statin-associated rhabdomyolysis triggered by drug-drug interaction with itraconazole.

    PubMed

    Dybro, Anne Mette; Damkier, Per; Rasmussen, Torsten Bloch; Hellfritzsch, Maja

    2016-01-01

    A 47-year-old woman had been treated with high-dose simvastatin for several years. After systemic treatment with the antifungal agent itraconazole, she developed muscle pain and highly elevated levels of creatine kinase and myoglobin. Muscle biopsy was compatible with statin-associated rhabdomyolysis, probably caused by a drug-drug interaction between simvastatin and itraconazole. The patient made full recovery. Three commonly used statins-simvastatin, atorvastatin and lovastatin-are metabolised by the liver enzyme CYP3A4. Several potent inhibitors of this enzyme are known, for example, azole antifungal agents such as itraconazole and posaconazole. If antifungal treatment is indicated in a patient using a CYP3A4-metabolised statin, we recommend (1) topical administration of the antifungal agent if possible, (2) the use of a non-CYP3A4-inhibiting antifungal drug such as terbinafine or (3) temporary discontinuation of statin treatment. PMID:27605198

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

    PubMed

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

    2013-01-01

    Drug-drug interactions (DDIs) can lead to increased toxicity or reduction in therapeutic efficacy. This study was designed to assess the incidence of potential drug interactions (PDI) and rank their clinical value in post coronary care unit (Post-CCU) of a teaching hospital in Tehran, Iran. In this prospective study, three pharmacists with supervision of a clinical pharmacist actively gathered necessary information for detection of DDIs. Data were tabulated according to the combinations of drugs in treatment chart. Verification of potential drug interactions was carried out using the online Lexi-Interact™ 2011. A total of 203 patients (113 males and 90 females) were enrolled in the study. The mean age of patients was 61 ± 12.55 years (range = 26-93). A total of 90 drugs were prescribed to 203 patients and most prescribed drugs were atorvastatin, clopidogrel and metoprolol. Mean of drugs was 11.22 per patient. A total of 3166 potential drug interactions have been identified by Lexi- Interact™, 149 (4.71%) and 55 (1.73%) of which were categorized as D and X, respectively. The most serious interactions were clopidogrel+omeprazole and metoprolol+salbutamol. Drug interactions leading to serious adverse effects are to be cautiously watched for when multiple drugs are used simultaneously. In settings with multiple drug use attendance of a pharmacist or clinical pharmacist, taking the responsibility for monitoring drug interactions and notifying the physician about potential problems could decrease the harm in patient and increase the patient safety. PMID:24250596

  17. Identification and Mechanistic Investigation of Drug-Drug Interactions Associated with Myopathy – A Translational Approach

    PubMed Central

    Han, Xu; Quinney, Sara K.; Wang, Zhiping; Zhang, Pengyue; Duke, Jon; Desta, Zeruesenay; Elmendorf, Jeffrey S.; Flockhart, David A.; Li, L

    2015-01-01

    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% 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 FDA Adverse Event Reporting System. PMID:25975815

  18. 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. PMID:25975815

  19. 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

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

    PubMed

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

    2014-09-01

    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

  1. Clinical pharmacokinetics and drug-drug interactions of endothelin receptor antagonists in pulmonary arterial hypertension.

    PubMed

    Venitz, Jürgen; Zack, Julia; Gillies, Hunter; Allard, Martine; Regnault, Jean; Dufton, Christopher

    2012-12-01

    The authors review the basic pharmacology and potential for adverse drug-drug interactions (DDIs) of bosentan and ambrisentan, the 2 endothelin receptor antagonists currently approved for pulmonary arterial hypertension (PAH) treatment. Bosentan, an endothelin (ET) receptor-type ET(A) and ET(B) antagonist, is metabolized to active metabolites by and an inducer of cytochrome P450 (CYP)2C9 and CYP3A. Ambrisentan, a selective ET(A) receptor antagonist, is metabolized primarily by uridine 5'diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S and, to a lesser extent, by CYP3A and CYP2C19. Drug interactions observed with bosentan DDI studies have demonstrated a potential for significant clinical implications during PAH management: bosentan is contraindicated with cyclosporine A and glyburide, and additional monitoring/dose adjustments are required when coadministered with hormonal contraceptives, simvastatin, lopinavir/ritonavir, and rifampicin. As bosentan carries a boxed warning regarding risks of liver injury and showed dose-dependant increases in serum aminotransferase abnormalities, drug interactions that increase bosentan exposure are of particular clinical concern. Ambrisentan DDI studies performed to date have shown only one clinically relevant DDI, an interaction with cyclosporine A that requires ambrisentan dose reduction. As the treatment of PAH moves toward multimodal combination therapy, scrutiny should be placed on ensuring that drug combinations achieve maximal clinical benefit while minimizing side effects. PMID:22205719

  2. Renal Transporter-Mediated Drug-Drug Interactions: Are They Clinically Relevant?

    PubMed

    Lepist, Eve-Irene; Ray, Adrian S

    2016-07-01

    The kidney, through the distinct processes of passive glomerular filtration and active tubular secretion, plays an important role in the elimination of numerous endobiotics (eg, hormones, metabolites), toxins, nutrients, and drugs. Renal transport pathways mediating active tubular secretion and reabsorption in the proximal tubule are complex, involving apical and basolateral transporters acting in concert. Detailed studies of the molecular mechanisms of net active tubular secretion have established the involvement of multiple transporters with overlapping substrate specificity mediating competing secretion and reabsorption pathways. Although drug interactions arising from inhibition of renal transporters are rare relative to other mechanisms, they can involve commonly administered drugs (eg, cimetidine, metformin), may be underappreciated due to muted effects on plasma pharmacokinetics relative to tissue levels, can affect narrow-therapeutic-index medications (eg, antiarrhythmic, oncology medications), and may disproportionately affect sensitive populations where polypharmacy is common (eg, the elderly, diabetics). In particular, there is the potential for larger-magnitude interactions in subjects with reduced glomerular filtration rates due to the increased relative contribution of tubular secretion. The assessment of additional endpoints in drug-drug interaction studies including pharmacodynamics, positron emission tomography imaging, and metabolomics promises to expand our understanding of the clinical relevance of renal drug interactions. PMID:27385181

  3. 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

  4. 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. PMID:27252068

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

    PubMed

    Adam, Terrence J; Vang, Joseph

    2015-01-01

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

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

    PubMed Central

    Adam, Terrence J.; Vang, Joseph

    2015-01-01

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

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

    PubMed

    Kim, Sun; Liu, Haibin; Yeganova, Lana; Wilbur, W John

    2015-06-01

    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

  8. 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

  9. 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

    2015-01-01

    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

  10. Detection of potential drug-drug interactions for outpatients across hospitals.

    PubMed

    Yeh, Yu-Ting; Hsu, Min-Hui; Chen, Chien-Yuan; Lo, Yu-Sheng; Liu, Chien-Tsai

    2014-02-01

    The National Health Insurance Administration (NHIA) has adopted smart cards (or NHI-IC cards) as health cards to carry patients' medication histories across hospitals in Taiwan. The aims of this study are to enhance a computerized physician order entry system to support drug-drug interaction (DDI) checking based on a patient's medication history stored in his/her NHI-IC card. For performance evaluation, we developed a transaction tracking log to keep track of every operation on NHI-IC cards. Based on analysis of the transaction tracking log from 1 August to 31 October 2007, physicians read patients' NHI-IC cards in 71.01% (8,246) of patient visits; 33.02% (2,723) of the card reads showed at least one medicine currently being taken by the patient, 82.94% of which were prescribed during the last visit. Among 10,036 issued prescriptions, seven prescriptions (0.09%) contained at least one drug item that might interact with the currently-taken medicines stored in NHI-IC cards and triggered pop-up alerts. This study showed that the capacity of an NHI-IC card is adequate to support DDI checking across hospitals. Thus, the enhanced computerized physician order entry (CPOE) system can support better DDI checking when physicians are making prescriptions and provide safer medication care, particularly for patients who receive medication care from different hospitals. PMID:24473112

  11. Design Features of Drug-Drug Interaction Trials Between Antivirals and Oral Contraceptives.

    PubMed

    Ayala, Ruben C; Arya, Vikram; Younis, Islam R

    2016-05-01

    The aim of this work was to explore the major design features of drug-drug interaction trials between antiviral medications (AVs) and oral contraceptives (OCs). Information on these trials (n = 27) was collected from approved drug labels and clinical pharmacology reviews conducted by the U.S. Food and Drug Administration. The primary objective of all trials was to evaluate changes in OC exposure following the coadministration of AVs. In addition, an evaluation of potential pharmacodynamic interaction was performed in 10 of these trials. Twenty-two trials were open label with a fixed-sequence design, and 5 trials used a double-blind crossover design. The trials were conducted using one, two, or three 28-day ovulatory cycles in 10, 8, and 9 trials, respectively. Only 1 trial enrolled HIV-infected women. The median number of women in a trial was 20 (range, 12 to 52). Norethindrone/ethinyl estradiol (EE) combination was the most commonly used OC (n = 16, 59%) followed by norgestimate/EE (n = 9, 33%). Labeling recommendations were based on exposure changes in 25 cases and on safety observations in the trial in 2 cases. In conclusion, a wide variety of trial designs was used, and there is no preferred design. The answer to the exposure question can be achieved using multiple designs. PMID:26384089

  12. Adverse drug reactions and drug-drug interactions with over-the-counter NSAIDs.

    PubMed

    Moore, Nicholas; Pollack, Charles; Butkerait, Paul

    2015-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen have a long history of safe and effective use as both prescription and over-the-counter (OTC) analgesics/antipyretics. The mechanism of action of all NSAIDs is through reversible inhibition of cyclooxygenase enzymes. Adverse drug reactions (ADRs) including gastrointestinal bleeding as well as cardiovascular and renal effects have been reported with NSAID use. In many cases, ADRs may occur because of drug-drug interactions (DDIs) between the NSAID and a concomitant medication. For example, DDIs have been reported when NSAIDs are coadministered with aspirin, alcohol, some antihypertensives, antidepressants, and other commonly used medications. Because of the pharmacologic nature of these interactions, there is a continuum of risk in that the potential for an ADR is dependent on total drug exposure. Therefore, consideration of dose and duration of NSAID use, as well as the type or class of comedication administered, is important when assessing potential risk for ADRs. Safety findings from clinical studies evaluating prescription-strength NSAIDs may not be directly applicable to OTC dosing. Health care providers can be instrumental in educating patients that using OTC NSAIDs at the lowest effective dose for the shortest required duration is vital to balancing efficacy and safety. This review discusses some of the most clinically relevant DDIs reported with NSAIDs based on major sites of ADRs and classes of medication, with a focus on OTC ibuprofen, for which the most data are available. PMID:26203254

  13. 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

  14. Drug-drug interactions and Idiosyncratic Hepatotoxicity in the Liver Transplant setting

    PubMed Central

    Tischer, Sarah; Fontana, Robert J.

    2016-01-01

    Preliminary studies of boceprevir and telaprevir based antiviral therapy in liver transplant (LT) recipients with hepatitis C have demonstrated dramatic increases in tacrolimus, cyclosporine, and the mTOR inhibitor exposure. In addition to empiric dose reductions, daily monitoring of immunosuppressant blood levels is required when initiating as well as discontinuing the protease inhibitors to maximize patient safety. Although improved suppression of HCV replication is anticipated, 20 to 40% of treated subjects have required early treatment discontinuation due to various adverse events including anemia (100%), infection (30%), nephrotoxicity (20%) and rejection (5 to 10%). Simeprevir and faldepravir are 2nd generation protease inhibitors which may have improved efficacy and tolerability profiles but potential drug interactions with other OATP1B1 substrates and unconjugated hyperbilirubinemia are expected. In contrast, sofosbuvir and daclatasvir based therapies are not expected to lead to clinically significant drug-drug interactions in LT recipients but confirmatory studies are needed. Liver transplant recipients may also be at increased risk of developing drug induced liver injury (DILI). Establishing a diagnosis of DILI in the transplant setting is very difficult with the variable latency, laboratory features and histopathological manifestations of hepatotoxicity associated with a given drug, the need to exclude competing causes of allograft injury, and the lack of an objective and verifiable confirmatory test. Nonetheless, a heightened awareness of the possibility of DILI is warranted in light of the large number of medications used in LT recipients and the potential adverse impact that DILI may have on patient outcomes. PMID:24280292

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

    PubMed Central

    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. PMID:26682218

  16. Discovery and explanation of drug-drug interactions via text mining.

    PubMed

    Percha, Bethany; Garten, Yael; Altman, Russ B

    2012-01-01

    Drug-drug interactions (DDIs) can occur when two drugs interact with the same gene product. Most available information about gene-drug relationships is contained within the scientific literature, but is dispersed over a large number of publications, with thousands of new publications added each month. In this setting, automated text mining is an attractive solution for identifying gene-drug relationships and aggregating them to predict novel DDIs. In previous work, we have shown that gene-drug interactions can be extracted from Medline abstracts with high fidelity - we extract not only the genes and drugs, but also the type of relationship expressed in individual sentences (e.g. metabolize, inhibit, activate and many others). We normalize these relationships and map them to a standardized ontology. In this work, we hypothesize that we can combine these normalized gene-drug relationships, drawn from a very broad and diverse literature, to infer DDIs. Using a training set of established DDIs, we have trained a random forest classifier to score potential DDIs based on the features of the normalized assertions extracted from the literature that relate two drugs to a gene product. The classifier recognizes the combinations of relationships, drugs and genes that are most associated with the gold standard DDIs, correctly identifying 79.8% of assertions relating interacting drug pairs and 78.9% of assertions relating noninteracting drug pairs. Most significantly, because our text processing method captures the semantics of individual gene-drug relationships, we can construct mechanistic pharmacological explanations for the newly-proposed DDIs. We show how our classifier can be used to explain known DDIs and to uncover new DDIs that have not yet been reported. PMID:22174296

  17. A graph kernel based on context vectors for extracting drug-drug interactions.

    PubMed

    Zheng, Wei; Lin, Hongfei; Zhao, Zhehuan; Xu, Bo; Zhang, Yijia; Yang, Zhihao; Wang, Jian

    2016-06-01

    The clinical recognition of drug-drug interactions (DDIs) is a crucial issue for both patient safety and health care cost control. Thus there is an urgent need that DDIs be extracted automatically from biomedical literature by text-mining techniques. Although the top-ranking DDIs systems explore various features of texts, these features can't yet adequately express long and complicated sentences. In this paper, we present an effective graph kernel which makes full use of different types of contexts to identify DDIs from biomedical literature. In our approach, the relations among long-range words, in addition to close-range words, are obtained by the graph representation of a parsed sentence. Context vectors of a vertex, an iterative vectorial representation of all labeled nodes adjacent and nonadjacent to it, adequately capture the direct and indirect substructures' information. Furthermore, the graph kernel considering the distance between context vectors is used to detect DDIs. Experimental results on the DDIExtraction 2013 corpus show that our system achieves the best detection and classification performance (F-score) of DDIs (81.8 and 68.4, respectively). Especially for the Medline-2013 dataset, our system outperforms the top-ranking DDIs systems by F-scores of 10.7 and 12.2 in detection and classification, respectively. PMID:27012903

  18. 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. PMID:23969513

  19. 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. PMID:26116278

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

    PubMed

    Feng, Bo; Varma, Manthena V

    2016-07-01

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

  1. Using improved serial blood sampling method of mice to study pharmacokinetics and drug-drug interaction.

    PubMed

    Watanabe, Ayahisa; Watari, Ryosuke; Ogawa, Keiko; Shimizu, Ryosuke; Tanaka, Yukari; Takai, Nozomi; Nezasa, Ken-ichi; Yamaguchi, Yoshitaka

    2015-03-01

    In pharmacokinetic evaluation of mice, using serial sampling methods rather than a terminal blood sampling method could reduce the number of animals needed and lead to more reliable data by excluding individual differences. In addition, using serial sampling methods can be valuable for evaluation of the drug-drug interaction (DDI) potential of drug candidates. In this study, we established an improved method for serially sampling the blood from one mouse by only one incision of the lateral tail vein, and investigated whether our method could be adapted to pharmacokinetic and DDI studies. After intravenous and oral administration of ibuprofen and fexofenadine (BCS class II and III), the plasma concentration and pharmacokinetic parameters were evaluated by our method and a terminal blood sampling method, with the result that both methods gave comparable results (ibuprofen: 63.8 ± 4.0% and 64.4%, fexofenadine: 6.5 ± 0.7% and 7.9%, respectively, in bioavailability). In addition, our method could be adapted to DDI study for cytochrome P450 and organic anion transporting polypeptide inhibition. These results demonstrate that our method can be useful for pharmacokinetic evaluation from the perspective of reliable data acquisition as well as easy handling and low stress to mice and improve the quality of pharmacokinetic and DDI studies. PMID:25452230

  2. Clinical assessment of drug-drug interactions of tasimelteon, a novel dual melatonin receptor agonist.

    PubMed

    Ogilvie, Brian W; Torres, Rosarelis; Dressman, Marlene A; Kramer, William G; Baroldi, Paolo

    2015-09-01

    Tasimelteon ([1R-trans]-N-[(2-[2,3-dihydro-4-benzofuranyl] cyclopropyl) methyl] propanamide), a novel dual melatonin receptor agonist that demonstrates specificity and high affinity for melatonin receptor types 1 and 2 (MT1 and MT2 receptors), is the first treatment approved by the US Food and Drug Administration for Non-24-Hour Sleep-Wake Disorder. Tasimelteon is rapidly absorbed, with a mean absolute bioavailability of approximately 38%, and is extensively metabolized primarily by oxidation at multiple sites, mainly by cytochrome P450 (CYP) 1A2 and CYP3A4/5, as initially demonstrated by in vitro studies and confirmed by the results of clinical drug-drug interactions presented here. The effects of strong inhibitors and moderate or strong inducers of CYP1A2 and CYP3A4/5 on the pharmacokinetics of tasimelteon were evaluated in humans. Coadministration with fluvoxamine resulted in an approximately 6.5-fold increase in tasimelteon's area under the curve (AUC), whereas cigarette smoking decreased tasimelteon's exposure by approximately 40%. Coadministration with ketoconazole resulted in an approximately 54% increase in tasimelteon's AUC, whereas rifampin pretreatment resulted in a decrease in tasimelteon's exposure of approximately 89%. PMID:25851638

  3. DINTO: Using OWL Ontologies and SWRL Rules to Infer Drug-Drug Interactions and Their Mechanisms.

    PubMed

    Herrero-Zazo, María; Segura-Bedmar, Isabel; Hastings, Janna; Martínez, Paloma

    2015-08-24

    The early detection of drug-drug interactions (DDIs) is limited by the diffuse spread of DDI information in heterogeneous sources. Computational methods promise to play a key role in the identification and explanation of DDIs on a large scale. However, such methods rely on the availability of computable representations describing the relevant domain knowledge. Current modeling efforts have focused on partial and shallow representations of the DDI domain, failing to adequately support computational inference and discovery applications. In this paper, we describe a comprehensive ontology for DDI knowledge (DINTO), which is the first formal representation of different types of DDIs and their mechanisms and its application in the prediction of DDIs. This project has been developed using currently available semantic web technologies, standards, and tools, and we have demonstrated that the combination of drug-related facts in DINTO and Semantic Web Rule Language (SWRL) rules can be used to infer DDIs and their different mechanisms on a large scale. The ontology is available from https://code.google.com/p/dinto/. PMID:26147071

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

    PubMed

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

    2014-01-01

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

  5. 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

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

    PubMed Central

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

    2015-01-01

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

  7. P450-Based Drug-Drug Interactions of Amiodarone and its Metabolites: Diversity of Inhibitory Mechanisms.

    PubMed

    McDonald, Matthew G; Au, Nicholas T; Rettie, Allan E

    2015-11-01

    In this study, IC50 shift and time-dependent inhibition (TDI) experiments were carried out to measure the ability of amiodarone (AMIO), and its circulating human metabolites, to reversibly and irreversibly inhibit CYP1A2, CYP2C9, CYP2D6, and CYP3A4 activities in human liver microsomes. The [I]u/Ki,u values were calculated and used to predict in vivo AMIO drug-drug interactions (DDIs) for pharmaceuticals metabolized by these four enzymes. Based on these values, the minor metabolite N,N-didesethylamiodarone (DDEA) is predicted to be the major cause of DDIs with xenobiotics primarily metabolized by CYP1A2, CYP2C9, or CYP3A4, while AMIO and its N-monodesethylamiodarone (MDEA) derivative are the most likely cause of interactions involving inhibition of CYP2D6 metabolism. AMIO drug interactions predicted from the reversible inhibition of the four P450 activities were found to be in good agreement with the magnitude of reported clinical DDIs with lidocaine, warfarin, metoprolol, and simvastatin. The TDI experiments showed DDEA to be a potent inactivator of CYP1A2 (KI = 0.46 μM, kinact = 0.030 minute(-1)), while MDEA was a moderate inactivator of both CYP2D6 (KI = 2.7 μM, kinact = 0.018 minute(-1)) and CYP3A4 (KI = 2.6 μM, kinact = 0.016 minute(-1)). For DDEA and MDEA, mechanism-based inactivation appears to occur through formation of a metabolic intermediate complex. Additional metabolic studies strongly suggest that CYP3A4 is the primary microsomal enzyme involved in the metabolism of AMIO to both MDEA and DDEA. In summary, these studies demonstrate both the diversity of inhibitory mechanisms with AMIO and the need to consider metabolites as the culprit in inhibitory P450-based DDIs. PMID:26296708

  8. 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

  9. Prediction of renal transporter mediated drug-drug interactions for pemetrexed using physiologically based pharmacokinetic modeling.

    PubMed

    Posada, Maria M; Bacon, James A; Schneck, Karen B; Tirona, Rommel G; Kim, Richard B; Higgins, J William; Pak, Y Anne; Hall, Stephen D; Hillgren, Kathleen M

    2015-03-01

    Pemetrexed, an anionic anticancer drug with a narrow therapeutic index, is eliminated mainly by active renal tubular secretion. The in vitro to in vivo extrapolation approach used in this work was developed to predict possible drug-drug interactions (DDIs) that may occur after coadministration of pemetrexed and nonsteroidal anti-inflammatory drugs (NSAIDs), and it included in vitro assays, risk assessment models, and physiologically based pharmacokinetic (PBPK) models. The pemetrexed transport and its inhibition parameters by several NSAIDs were quantified using HEK-PEAK cells expressing organic anion transporter (OAT) 3 or OAT4. The NSAIDs were ranked according to their DDI index, calculated as the ratio of their maximum unbound concentration in plasma over the concentration inhibiting 50% (IC50) of active pemetrexed transport. A PBPK model for ibuprofen, the NSAID with the highest DDI index, was built incorporating active renal secretion in Simcyp Simulator. The bottom-up model for pemetrexed underpredicted the clearance by 2-fold. The model we built using a scaling factor of 5.3 for the maximal uptake rate (Vmax) of OAT3, which estimated using plasma concentration profiles from patients given a 10-minute infusion of 500 mg/m(2) of pemetrexed supplemented with folic acid and vitamin B12, recovered the clinical data adequately. The observed/predicted increases in Cmax and the area under the plasma-concentration time curve (AUC0-inf) of pemetrexed when ibuprofen was coadministered were 1.1 and 1.0, respectively. The coadministration of all other NSAIDs was predicted to have no significant impact on the AUC0-inf based on their DDI indexes. The PBPK model reasonably reproduced pemetrexed concentration time profiles in cancer patients and its interaction with ibuprofen. PMID:25504564

  10. Drug-drug interaction studies on first-line anti-tuberculosis drugs.

    PubMed

    Bhutani, Hemant; Singh, Saranjit; Jindal, K C

    2005-01-01

    The purpose of this study was to carry out drug-drug compatibility studies on pure first line anti-tuberculosis drugs, viz., rifampicin (R), isoniazid (H), pyrazinamide (Z), and ethambutol hydrochloride (E). Various possible binary, ternary, and quaternary combinations of the four drugs were subjected to accelerated stability test conditions of 40 degrees C and 75% relative humidity (RH) for 3 months. For comparison, parallel studies were also conducted on single drugs. Changes were looked for in the samples drawn after 15, 30, 60, and 90 days of storage. Analyses for R, H, and Z were carried out using a validated HPLC method. The E was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), as it does not absorb in ultraviolet (UV). All single pure drugs were relatively stable and showed only 3%-5% degradation under accelerated conditions for 3 months. However, significant interactions were observed in case of the drug mixtures. In particular, ternary and quaternary drug combinations containing R and H along with Z and/or E were very unstable, showing 90%-95% and 70%-75% loss of R and H, respectively. In all these cases, isonicotinyl hydrazone (HYD) of 3-formylrifamycin and H was found to be the major degradation product. In case of RE and RZE mixtures, where H was absent, 3-formylrifamycin was instead the key degradation product. Another unidentified peak was observed in the mixture containing RZE. Apart from these chemical changes, considerable physical changes were also observed in pure E and the mixtures containing E, viz., RE, ZE, RHE, RZE, and RHZE. In addition, significant physical changes associated with noteworthy loss of H and E were also observed in mixtures containing HE and HZE. The present study thus amply shows that the four primary anti-tuberculosis drugs, when present together, interact with each other in a multiple and complex manner. PMID:16370181

  11. Herb-drug, food-drug, nutrient-drug, and drug-drug interactions: mechanisms involved and their medical implications.

    PubMed

    Sørensen, Janina Maria

    2002-06-01

    Adverse drug reactions (ADRs) and iatrogenic diseases have been identified as significant factors responsible for patient morbidity and mortality. Significant studies on drug metabolism in humans have been published during the last few years, offering a deeper comprehension of the mechanisms underlying adverse drug reactions and interactions. More understanding of these mechanisms, and of recent advances in laboratory technology, can help to evaluate potential drug interactions when drugs are prescribed concurrently. Increasing knowledge of interindividual variation in drug breakdown capacity and recent findings concerning the influence of environment, diet, nutrients, and herbal products can be used to reduce ADRs and iatrogenic diseases. Reviewed data suggest that drug treatment should be increasingly custom tailored to suit the individual patient and that appropriately co-prescribed diet and herbal remedies, could increase drug efficacy and lessen drug toxicity. This review focuses mainly on recently published research material. The cytochrome p450 enzymes, their role in metabolism, and their mechanisms of action are reviewed, and their role in drug-drug interactions are discussed. Drug-food and drug-herb interactions have garnered attention. Interdisciplinary communication among medical herbalists, medical doctors, and dietetic experts needs to be improved and encouraged. Internet resources for obtaining current information regarding drug-drug, drug-herb, and drug-nutrient interactions are provided. PMID:12165187

  12. Risk Assessment of Mechanism-Based Inactivation in Drug-Drug Interactions

    PubMed Central

    Fujioka, Yasushi; Kunze, Kent L.

    2012-01-01

    Drug-drug interactions (DDIs) that occur via mechanism-based inactivation of cytochrome P450 are of serious concern. Although several predictive models have been published, early risk assessment of MBIs is still challenging. For reversible inhibitors, the DDI risk categorization using [I]/Ki ([I], the inhibitor concentration; Ki, the inhibition constant) is widely used in drug discovery and development. Although a simple and reliable methodology such as [I]/Ki categorization for reversible inhibitors would be useful for mechanism-based inhibitors (MBIs), comprehensive analysis of an analogous measure reflecting in vitro potency for inactivation has not been reported. The aim of this study was to evaluate whether the term λ/kdeg (λ, first-order inactivation rate at a given MBI concentration; kdeg, enzyme degradation rate constant) would be useful in the prediction of the in vivo DDI risk of MBIs. Twenty-one MBIs with both in vivo area under the curve (AUC) change of marker substrates and in vitro inactivation parameters were identified in the literature and analyzed. The results of this analysis show that in vivo DDIs with >2-fold change of object drug AUC can be identified with the cutoff value of λ/kdeg = 1, where unbound steady-state Cmax is used for inhibitor concentration. However, the use of total Cmax led to great overprediction of DDI risk. The risk assessment using λ/kdeg coupled with unbound Cmax can be useful for the DDI risk evaluation of MBIs in drug discovery and development. PMID:22685217

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

    PubMed

    Langer, Oliver

    2016-07-01

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

  14. 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

  15. Extraction of pharmacokinetic evidence of drug-drug interactions from the literature.

    PubMed

    Kolchinsky, Artemy; Lourenço, Anália; Wu, Heng-Yi; Li, Lang; Rocha, Luis M

    2015-01-01

    Drug-drug interaction (DDI) is a major cause of morbidity and mortality and a subject of intense scientific interest. Biomedical literature mining can aid DDI research by extracting evidence for large numbers of potential interactions from published literature and clinical databases. Though DDI is investigated in domains ranging in scale from intracellular biochemistry to human populations, literature mining has not been used to extract specific types of experimental evidence, which are reported differently for distinct experimental goals. We focus on pharmacokinetic evidence for DDI, essential for identifying causal mechanisms of putative interactions and as input for further pharmacological and pharmacoepidemiology investigations. We used manually curated corpora of PubMed abstracts and annotated sentences to evaluate the efficacy of literature mining on two tasks: first, identifying PubMed abstracts containing pharmacokinetic evidence of DDIs; second, extracting sentences containing such evidence from abstracts. We implemented a text mining pipeline and evaluated it using several linear classifiers and a variety of feature transforms. The most important textual features in the abstract and sentence classification tasks were analyzed. We also investigated the performance benefits of using features derived from PubMed metadata fields, various publicly available named entity recognizers, and pharmacokinetic dictionaries. Several classifiers performed very well in distinguishing relevant and irrelevant abstracts (reaching F1≈0.93, MCC≈0.74, iAUC≈0.99) and sentences (F1≈0.76, MCC≈0.65, iAUC≈0.83). We found that word bigram features were important for achieving optimal classifier performance and that features derived from Medical Subject Headings (MeSH) terms significantly improved abstract classification. We also found that some drug-related named entity recognition tools and dictionaries led to slight but significant improvements, especially in

  16. 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

  17. 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

  18. [OATP1B1 in drug-drug interactions between traditional Chinese medicine Danshensu and rosuvastatin].

    PubMed

    Wen, Jin-hua; Wei, Xiao-hua; Cheng, Xiao-hua; Zuo, Rong; Peng, Hong-wei; Lü, Yan-ni; Zhou, Jian; Zheng, Xue-lian; Cai, Jun; Xiong, Yu-qing; Cao, Li

    2016-01-01

    The study was designed to explore the drug-drug interactions mechanisms mediated by OATP1B1 between traditional Chinese medicine Danshensu and rosuvastatin. First, the changes of rosuvastatin pharmacokinetics were investigated in presence of Danshensu in rats. Then, the primary rat hepatocytes model was established to explore the effects of Danshensu on the uptake of rosuvastatin by hepatocytes. Finally, HEK293T cells with overexpression of OATP1B1*a and OATP1B1*5 were established using a lentiviral delivery system to explore the effects of Danshensu on the uptake of rosuvastatin. Rosuvastatin pharmacokinetic parameters of C(max0, AUCO(0-t), AUC(0-∞) were increased about 123%, 194% and 195%, by Danshensu in rats, while the CL z/F value was decreased by 60%. Uptake of rosuvastatin in the primary rat hepatocytes was decreased by 3.13%, 41.15% and 74.62%, respectively in the presence of 20, 40 and 80 μmol x L(-1) Danshensu. The IC50 parameters was (53.04 ± 2.43) μmol x L(-1). The inhibitory effect of Danshensu on OATP1B1 mediated transport of rosuvastatin was related to the OATP1B1 gene type. In OATP1B1*5-HEK293T mutant cells, transport of rosuvastatin were reduced by (39.11 ± 4.94)% and (63.61 ± 3.94)%, respectively, by Danshensu at 1 and 10 μmol x L(-1). While transport of rosuvastatin was reduced by (8.22 ± 2.40)% and (11.56 ± 3.04)% and in OATP1B1*1a cells, respectively. Danshensu significantly altered the pharmacokinetics of rosuvastatin in rats, which was related to competitive inhibition of transport by OATPJBI. Danshensu exhibited a significant activity in the inhibition of rosuvastatin transport by OATP1B1*5-HEK293T, but not by OATP1B1*1a, suggesting a dependence on OATP1B1 sequence. PMID:27405165

  19. Drug-drug interactions in inpatient and outpatient settings in Iran: a systematic review of the literature

    PubMed Central

    2014-01-01

    Drug-drug interactions (DDIs) are an important type of adverse drug events. Yet overall incidence and pattern of DDIs in Iran has not been well documented and little information is available about the strategies that have been used for their prevention. The purpose of this study was to systematically review the literature on the incidence and pattern of DDIs in Iran as well as the used strategies for their prevention. PubMed, Scopus, electronic Persian databases, and Google Scholar were searched to identify published studies on DDIs in Iran. Additionally, the reference lists of all retrieved articles were reviewed to identify additional relevant articles. Eligible studies were those that analyzed original data on the incidence of DDIs in inpatient or outpatient settings in Iran. Articles about one specific DDI and drug interactions with herbs, diseases, and nutrients were excluded. The quality of included studies was assessed using quality assessment criteria. Database searches yielded 1053 potentially eligible citations. After removing duplicates, screening titles and abstracts, and reading full texts, 34 articles were found to be relevant. The quality assessment of the included studies showed a relatively poor quality. In terms of study setting, 18 and 16 studies have been conducted in inpatient and outpatient settings, respectively. All studies focused on potential DDIs while no study assessed actual DDIs. The median incidence of potential DDIs in outpatient settings was 8.5% per prescription while it was 19.2% in inpatient settings. The most indicated factor influencing DDIs incidence was patient age. The most involved drug classes in DDIs were beta blockers, angiotensin-converting-enzyme inhibitors (ACEIs), diuretic agents, and non-steroidal anti-inflammatory drugs (NSAIDs). Thirty-one studies were observational and three were experimental in which the strategies to reduce DDIs were applied. Although almost all studies concluded that the incidence of potential

  20. Are We Heeding the Warning Signs? Examining Providers’ Overrides of Computerized Drug-Drug Interaction Alerts in Primary Care

    PubMed Central

    Slight, Sarah P.; Seger, Diane L.; Nanji, Karen C.; Cho, Insook; Maniam, Nivethietha; Dykes, Patricia C.; Bates, David W.

    2013-01-01

    Background Health IT can play a major role in improving patient safety. Computerized physician order entry with decision support can alert providers to potential prescribing errors. However, too many alerts can result in providers ignoring and overriding clinically important ones. Objective To evaluate the appropriateness of providers’ drug-drug interaction (DDI) alert overrides, the reasons why they chose to override these alerts, and what actions they took as a consequence of the alert. Design A cross-sectional, observational study of DDI alerts generated over a three-year period between January 1st, 2009, and December 31st, 2011. Setting Primary care practices affiliated with two Harvard teaching hospitals. The DDI alerts were screened to minimize the number of clinically unimportant warnings. Participants A total of 24,849 DDI alerts were generated in the study period, with 40% accepted. The top 62 providers with the highest override rate were identified and eight overrides randomly selected for each (a total of 496 alert overrides for 438 patients, 3.3% of the sample). Results Overall, 68.2% (338/496) of the DDI alert overrides were considered appropriate. Among inappropriate overrides, the therapeutic combinations put patients at increased risk of several specific conditions including: serotonin syndrome (21.5%, n=34), cardiotoxicity (16.5%, n=26), or sharp falls in blood pressure or significant hypotension (28.5%, n=45). A small number of drugs and DDIs accounted for a disproportionate share of alert overrides. Of the 121 appropriate alert overrides where the provider indicated they would “monitor as recommended”, a detailed chart review revealed that only 35.5% (n=43) actually did. Providers sometimes reported that patients had already taken interacting medications together (15.7%, n=78), despite no evidence to confirm this. Conclusions and Relevance We found that providers continue to override important and useful alerts that are likely to cause

  1. Pharmacologic Therapy for Posttraumatic Stress Disorder: Review of Prescriptions and Potential Drug-Drug Interactions in a Military Cohort

    PubMed Central

    Jablonski, Kara L.; Devore, Maria D.; Ryan, Margaret A.; Streeter, Emily L.; Tolentino, Jerlyn C.; Klinski, Angelica A.; Bahlawan, Nahed

    2015-01-01

    Objective: To describe outpatient prescription treatment for active-duty military members with posttraumatic stress disorder (PTSD). Medical records were screened for drug-drug interactions with PTSD-related medications and for adverse drug events. Method: A retrospective chart review was conducted of the medical records of active-duty service members aged 18 to 65 years who had a diagnosis of PTSD (ICD-9 criteria) and received psychiatric treatment at Naval Hospital Camp Pendleton, Camp Pendleton, California, between October 1, 2010, and October 31, 2010. Prescription medication treatment over a 6-month period (October 1, 2010, through March 31, 2011) was reviewed. Results: Among 275 patients, 243 (88.4%) had at least 1 prescription dispensed and 219 (79.6%) had at least 1 PTSD-related medication dispensed. More than 1 PTSD-related medication was dispensed to 153 (55.6%) patients. The most common medication classes dispensed were selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) (35.1%), novel antidepressants (15.6%), and anticonvulsants (15.0%). The most frequently dispensed PTSD-related medications were zolpidem: 149 (9.8%), sertraline: 147 (9.7%), gabapentin: 134 (8.8%), prazosin: 111 (7.3%), and trazodone: 110 (7.2%). In the subgroup of 219 patients who received PTSD-related medications, overlapping periods of treatment between an SSRI and another PTSD-related medication occurred in 58 (26.5%) patients. Potential drug-drug interactions with this combination involved 44 (20.1%) patients; no adverse drug events were reported. Among these 44 patients, 55 different potential drug-drug interactions were identified. Conclusions: Patients receiving medications for PTSD are frequently treated with SSRIs or SNRIs and are likely to be prescribed more than 1 PTSD-related medication. PMID:27057415

  2. Clinical pharmacology profile of boceprevir, a hepatitis C virus NS3 protease inhibitor: focus on drug-drug interactions.

    PubMed

    Khalilieh, Sauzanne; Feng, Hwa-Ping; Hulskotte, Ellen G J; Wenning, Larissa A; Butterton, Joan R

    2015-06-01

    Boceprevir is a potent, orally administered ketoamide inhibitor that targets the active site of the hepatitis C virus (HCV) non-structural (NS) 3 protease. The addition of boceprevir to peginterferon plus ribavirin resulted in higher rates of sustained virologic response (SVR) than for peginterferon plus ribavirin alone in phase III studies in both previously treated and untreated patients with HCV infection. Because boceprevir is metabolized by metabolic routes common to many other drugs, and is an inhibitor of cytochrome P450 (CYP) 3A4/5, there is a high potential for drug-drug interactions when boceprevir is administered with other therapies, particularly when treating patients with chronic HCV infection who are often receiving other medications concomitantly. Boceprevir is no longer widely used in the US or EU due to the introduction of second-generation treatments for HCV infection. However, in many other geographic regions, first-generation protease inhibitors such as boceprevir continue to form an important treatment option for patients with HCV infection. This review summarizes the interactions between boceprevir and other therapeutic agents commonly used in this patient population, indicating dose adjustment requirements where needed. Most drug interactions do not affect boceprevir plasma concentrations to a clinically meaningful extent, and thus efficacy is likely to be maintained when boceprevir is coadministered with the majority of other therapeutics. Overall, the drug-drug interaction profile of boceprevir suggests that this agent is suitable for use in a wide range of HCV-infected patients receiving concomitant therapies. PMID:25787025

  3. Estimation of Severe Drug-Drug Interaction Warnings by Medical Specialist Groups for Austrian Nationwide eMedication

    PubMed Central

    Sauter, S. K.; Neuhofer, L. M.; Edlinger, D.; Grossmann, W.; Wolzt, M.; Endel, G.; Gall, W.

    2014-01-01

    Summary Objective The objective of this study is to estimate the amount of severe drug-drug interaction warnings per medical specialist group triggered by prescribed drugs of a patient before and after the introduction of a nationwide eMedication system in Austria planned for 2015. Methods The estimations of interaction warnings are based on patients’ prescriptions of a single health care professional per patient, as well as all patients’ prescriptions from all visited health care professionals. We used a research database of the Main Association of Austrian Social Security Organizations that contains health claims data of the years 2006 and 2007. Results The study cohort consists of about 1 million patients, with 26.4 million prescribed drugs from about 3,400 different health care professionals. The estimation of interaction warnings show a heterogeneous pattern of severe drug-drug-interaction warnings across medical specialist groups. Conclusion During an eMedication implementation it must be taken into consideration that different medical specialist groups require customized support. PMID:25298801

  4. 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. PMID:27052879

  5. Pharmacokinetic drug-drug interaction assessment between LCZ696, an angiotensin receptor neprilysin inhibitor, and hydrochlorothiazide, amlodipine, or carvedilol.

    PubMed

    Hsiao, Hsiu-Ling; Langenickel, Thomas Heiko; Greeley, Michael; Roberts, John; Zhou, Wei; Pal, Parasar; Rebello, Sam; Rajman, Iris; Sunkara, Gangadhar

    2015-11-01

    LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor in development for treatments of hypertension and heart failure indications. In 3 separate studies, pharmacokinetic drug-drug interactions (DDIs) potential was assessed when LCZ696 was coadministered with hydrochlorothiazide (HCTZ), amlodipine, or carvedilol. The studies used a open-label, single-sequence, 3-period, crossover design in healthy subjects. Blood samples were collected to determine the pharmacokinetic parameters of LCZ696 analytes (AHU377, LBQ657, and valsartan), HCTZ, amlodipine, or carvedilol (R[+]- and S[-]-carvedilol) for statistical analysis. When coadministered LCZ696 with HCTZ, the 90% CIs of the geometric mean ratios of AUCtau,ss of HCTZ and that of LBQ657 were within a 0.80-1.25 interval, whereas HCTZ Cmax,ss decreased by 26%, LBQ657 Cmax,ss increased by 19%, and the AUCtau,ss and Cmax,ss of valsartan increased by 14% and 16%, respectively. Pharmacokinetics of amlodipine, R(+)- and S(-)-carvedilol, or LBQ657 were not altered after coadministration of LCZ696 with amlodipine or carvedilol. Coadministration of LCZ696 400 mg once daily (qd) with HCTZ 25 mg qd, amlodipine 10 mg qd, or carvedilol 25 mg twice a day (bid) had no clinically relevant pharmacokinetic drug-drug interactions. LCZ696, HCTZ, amlodipine, and carvedilol were safe and well tolerated when given alone or concomitantly in the investigated studies. PMID:27137712

  6. Development of an ADME and drug-drug interactions knowledge database for the acceleration of drug discovery and development.

    PubMed

    Petitet, François; Barberan, Olivier; Dubus, Elodie; Ijjaali, Ismail; Donlan, Mary; Ollivier, Sophie; Michel, André

    2006-12-01

    It is widely recognised that predicting or determining the absorption, distribution, metabolism and excretion (ADME) properties of a compound as early as possible in the drug discovery process helps to prevent costly late-stage failures. Although in recent years high-throughput in vitro absorption distribution metabolism excretion toxicity (ADMET) screens have been implemented, more efficient in silico filters are still highly needed to predict and model the most relevant metabolic and pharmacokinetic end points, and thereby accelerate drug discovery and development. The usefulness of the data generated and published for the chemist, biologist or project manager who ultimately wants to understand and optimise the ADME properties of lead compounds cannot be argued with. Collecting and comparing data is an overwhelming task for the time-pressed scientist. Aureus Pharma provides a uniquely specialised solution for knowledge generation in drug discovery. AurSCOPE(®) ADME/DDI (drug-drug interaction) is a fully annotated, structured knowledge database containing all the pertinent biological and chemical information on the metabolic properties of drugs. This Aureus knowledge database has proven to be highly useful in designing predictive models and identifying potential drug-drug interactions. PMID:23495997

  7. Mechanism of Drug-Drug Interactions Mediated by Human Cytochrome P450 CYP3A4 Monomer

    PubMed Central

    Denisov, Ilia G.; Grinkova, Yelena V.; Baylon, Javier L.; Tajkhorshid, Emad; Sligar, Stephen G.

    2016-01-01

    Using Nanodiscs, we quantitate the heterotropic interaction between two different drugs mediated by monomeric CYP3A4 incorporated into a native-like membrane environment. The mechanism of this interaction is deciphered by global analysis of multiple turnover experiments performed under identical conditions using the pure substrates progesterone (PGS) and carbamazepine (CBZ) and their mixtures. Activation of CBZ epoxidation and simultaneous inhibition of PGS hydroxylation are measured and quantitated through differences in their respective affinities towards both a remote allosteric site and the productive catalytic site near the heme iron. Preferred binding of PGS at the allosteric site and higher preference of CBZ binding at the productive site give rise to a non-trivial drug-drug interaction. Molecular dynamics simulations indicate functionally important conformational changes caused by PGS binding at the allosteric site and by two CBZ molecules positioned inside the substrate binding pocket. Structural changes involving Phe-213, Phe-219, and Phe-241 are suggested to be responsible for the observed synergetic effects and positive allosteric interactions between these two substrates. Such a mechanism is likely of general relevance to the mutual heterotropic effects caused by biologically active compounds which exhibit different patterns of interaction with the distinct allosteric and productive sites of CYP3A4, as well as other xenobiotic metabolizing cytochromes P450 that are also involved in drug-drug interactions. Importantly, this work demonstrates that a monomeric CYP3A4 can display the full spectrum of activation and cooperative effects that are observed in hepatic membranes. PMID:25777547

  8. Is pomegranate juice a potential perpetrator of clinical drug-drug interactions? Review of the in vitro, preclinical and clinical evidence.

    PubMed

    Srinivas, Nuggehally R

    2013-12-01

    The area of fruit juice-drug interaction has received wide attention with numerous scientific and clinical investigations performed and reported for scores of drugs metabolized by CYP3A4/CYP2C9. While grapefruit juice has been extensively studied with respect to its drug-drug interaction potential, numerous other fruit juices such as cranberry juice, orange juice, grape juice, pineapple juice and pomegranate juice have also been investigated for its potential to show drug-drug interaction of any clinical relevance. This review focuses on establishing any relevance for clinical drug-drug interaction potential with pomegranate juice, which has been shown to produce therapeutic benefits over a wide range of disease areas. The review collates and evaluates relevant published in vitro, preclinical and clinical evidence of the potential of pomegranate juice to be a perpetrator in drug-drug interactions mediated by CYP3A4 and CYP2C9. In vitro and animal pharmacokinetic data support the possibility of CYP3A4/CYP2C9 inhibition by pomegranate juice; however, the human relevance for drug-drug interaction was not established based on the limited case studies. PMID:23673492

  9. A Study on Polypharmacy and Potential Drug-Drug Interactions among Elderly Patients Admitted in Department of Medicine of a Tertiary Care Hospital in Puducherry

    PubMed Central

    Kalyansundaram, Dharani; Bahurupi, Yogesh

    2016-01-01

    Introduction The proportion of elderly population has been constantly increasing over last few years. Polypharmacy is unavoidable in the elderly as they often suffer from multiple co-morbidities. Potential drug-drug interaction due to polypharmacy and potential inappropriate medication among the elderly must be carefully assessed. Aim To find out polypharmacy and potential drug-drug interactions among elderly patients admitted and discharged in Department of Medicine. Materials and Methods This study was carried out on 100 patients above 65 years of age both males and females. Data was collected through review of case sheets. Polypharmacy was observed based on admission and discharge prescriptions. Frequently occurring drug-drug interactions were assessed using online checks. Results Mean number of drugs prescribed to patients on admission (7.61 ± 3.37) was more than that on discharge (5.48±2.46). More than half of these patients received 5 to 9 number of drugs. On admission 52.69% potential drug-drug interactions were observed and on discharge 52.91%. Most common drug interactions observed in both the groups were of moderate grade. Conclusion From the present study we can conclude that polypharmacy leads to more potential drug-drug interactions. To improve drug safety in this high-risk population, appropriate prescribing is very important. PMID:27042480

  10. Use of three-compartment physiologically based pharmacokinetic modeling to predict hepatic blood levels of fluvoxamine relevant for drug-drug interactions.

    PubMed

    Iga, Katsumi

    2015-04-01

    Using a three-compartment physiologically based pharmacokinetic (PBPK) model and a tube model for hepatic extraction kinetics, equations for calculating blood drug levels (Cb s) and hepatic blood drug levels (Chb s, proportional to actual hepatic drug levels), were derived mathematically. Assuming the actual values for total body clearance (CLtot ), oral bioavailability (F), and steady-state distribution volume (Vdss ), Cb s, and Chb s after intravenous and oral administration of fluvoxamine (strong perpetrator in drug-drug interactions, DDIs), propranolol, imipramine, and tacrine were simulated. Values for Cb s corresponded to the actual values for all tested drugs, and mean Chb and maximal Chb -to-maximal Cb ratio predicted for oral fluvoxamine administration (50 mg twice-a-day administration) were nearly 100 nM and 2.3, respectively, which would be useful for the predictions of the DDIs caused by fluvoxamine. Fluvoxamine and tacrine are known to exhibit relatively large F values despite having CLtot similar to or larger than hepatic blood flow, which may be because of the high liver uptake (almost 0.6) upon intravenous administration. The present method is thus considered to be more predictive of the Chb for perpetrators of DDIs than other methods. PMID:25558834

  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. PMID:25721922

  12. 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. PMID:26068584

  13. Impact of drug-drug and drug-disease interactions on gait speed in community-dwelling older adults

    PubMed Central

    Naples, Jennifer G.; Marcum, Zachary A.; Perera, Subashan; Newman, Anne B.; Greenspan, Susan L.; Gray, Shelly L.; Bauer, Douglas C.; Simonsick, Eleanor M.; Shorr, Ronald I.; Hanlon, Joseph T.

    2016-01-01

    Background Gait speed decline, an early marker of functional impairment, is a sensitive predictor of adverse health outcomes in older adults. The effect of potentially inappropriate prescribing on gait speed decline is not well known. Objective To determine if potentially inappropriate drug interactions impair functional status as measured by gait speed. Methods The sample included 2,402 older adults with medication and gait speed data from the Health, Aging and Body Composition study. The independent variable was the frequency of drug-disease and/or drug-drug interactions at baseline and three additional years. The main outcome was a clinically meaningful gait speed decline ≥ 0.1 m/s the year following drug interaction assessment. Adjusted odds ratios and 95% confidence intervals were calculated using multivariate generalized estimating equations for both the overall sample and a sample stratified by gait speed at time of drug interaction assessment. Results The prevalence of drug-disease and drug-drug interactions ranged from 7.6–9.3% and 10.5–12.3%, respectively, with few participants (3.8–5.7%) having multiple drug interactions. At least 22% of participants had a gait speed decline of ≥ 0.1 m/s annually. Drug interactions were not significantly associated with gait speed decline overall or in the stratified sample of fast walkers. There was some evidence, however, that drug interactions increased the risk of gait speed decline among those participants with slower gait speeds, though p values did not reach statistical significance (adjusted odds ratio 1.22, 95% confidence intervals 0.96–1.56, p=0.11). Moreover, a marginally significant dose-response relationship was seen with multiple drug interactions and gait speed decline (adjusted odds ratio 1.40; 95% confidence intervals 0.95–2.04, p=0.08). Conclusions Drug interactions may increase the likelihood of gait speed decline among older adults with evidence of preexisting debility. Future studies

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

    PubMed Central

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

    2014-01-01

    Objective: This study aim to evaluate and compare type and prevalence of drug-drug interactions (DDIs) in prescriptions dispensed in both community and hospital setting in Zabol, Iran. Methods: A total of 2796 prescriptions were collected from community and inpatient and outpatient pharmacy of Amir-al-momenin only current acting hospital in Zabol, Iran. The prescriptions were processed using Lexi-Comp drug interaction software. The identified DDIs were categorized into five classes (A, B, C, D, X). Findings: Overall 41.6% of prescriptions had at last one potential DDI. The most common type of interactions was type C (66%). The percentage of drug interactions in community pharmacies were significantly lower than hospital pharmacies (P < 0.0001). Conclusion: Our results indicate that patients in Zabol are at high risk of adverse drug reactions caused by medications due to potential DDIs. Appropriate education for physicians about potentially harmful DDIs, as well as active participation of pharmacists in detection and prevention of drug-related injuries, could considerably prevent the consequence of DDIs among patients. PMID:25328901

  16. 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

  17. Drug-drug interactions with the use of psychotropic medications. Interview by Diane M. Sloan.

    PubMed

    Ereshefsky, Larry

    2009-08-01

    Drug interactions with psychotropics can result in poor tolerability or reduced efficacy, or both, which can negatively impact patient outcomes. Most drug interactions with psychotropics are pharmacokinetic and involve the CYP family of enzymes. Clinicians can improve outcomes for patients by considering the potential for DDIs when selecting a specific psychotropic, and when evaluating patient progress, compliance, and the incidence of AEs throughout the course of treatment. Resources for clinicians include internet databases, software programs, package inserts, and consultation with pharmacists. PMID:20085108

  18. Criteria for assessing high-priority drug-drug interactions for clinical decision support in electronic health records

    PubMed Central

    2013-01-01

    Background High override rates for drug-drug interaction (DDI) alerts in electronic health records (EHRs) result in the potentially dangerous consequence of providers ignoring clinically significant alerts. Lack of uniformity of criteria for determining the severity or validity of these interactions often results in discrepancies in how these are evaluated. The purpose of this study was to identify a set of criteria for assessing DDIs that should be used for the generation of clinical decision support (CDS) alerts in EHRs. Methods We conducted a 20-year systematic literature review of MEDLINE and EMBASE to identify characteristics of high-priority DDIs. These criteria were validated by an expert panel consisting of medication knowledge base vendors, EHR vendors, in-house knowledge base developers from academic medical centers, and both federal and private agencies involved in the regulation of medication use. Results Forty-four articles met the inclusion criteria for assessing characteristics of high-priority DDIs. The panel considered five criteria to be most important when assessing an interaction- Severity, Probability, Clinical Implications of the interaction, Patient characteristics, and the Evidence supporting the interaction. In addition, the panel identified barriers and considerations for being able to utilize these criteria in medication knowledge bases used by EHRs. Conclusions A multi-dimensional approach is needed to understanding the importance of an interaction for inclusion in medication knowledge bases for the purpose of CDS alerting. The criteria identified in this study can serve as a first step towards a uniform approach in assessing which interactions are critical and warrant interruption of a provider’s workflow. PMID:23763856

  19. Measuring Drug Metabolism Kinetics and Drug-Drug Interactions Using Self-Assembled Monolayers for Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry.

    PubMed

    Anderson, Lyndsey L; Berns, Eric J; Bugga, Pradeep; George, Alfred L; Mrksich, Milan

    2016-09-01

    The competition of two drugs for the same metabolizing enzyme is a common mechanism for drug-drug interactions that can lead to altered kinetics in drug metabolism and altered elimination rates in vivo. With the prevalence of multidrug therapy, there is great potential for serious drug-drug interactions and adverse drug reactions. In an effort to prevent adverse drug reactions, the FDA mandates the evaluation of the potential for metabolic inhibition by every new chemical entity. Conventional methods for assaying drug metabolism (e.g., those based on HPLC) have been established for measuring drug-drug interactions; however, they are low-throughput. Here we describe an approach to measure the catalytic activity of CYP2C9 using the high-throughput technique self-assembled monolayers for matrix-assisted laser desorption-ionization (SAMDI) mass spectrometry. We measured the kinetics of CYP450 metabolism of the substrate, screened a set of drugs for inhibition of CYP2C9 and determined the Ki values for inhibitors. The throughput of this platform may enable drug metabolism and drug-drug interactions to be interrogated at a scale that cannot be achieved with current methods. PMID:27467208

  20. A review of pharmacokinetic drug-drug interactions with the anthelmintic medications albendazole and mebendazole.

    PubMed

    Pawluk, Shane Ashley; Roels, Craig Allan; Wilby, Kyle John; Ensom, Mary H H

    2015-04-01

    Medications indicated for helminthes and other parasitic infections are frequently being used in mass populations in endemic areas. Currently, there is a lack of guidance for clinicians on how to appropriately manage drug interactions when faced with patients requiring short-term anthelmintic therapy with albendazole or mebendazole while concurrently taking other agents. The objective of this review was to systematically summarize and evaluate published literature on the pharmacokinetics of albendazole or mebendazole when taken with other interacting medications. A search of MEDLINE (1946 to October 2014), EMBASE (1974 to October 2014), International Pharmaceutical Abstracts (1970 to October 2014), Google, and Google Scholar was conducted for articles describing the pharmacokinetics of albendazole or mebendazole when given with other medications (and supplemented by a bibliographic review of all relevant articles). Altogether, 17 articles were included in the review. Studies reported data on pharmacokinetic parameters for albendazole or mebendazole when taken with cimetidine, dexamethasone, ritonavir, phenytoin, carbamazepine, phenobarbital, ivermectin, praziquantel, diethylcarbamazine, azithromycin, and levamisole. Cimetidine increased the elimination half-life of albendazole and maximum concentration (Cmax) of mebendazole; dexamethasone increased the area under the plasma concentration-time curve (AUC) of albendazole; levamisole decreased the Cmax of albendazole; anticonvulsants (phenytoin, phenobarbital, carbamazepine) decreased the AUC of albendazole; praziquantel increased the AUC of albendazole; and ritonavir decreased the AUC of both albendazole and mebendazole. No major interactions were found with ivermectin, azithromycin, or diethylcarbamazine. Future research is required to clarify the clinical relevance of the interactions observed. PMID:25691367

  1. CLINICALLY SIGNIFICANT PSYCHOTROPIC DRUG-DRUG INTERACTIONS IN THE PRIMARY CARE SETTING

    PubMed Central

    English, Brett A.; Dortch, Marcus; Ereshefsky, Larry; Jhee, Stanford

    2014-01-01

    In recent years, the growing numbers of patients seeking care for a wide range of psychiatric illnesses in the primary care setting has resulted in an increase in the number of psychotropic medications prescribed. Along with the increased utilization of psychotropic medications, considerable variability is noted in the prescribing patterns of primary care providers and psychiatrists. Because psychiatric patients also suffer from a number of additional medical comorbidities, the increased utilization of psychotropic medications presents an elevated risk of clinically significant drug interactions in these patients. While life-threatening drug interactions are rare, clinically significant drug interactions impacting drug response or appearance of serious adverse drug reactions have been documented and can impact long-term outcomes. Additionally, the impact of genetic variability on the psychotropic drug’s pharmacodynamics and/or pharmacokinetics may further complicate drug therapy. Increased awareness of clinically relevant psychotropic drug interactions can aid clinicians to achieve optimal therapeutic outcomes in patients in the primary care setting. PMID:22707017

  2. Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2

    PubMed Central

    Kido, Yasuto; Matsson, Pär; Giacomini, Kathleen M.

    2011-01-01

    Drug-drug interactions (DDIs) are major causes of serious adverse drug reactions. Most DDIs have a pharmacokinetic basis in which one drug reduces the elimination of a second drug, leading to potentially toxic drug levels. As a major organ of drug elimination, the kidney represents an important site for DDIs. Here, we screened a prescription drug library against the renal organic cation transporter OCT2/SLC22A2, which mediates the first step in the renal secretion of many cationic drugs. Of the 910 compounds screened, 244 inhibited OCT2. Computational analyses revealed key properties of inhibitors versus non-inhibitors, which included overall molecular charge. Four of six potential clinical inhibitors were transporter-selective in follow-up screens against additional transporters: OCT1/SLC22A1, MATE1/SLC47A1 and MATE2-K/SLC47A2. Two compounds showed different kinetics of interaction with the common polymorphism OCT2-A270S, suggesting a role of genetics in modulating renal DDIs. PMID:21599003

  3. Drug/drug interaction of common NSAIDs with antiplatelet effect of aspirin in human platelets.

    PubMed

    Saxena, Aaruni; Balaramnavar, Vishal M; Hohlfeld, Thomas; Saxena, Anil K

    2013-12-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with the anti-platelet activity of aspirin at the level of the platelet cyclooxygenase-1 (COX-1) enzyme. In order to examine the interference of common NSAIDs with the anti-platelet activity of aspirin the human platelet rich plasma from voluntary donors was used for arachidonic acid-induced aggregation and determination of thromboxane synthesis. Further, docking studies were used to explain the molecular basis of the NSAID/aspirin interaction. The experimental results showed that celecoxib, dipyrone (active metabolite), ibuprofen, flufenamic acid, naproxen, nimesulide, oxaprozin, and piroxicam significantly interfere with the anti-platelet activity of aspirin, while diclofenac, ketorolac and acetaminophen do not. Docking studies suggested that NSAIDs forming hydrogen bonds with Ser530, Arg120, Tyr385 and other amino acids of the COX-1 hydrophobic channel interfere with antiplatelet activity of aspirin while non interfering NSAIDs do not form relevant hydrogen bond interactions within the aspirin binding site. In conclusion, docking analysis of NSAID interactions at the COX-1 active site appears useful to predict their interference with the anti-platelet activity of aspirin. The results, demonstrate that some NSAIDs do not interfere with the antiplatelet action of aspirin while many others do and provide a basis for understanding the observed differences among individual non-aspirin NSAIDs. PMID:24075938

  4. 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

  5. Cranberry juice ingestion and clinical drug-drug interaction potentials; review of case studies and perspectives.

    PubMed

    Srinivas, Nuggehally R

    2013-01-01

    Cranberry juice is a popular beverage with many health benefits. It has anthocyanins to supplement dietary needs. Based on in vitro evidence cranberry juice is an inhibitor of CYP enzymes and at higher amounts as potent as ketoconazole (CYP3A) and fluconazole (CYP2C9). There is, however, a discrepancy between in vitro and in vivo observations with respect to a number of substrates (cyclosporine, warfarin, flurbiprofen, tizanidine, diclofenac, amoxicillin, ceflacor); with the exception of a single report on midazolam, where there was a moderate increase in the AUC of midazolam in subjects pre-treated with cranberry juice. However, another study questions the clinical relevancy of in vivo pharmacokinetic interaction between cranberry juice and midazolam. The controversy may be due to a) under in vitro conditions all anthocyanin principles may be available to have a concerted effort in CYP inhibition; however, limited anthocyanin principles may be bioavailable with varying low levels in the in vivo studies; b) a faster clearance of the active anthocyanin principles under in vivo conditions may occur, leading to low threshold levels for CYP inhibition; c) efficient protein binding and/or rapid tissue uptake of the substrate may have precluded the drug availability to the enzymes in the in vivo studies. With respect to pharmacodynamic aspects, while the debate continues on the issue of an interaction between warfarin and cranberry juice, the summation of the pharmacodynamics data obtained in patients and healthy subjects from different prospectively designed and controlled clinical trials does not provide overwhelming support for the existence of a pharmacodynamic drug interaction for normal cranberry juice ingestion. However, it is apparent that consumption of large quantities of cranberry juice (about 1-2 L per day) or cranberry juice concentrates in supplements for an extended time period (>3-4 weeks) may temporally alter the effect of warfarin. Therefore, the total

  6. 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. PMID:26044116

  7. Drug-metabolism mechanism: Knowledge-based population pharmacokinetic approach for characterizing clobazam drug-drug interactions.

    PubMed

    Tolbert, Dwain; Bekersky, Ihor; Chu, Hui-May; Ette, Ene I

    2016-03-01

    A metabolic mechanism-based characterization of antiepileptic drug-drug interactions (DDIs) with clobazam in patients with Lennox-Gastaut syndrome (LGS) was performed using a population pharmacokinetic (PPK) approach. To characterize potential DDIs with clobazam, pharmacokinetic (PK) data from 153 patients with LGS in study OV-1012 (NCT00518713) and 18 healthy participants in bioavailability study OV-1017 were pooled. Antiepileptic drugs (AEDs) were grouped based on their effects on the cytochrome P450 (CYP) isozymes responsible for the metabolism of clobazam and its metabolite, N-desmethylclobazam (N-CLB): CYP3A inducers (phenobarbital, phenytoin, and carbamazepine), CYP2C19 inducers (valproic acid, phenobarbital, phenytoin, and carbamazepine), or CYP2C19 inhibitors (felbamate, oxcarbazepine). CYP3A4 inducers-which did not affect the oral clearance of clobazam-significantly increased the formation of N-CLB by 9.4%, while CYP2C19 inducers significantly increased the apparent elimination rate of N-CLB by 10.5%, resulting in a negligible net change in the PK of the active metabolite. CYP2C19 inhibitors did not affect N-CLB elimination. Because concomitant use of AEDs that are either CYP450 inhibitors or inducers with clobazam in the treatment of LGS patients had negligible to no effect on clobazam PK in this study, dosage adjustments may not be required for clobazam in the presence of the AEDs investigated here. PMID:26224203

  8. The current status of time dependent CYP inhibition assay and in silico drug-drug interaction predictions.

    PubMed

    Yan, Zhengyin; Caldwell, Gary W

    2012-01-01

    Various CYP time-dependent inhibition (TDI) assays have been widely implemented in drug discovery and development which has led to great success in positively identifying compounds with mechanism-base inhibition liability. However, drug-drug interaction (DDI) predictions by various in-silico models utilizing kinetic parameters obtained from TDI assays have met with significant challenges including questionable kinetic data, over-simplified in-vitro models and unreliable mathematic algorithms. Although significant efforts have been made to standardize the TDI assay and refine mathematical models, recent evaluation studies have revealed that the kinetic parameters of TDI, the most important in-vitro data required by all DDI prediction models, are significantly impacted by a variety of experimental variables including microsomal protein concentration, metabolic stability, CYP-specific probes, and post-incubation time. This review attempts to provide medicinal chemists a brief overview on the current status of TDI assays, determination of kinetic parameters and in silico DDI predictions with emphasis on the complexity of the TDI kinetics and limitations of current in-vitro models and DDI prediction methodologies. PMID:22571791

  9. Human hepatoma cell lines on gas foaming templated alginate scaffolds for in vitro drug-drug interaction and metabolism studies.

    PubMed

    Stampella, A; Rizzitelli, G; Donati, F; Mazzarino, M; de la Torre, X; Botrè, F; Giardi, M F; Dentini, M; Barbetta, A; Massimi, M

    2015-12-25

    Liver in vitro systems that allow reliable prediction of major human in vivo metabolic pathways have a significant impact in drug screening and drug metabolism research. In the present study, a novel porous scaffold composed of alginate was prepared by employing a gas-in-liquid foaming approach. Galactose residues were introduced on scaffold surfaces to promote cell adhesion and to enhance liver specific functions of the entrapped HepG2/C3A cells. Hepatoma cells in the gal-alginate scaffold showed higher levels of liver specific products (albumin and urea) and were more responsive to specific inducers (e.g. dexamethasone) and inhibitors (e.g. ketoconazole) of the CYP3A4 system than in conventional monolayer culture. HepG2/C3A cells were also more efficient in terms of rapid elimination of testosterone, used as a model substance, at rates comparable to those of in vivo excretion. In addition, an improvement in metabolism of testosterone, in terms of phase II metabolite formation, was also observed when the more differentiated HepaRG cells were used. Together the data suggest that hepatocyte/gas templated alginate-systems provide an innovative high throughput platform for in vitro drug metabolism and drug-drug interaction studies, with broad fields of application, and might provide a valid tool for minimizing animal use in preclinical testing of human relevance. PMID:26456671

  10. Using chimeric mice with humanized livers to predict human drug metabolism and a drug-drug interaction.

    PubMed

    Nishimura, Toshihiko; Nishimura, Toshiko; Hu, Yajing; Wu, Manhong; Pham, Edward; Suemizu, Hiroshi; Elazar, Menashe; Liu, Michael; Idilman, Ramazan; Yurdaydin, Cihan; Angus, Peter; Stedman, Catherine; Murphy, Brian; Glenn, Jeffrey; Nakamura, Masato; Nomura, Tatsuji; Chen, Yuan; Zheng, Ming; Fitch, William L; Peltz, Gary

    2013-02-01

    Interspecies differences in drug metabolism have made it difficult to use preclinical animal testing data to predict the drug metabolites or potential drug-drug interactions (DDIs) that will occur in humans. Although chimeric mice with humanized livers can produce known human metabolites for test substrates, we do not know whether chimeric mice can be used to prospectively predict human drug metabolism or a possible DDI. Therefore, we investigated whether they could provide a more predictive assessment for clemizole, a drug in clinical development for the treatment of hepatitis C virus (HCV) infection. Our results demonstrate, for the first time, that analyses performed in chimeric mice can correctly identify the predominant human drug metabolite before human testing. The differences in the rodent and human pathways for clemizole metabolism were of importance, because the predominant human metabolite was found to have synergistic anti-HCV activity. Moreover, studies in chimeric mice also correctly predicted that a DDI would occur in humans when clemizole was coadministered with a CYP3A4 inhibitor. These results demonstrate that using chimeric mice can improve the quality of preclinical drug assessment. PMID:23143674

  11. 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. PMID:26432353

  12. Induction of P-glycoprotein expression and activity by Aconitum alkaloids: Implication for clinical drug-drug interactions.

    PubMed

    Wu, Jinjun; Lin, Na; Li, Fangyuan; Zhang, Guiyu; He, Shugui; Zhu, Yuanfeng; Ou, Rilan; Li, Na; Liu, Shuqiang; Feng, Lizhi; Liu, Liang; Liu, Zhongqiu; Lu, Linlin

    2016-01-01

    The Aconitum species, which mainly contain bioactive Aconitum alkaloids, are frequently administered concomitantly with other herbal medicines or chemical drugs in clinics. The potential risk of drug-drug interactions (DDIs) arising from co-administration of Aconitum alkaloids and other drugs against specific targets such as P-glycoprotein (P-gp) must be evaluated. This study focused on the effects of three representative Aconitum alkaloids: aconitine (AC), benzoylaconine (BAC), and aconine, on the expression and activity of P-gp. We observed that Aconitum alkaloids increased P-gp expression in LS174T and Caco-2 cells in the order AC > BAC > aconine. Nuclear receptors were involved in the induction of P-gp. AC and BAC increased the P-gp transport activity. Strikingly, intracellular ATP levels and mitochondrial mass also increased. Furthermore, exposure to AC decreased the toxicity of vincristine and doxorubicin towards the cells. In vivo, AC significantly up-regulated the P-gp protein levels in the jejunum, ileum, and colon of FVB mice, and protected them against acute AC toxicity. Taken together, the findings of our in vitro and in vivo experiments indicate that AC can induce P-gp expression, and that co-administration of AC with P-gp substrate drugs may cause DDIs. Our findings have important implications for Aconitum therapy in clinics. PMID:27139035

  13. 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. PMID:24733008

  14. Assessment of Drug-Drug Interactions between Daclatasvir and Methadone or Buprenorphine-Naloxone

    PubMed Central

    Wang, R.; Luo, W.-L.; Wastall, P.; Kandoussi, H.; DeMicco, M.; Bruce, R. D.; Hwang, C.; Bertz, R.; Bifano, M.

    2015-01-01

    Hepatitis C virus (HCV) infection is common among people who inject drugs, including those managed with maintenance opioids. Pharmacokinetic interactions between opioids and emerging oral HCV antivirals merit evaluation. Daclatasvir is a potent pangenotypic inhibitor of the HCV NS5A replication complex recently approved for HCV treatment in Europe and Japan in combination with other antivirals. The effect of steady-state daclatasvir (60 mg daily) on stable plasma exposure to oral opioids was assessed in non-HCV-infected subjects receiving methadone (40 to 120 mg; n = 14) or buprenorphine plus naloxone (8 to 24 mg plus 2 to 6 mg; n = 11). No relevant interaction was inferred if the 90% confidence interval (CI) of the geometric mean ratio (GMR) of opioid area under the plasma concentration-time curve over the dosing interval (AUCτ) or maximum concentration in plasma (Cmax) with versus without daclatasvir was within literature-derived ranges of 0.7 to 1.43 (R- and S-methadone) or 0.5 to 2.0 (buprenorphine and norbuprenorphine). Dose-normalized AUCτ for R-methadone (GMR, 1.08; 90% CI, 0.94 to 1.24), S-methadone (1.13; 0.99 to 1.30), and buprenorphine (GMR, 1.37; 90% CI, 1.24 to 1.52) were within the no-effect range. The norbuprenorphine AUCτ was slightly elevated in the primary analysis (GMR, 1.62; 90% CI, 1.30 to 2.02) but within the no-effect range in a supplementary analysis of all evaluable subjects. Dose-normalized Cmax for both methadone enantiomers, buprenorphine and norbuprenorphine, were within the no-effect range. Standardized assessments of opioid pharmacodynamics were unchanged throughout daclatasvir administration with methadone or buprenorphine. Daclatasvir pharmacokinetics were similar to historical data. Coadministration of daclatasvir and opioids was generally well tolerated. In conclusion, these data suggest that daclatasvir can be administered with buprenorphine or methadone without dose adjustments. PMID:26124175

  15. Assessment of drug-drug interactions between daclatasvir and methadone or buprenorphine-naloxone.

    PubMed

    Garimella, T; Wang, R; Luo, W-L; Wastall, P; Kandoussi, H; DeMicco, M; Bruce, R D; Hwang, C; Bertz, R; Bifano, M

    2015-09-01

    Hepatitis C virus (HCV) infection is common among people who inject drugs, including those managed with maintenance opioids. Pharmacokinetic interactions between opioids and emerging oral HCV antivirals merit evaluation. Daclatasvir is a potent pangenotypic inhibitor of the HCV NS5A replication complex recently approved for HCV treatment in Europe and Japan in combination with other antivirals. The effect of steady-state daclatasvir (60 mg daily) on stable plasma exposure to oral opioids was assessed in non-HCV-infected subjects receiving methadone (40 to 120 mg; n = 14) or buprenorphine plus naloxone (8 to 24 mg plus 2 to 6 mg; n = 11). No relevant interaction was inferred if the 90% confidence interval (CI) of the geometric mean ratio (GMR) of opioid area under the plasma concentration-time curve over the dosing interval (AUCτ) or maximum concentration in plasma (C max) with versus without daclatasvir was within literature-derived ranges of 0.7 to 1.43 (R- and S-methadone) or 0.5 to 2.0 (buprenorphine and norbuprenorphine). Dose-normalized AUCτ for R-methadone (GMR, 1.08; 90% CI, 0.94 to 1.24), S-methadone (1.13; 0.99 to 1.30), and buprenorphine (GMR, 1.37; 90% CI, 1.24 to 1.52) were within the no-effect range. The norbuprenorphine AUCτ was slightly elevated in the primary analysis (GMR, 1.62; 90% CI, 1.30 to 2.02) but within the no-effect range in a supplementary analysis of all evaluable subjects. Dose-normalized C max for both methadone enantiomers, buprenorphine and norbuprenorphine, were within the no-effect range. Standardized assessments of opioid pharmacodynamics were unchanged throughout daclatasvir administration with methadone or buprenorphine. Daclatasvir pharmacokinetics were similar to historical data. Coadministration of daclatasvir and opioids was generally well tolerated. In conclusion, these data suggest that daclatasvir can be administered with buprenorphine or methadone without dose adjustments. PMID:26124175

  16. Drug-drug interaction profile of components of a fixed combination of netupitant and palonosetron: Review of clinical data.

    PubMed

    Natale, James J; Spinelli, Tulla; Calcagnile, Selma; Lanzarotti, Corinna; Rossi, Giorgia; Cox, David; Kashef, Kimia

    2016-06-01

    Neurokinin-1 (NK1) receptor antagonists (RAs) are commonly coadministered with serotonin (5-HT3) RAs (e.g. palonosetron (PALO)) to prevent chemotherapy-induced nausea/vomiting. Netupitant/palonosetron (NEPA), an oral fixed combination of netupitant (NETU)-a new NK1 RA-and PALO, is currently under development. In vitro data suggest that NETU inhibits CYP3A4 and is a substrate for and weak inhibitor of P-glycoprotein (P-gp). This review evaluates potential drug-drug interactions between NETU or NEPA and CYP3A4 substrates/inducers/inhibitors or P-gp substrates in healthy subjects. Pharmacokinetic (PK) parameters were evaluated for each drug when NETU was coadministered with PALO (single doses) and when single doses of NETU or NEPA were coadministered with CYP3A4 substrates (erythromycin (ERY), midazolam (MID), dexamethasone (DEX), or oral contraceptives), inhibitors (ketoconazole (KETO)), or inducers (rifampicin (RIF)), or a P-gp substrate (digoxin (DIG)). Results showed no relevant PK interactions between NETU and PALO. Coadministration of NETU increased MID and ERY exposure and significantly increased DEX exposure in a dose-dependent manner; NETU exposure was unaffected. NEPA coadministration had no clinically significant effect on oral contraception, although levonorgestrel exposure increased. NETU exposure increased after coadministration of NEPA with KETO and decreased after coadministration with RIF; PALO exposure was unaffected. NETU coadministration did not influence DIG exposure. In conclusion, there were no clinically relevant interactions between NETU and PALO, or NEPA and oral contraceptives (based on levonorgestrel and ethinylestradiol exposure). Coadministration of NETU or NEPA with CYP3A4 inducers/inhibitors/substrates should be done with caution. Dose reduction is recommended for DEX. Dose adjustments are not needed for NETU coadministration with P-gp substrates. PMID:25998320

  17. Potential drug-drug interactions in hospitalized patients with chronic heart failure and chronic obstructive pulmonary disease

    PubMed Central

    Roblek, Tina; Trobec, Katja; Mrhar, Ales

    2014-01-01

    Introduction Polypharmacy is common in patients with chronic heart failure (HF) and/or chronic obstructive pulmonary disease (COPD), but little is known about the prevalence and significance of drug-drug interactions (DDIs). This study evaluates DDIs in hospitalized patients. Material and methods We retrospectively screened medical charts over a 6-month period for diagnosis of chronic HF and/or COPD. Potential DDIs were evaluated using Lexi-Interact software. Results Seven hundred and seventy-eight patients were included in the study (median age 75 years, 61% men). The median number of drugs on admission and discharge was 6 (interquartile range (IQR) 4–9) and 7 (IQR 5–), respectively (p = 0.10). We recorded 6.5 ±5.7 potential DDIs per patient on admission and 7.2 ±5.6 on discharge (p = 0.2). From admission to discharge, type-C and type-X potential DDIs increased (p < 0.05 for both). Type X interactions were rare (< 1%), with the combination of a β-blocker and a β2 agonist being the most common (64%). There were significantly more type-C and type-D potential DDIs in patients with chronic HF as compared to patients with COPD (p < 0.001). Patients with concomitant chronic HF and COPD had more type-C and type-X potential DDIs when compared to those with individual disease (p < 0.005). An aldosterone antagonist and ACE inhibitor/ARB were prescribed to 3% of chronic HF patients with estimated glomerular filtration rate < 30 ml/(min × 1.73 m2). Conclusions The DDIs are common in patients with chronic HF and/or COPD, but only a few appear to be of clinical significance. The increase in potential DDIs from admission to discharge may reflect better guideline implementation rather than poor clinical practice. PMID:25395943

  18. Pharmacokinetic drug-drug interaction study of ranolazine and metformin in subjects with type 2 diabetes mellitus.

    PubMed

    Zack, Julia; Berg, Jolene; Juan, Axel; Pannacciulli, Nicola; Allard, Martine; Gottwald, Mildred; Zhang, Heather; Shao, Yongwu; Ben-Yehuda, Ori; Jochelson, Phil

    2015-03-01

    Ranolazine and metformin may be frequently co-administered in subjects with chronic angina and co-morbid type 2 diabetes mellitus (T2DM). The potential for a drug-drug interaction was explored in two phase 1 clinical studies in subjects with T2DM to evaluate the pharmacokinetics and safety of metformin 1000 mg BID when administered with ranolazine 1000 mg BID (Study 1, N = 28) or ranolazine 500 mg BID (Study 2, N = 25) as compared to metformin alone. Co-administration of ranolazine 1000 mg BID with metformin 1000 mg BID resulted in 1.53- and 1.79-fold increases in steady-state metformin Cmax and AUCtau , respectively; co-administration of ranolazine 500 mg BID with metformin 1000 mg BID resulted in 1.22- and 1.37-fold increases in steady-state metformin Cmax and AUCtau , respectively. Co-administration of ranolazine and metformin was well tolerated in these T2DM subjects, with no serious adverse events or drug-related adverse events leading to discontinuation. The most common adverse events were nausea, diarrhea, and dizziness. These findings are consistent with a dose-related interaction between ranolazine and metformin, and suggest that a dose adjustment of metformin may not be required with ranolazine 500 mg BID; whereas, the metformin dose should not exceed 1700 mg of total daily dose when using ranolazine 1000 mg BID. PMID:27128216

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

    PubMed

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

    2016-06-01

    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

  20. 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

  1. 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

  2. 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

  3. Drug-drug interactions between rosuvastatin and oral antidiabetic drugs occurring at the level of OATP1B1.

    PubMed

    van de Steeg, E; Greupink, R; Schreurs, M; Nooijen, I H G; Verhoeckx, K C M; Hanemaaijer, R; Ripken, D; Monshouwer, M; Vlaming, M L H; DeGroot, J; Verwei, M; Russel, F G M; Huisman, M T; Wortelboer, H M

    2013-03-01

    Organic anion-transporting polypeptide 1B1 (OATP1B1) is an important hepatic uptake transporter, of which the polymorphic variant OATP1B1*15 (Asn130Asp and Val174Ala) has been associated with decreased transport activity. Rosuvastatin is an OATP1B1 substrate and often concomitantly prescribed with oral antidiabetics in the clinic. The aim of this study was to investigate possible drug-drug interactions between these drugs at the level of OATP1B1 and OATP1B1*15. We generated human embryonic kidney (HEK)293 cells stably overexpressing OATP1B1 or OATP1B1*15 that showed similar protein expression levels of OATP1B1 and OATP1B1*15 at the cell membrane as measured by liquid chromatography-tandem mass spectrometry. In HEK-OATP1B1*15 cells, the V(max) for OATP1B1-mediated transport of E(2)17β-G (estradiol 17β-d-glucuronide) was decreased >60%, whereas K(m) values (Michaelis constant) were comparable. Uptake of rosuvastatin in HEK-OATP1B1 cells (K(m) 13.1 ± 0.43 μM) was nearly absent in HEK-OATP1B1*15 cells. Interestingly, several oral antidiabetics (glyburide, glimepiride, troglitazone, pioglitazone, glipizide, gliclazide, and tolbutamide), but not metformin, were identified as significant inhibitors of the OATP1B1-mediated transport of rosuvastatin. The IC(50) values for inhibition of E(2)17β-G uptake were similar between OATP1B1 and OATP1B1*15. In conclusion, these studies indicate that several oral antidiabetic drugs affect the OATP1B1-mediated uptake of rosuvastatin in vitro. The next step will be to translate these data to the clinical situation, as it remains to be established whether the studied oral antidiabetics indeed affect the clinical pharmacokinetic profile of rosuvastatin in patients. PMID:23248200

  4. Role of Human Organic Cation Transporter 1 (hOCT1) Polymorphisms in Lamivudine (3TC) Uptake and Drug-Drug Interactions

    PubMed Central

    Arimany-Nardi, Cristina; Minuesa, Gerard; Keller, Thorsten; Erkizia, Itziar; Koepsell, Hermann; Martinez-Picado, Javier; Pastor-Anglada, Marçal

    2016-01-01

    Lamivudine (3TC), a drug used in the treatment of HIV infection, needs to cross the plasma membrane to exert its therapeutic action. Human Organic cation transporter 1 (hOCT1), encoded by the SLC22A1 gene, is the transporter responsible for its uptake into target cells. As SLC22A1 is a highly polymorphic gene, the aim of this study was to determine how SNPs in the OCT1-encoding gene affected 3TC internalization and its interaction with other co-administered drugs. HEK293 cells stably transfected with either the wild type form or the polymorphic variants of hOCT1 were used to perform kinetic and drug-drug interaction studies. Protein co-immunoprecipitation was used to assess the impact of selected polymorphic cysteines on the oligomerization of the transporter. Results showed that 3TC transport efficiency was reduced in all polymorphic variants tested (R61C, C88R, S189L, M420del, and G465R). This was not caused by lack of oligomerization in case of variants located at the transporter extracellular loop (R61C and C88R). Drug-drug interaction measurements showed that co-administered drugs [abacavir (ABC), zidovudine (AZT), emtricitabine (FTC), tenofovir diproxil fumarate (TDF), efavirenz (EFV) and raltegravir (RAL)], differently inhibited 3TC uptake depending upon the polymorphic variant analyzed. These data highlight the need for accurate analysis of drug transporter polymorphic variants of clinical relevance, because polymorphisms can impact on substrate (3TC) translocation but even more importantly they can differentially affect drug-drug interactions at the transporter level. PMID:27445813

  5. Role of Human Organic Cation Transporter 1 (hOCT1) Polymorphisms in Lamivudine (3TC) Uptake and Drug-Drug Interactions.

    PubMed

    Arimany-Nardi, Cristina; Minuesa, Gerard; Keller, Thorsten; Erkizia, Itziar; Koepsell, Hermann; Martinez-Picado, Javier; Pastor-Anglada, Marçal

    2016-01-01

    Lamivudine (3TC), a drug used in the treatment of HIV infection, needs to cross the plasma membrane to exert its therapeutic action. Human Organic cation transporter 1 (hOCT1), encoded by the SLC22A1 gene, is the transporter responsible for its uptake into target cells. As SLC22A1 is a highly polymorphic gene, the aim of this study was to determine how SNPs in the OCT1-encoding gene affected 3TC internalization and its interaction with other co-administered drugs. HEK293 cells stably transfected with either the wild type form or the polymorphic variants of hOCT1 were used to perform kinetic and drug-drug interaction studies. Protein co-immunoprecipitation was used to assess the impact of selected polymorphic cysteines on the oligomerization of the transporter. Results showed that 3TC transport efficiency was reduced in all polymorphic variants tested (R61C, C88R, S189L, M420del, and G465R). This was not caused by lack of oligomerization in case of variants located at the transporter extracellular loop (R61C and C88R). Drug-drug interaction measurements showed that co-administered drugs [abacavir (ABC), zidovudine (AZT), emtricitabine (FTC), tenofovir diproxil fumarate (TDF), efavirenz (EFV) and raltegravir (RAL)], differently inhibited 3TC uptake depending upon the polymorphic variant analyzed. These data highlight the need for accurate analysis of drug transporter polymorphic variants of clinical relevance, because polymorphisms can impact on substrate (3TC) translocation but even more importantly they can differentially affect drug-drug interactions at the transporter level. PMID:27445813

  6. Suspicion of drug-drug interaction between high-dose methotrexate and proton pump inhibitors: a case report - should the practice be changed?

    PubMed

    Ranchon, F; Vantard, N; Gouraud, A; Schwiertz, V; Franchon, E; Pham, B N; Vial, T; You, B; Bouafia, F; Salles, G; Rioufol, C

    2011-01-01

    We report a case of a potential drug-drug interaction in a woman treated by a first injection of high-dose methotrexate for a T-lymphoblastic lymphoma. Valaciclovir, fluoxetine and pantoprazole were given concomitantly. A methotrexate overdosage was shown at 36 h after infusion associated with a severe renal failure. Alkaline hyperhydration, folinic acid and carboxypeptidase G2 were given. Prescription analyses by pharmacists and literature research have permitted us to suggest that a drug-drug interaction between methotrexate and proton pump inhibitors (PPI) was responsible for this renal failure. Several mechanisms of interaction were suggested and might be related to the inhibition of renal methotrexate transporters by PPI, an increase in the methotrexate efflux to the blood by an upregulation of multidrug resistance protein 3 by PPI or genetic polymorphisms. This case shows that pharmacists can help physicians to optimize patient treatment: they consensually decided on the systematic discontinuation of PPI or a switch to ranitidine when patients were treated by high-dose methotrexate. PMID:21597286

  7. Drug-Drug Interactions Based on Pharmacogenetic Profile between Highly Active Antiretroviral Therapy and Antiblastic Chemotherapy in Cancer Patients with HIV Infection.

    PubMed

    Berretta, Massimiliano; Caraglia, Michele; Martellotta, Ferdinando; Zappavigna, Silvia; Lombardi, Angela; Fierro, Carla; Atripaldi, Luigi; Muto, Tommaso; Valente, Daniela; De Paoli, Paolo; Tirelli, Umberto; Di Francia, Raffaele

    2016-01-01

    The introduction of Highly Active Antiretroviral Therapy (HAART) into clinical practice has dramatically changed the natural approach of HIV-related cancers. Several studies have shown that intensive antiblastic chemotherapy (AC) is feasible in HIV-infected patients with cancer, and that the outcome is similar to that of HIV-negative patients receiving the same AC regimens. However, the concomitant use of HAART and AC can result in drug accumulation or possible toxicity with consequent decreased efficacy of one or both classes of drugs. In fact, many AC agents are preferentially metabolized by CYP450 and drug-drug interactions (DDIs) with HAART are common. Therefore, it is important that HIV patients with cancer in HAART receiving AC treatment at the same time receive an individualized cancer management plan based on their liver and renal functions, their level of bone marrow suppression, their mitochondrial dysfunction, and their genotype profile. The rationale of this review is to summarize the existing data on the impact of HAART on the clinical management of cancer patients with HIV/AIDS and DDIs between antiretrovirals and AC. In addition, in order to maximize the efficacy of antiblastic therapy and minimize the risk of drug-drug interaction, a useful list of pharmacogenomic markers is provided. PMID:27065862

  8. Evaluation of change in the skin concentration of tazarotene and betamethasone dipropionate based on drug-drug interaction for transdermal drug delivery in miniature pig.

    PubMed

    Yu, Biao; Ma, Pengcheng; Yuan, Linwen; Chen, Dingding; Yang, Jin

    2015-05-01

    1. The present study was designed to investigate drug-drug interaction in a new combination cream which contains both tazarotene (TZRT) and betamethasone dipropionate (BTMSDP) by comparing the pharmacokinetic (PK) behaviors of TZRT, BTMSDP, and their major metabolites, tazarotenic acid (TZRTAC) and betamethasone (BTMS) with those in the commonly prescribed TZRT gel and BTMSDP cream. 2. The trial was performed on six Bama mini-pigs. The different regions on the back side of each pig were randomly assigned to one of three treatment groups: TZRT 0.05% gel, BTMSDP 0.05% cream, and combination cream. The stratum corneum and epidermis-dermis samples were collected at various times after drug administration and analyzed for TZRT, TZRTAC, BTMSDP, and BTMS by LC-MS/MS. Compared with TZRT gel alone, TZRT + BTMSDP did not significantly change the PK profiles of TZRT; neither did BTMSDP + TZRT significantly change the PK profiles of BTMSDP, compared with the BTMSDP cream alone. In addition, the concentrations of TZRTAC and BTMS in most samples were below the lower limit of quantitation (LLOQ). 3. The results suggest that there was no significant drug-drug interaction trend between TZRT and BTMSDP in the process of transdermal permeation of combination cream into the stratum corneum and epidermis-dermis of mini-pigs. PMID:25410121

  9. 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. PMID:27045668

  10. 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. PMID:24431005

  11. Drug-drug interaction and doping, part 2: an in vitro study on the effect of non-prohibited drugs on the phase I metabolic profile of stanozolol.

    PubMed

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

    2014-10-01

    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 prohibited agents. In vitro assays based on the use of human liver microsomes and recombinant cytochrome P450 isoforms were developed and applied to characterize the phase I metabolic profile of the prohibited agent stanozolol, both in the absence and in the presence of substances (ketoconazole, itraconazole, miconazole, cimetidine, ranitidine, and nefazodone) not included in the World Anti-Doping Agency (WADA) list of prohibited substances and methods and frequently administered to athletes. The results show that the in vitro model utilized in this study is adequate to simulate the in vivo metabolism of stanozolol. Furthermore, our data showed that ketoconazole, itraconazole, miconazole, and nefazodone caused a marked modification in the production of the metabolic products (3'-hydroxy-stanozolol, 4β-hydroxy-stanozolol and 16β-hydroxy-stanozolol) normally selected by the anti-doping laboratories as target analytes to detect stanozolol intake. On the contrary, moderate variations were registered in the presence of cimetidine and no significant modifications were measured in the presence of ranitidine. This evidence confirms that the potential effect of drug-drug interactions is duly taken into account also in anti-doping analysis. PMID:24535830

  12. Potential for Drug-Drug Interactions between Antiretrovirals and HCV Direct Acting Antivirals in a Large Cohort of HIV/HCV Coinfected Patients

    PubMed Central

    Poizot-Martin, Isabelle; Naqvi, Alissa; Obry-Roguet, Véronique; Valantin, Marc-Antoine; Cuzin, Lise; Billaud, Eric; Cheret, Antoine; Rey, David; Jacomet, Christine; Duvivier, Claudine; Pugliese, Pascal; Pradat, Pierre; Cotte, Laurent

    2015-01-01

    Objectives Development of direct acting antivirals (DAA) offers new benefits for patients with chronic hepatitis C. The combination of these drugs with antiretroviral treatment (cART) is a real challenge in HIV/HCV coinfected patients. The aim of this study was to describe potential drug-drug interactions between DAAs and antiretroviral drugs in a cohort of HIV/HCV coinfected patients. Methods Cross-sectional study of all HIV/HCV coinfected patients attending at least one visit in 2012 in the multicenter French Dat’AIDS cohort. A simulation of drug-drug interactions between antiretroviral treatment and DAAs available in 2015 was performed. Results Of 16,634 HIV-infected patients, 2,511 had detectable anti-HCV antibodies, of whom 1,196 had a detectable HCV-RNA and were not receiving HCV treatment at the time of analysis. 97.1% of these patients were receiving cART and 81.2% had a plasma HIV RNA <50 copies/mL. cART included combinations of nucleoside reverse transcriptase inhibitors with a boosted protease inhibitor in 43.6%, a non-nucleoside reverse transcriptase inhibitor in 17.3%, an integrase inhibitor in 15.4% and various combinations or antiretroviral drugs in 23.7% of patients. A previous treatment against HCV had been administered in 64.4% of patients. Contraindicated associations/potential interactions were expected between cART and respectively sofosbuvir (0.2%/0%), sofosbuvir/ledipasvir (0.2%/67.6%), daclatasvir (0%/49.4%), ombitasvir/boosted paritaprevir (with or without dasabuvir) (34.4%/52.2%) and simeprevir (78.8%/0%). Conclusions Significant potential drug-drug interactions are expected between cART and the currently available DAAs in the majority of HIV/HCV coinfected patients. Sofosbuvir/ledipasvir and sofosbuvir/daclatasvir with or without ribavirin appeared the most suitable combinations in our population. A close collaboration between hepatologists and HIV/AIDS specialists appears necessary for the management of HCV treatment concomitantly to c

  13. In vitro assessment of metabolic drug-drug interaction potential of apixaban through cytochrome P450 phenotyping, inhibition, and induction studies.

    PubMed

    Wang, Lifei; Zhang, Donglu; Raghavan, Nirmala; Yao, Ming; Ma, Li; Frost, Charles E; Frost, Charles A; Maxwell, Brad D; Chen, Shiang-yuan; He, Kan; Goosen, Theunis C; Humphreys, W Griffith; Grossman, Scott J

    2010-03-01

    Apixaban is an oral, direct, and highly selective factor Xa inhibitor in late-stage clinical development for the prevention and treatment of thromboembolic diseases. The metabolic drug-drug interaction potential of apixaban was evaluated in vitro. The compound did not show cytochrome P450 inhibition (IC(50) values >20 microM) in incubations of human liver microsomes with the probe substrates of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Apixaban did not show any effect at concentrations up to 20 muM on enzyme activities or mRNA levels of selected P450 enzymes (CYP1A2, 2B6, and 3A4/5) that are sensitive to induction in incubations with primary human hepatocytes. Apixaban showed a slow metabolic turnover in incubations of human liver microsomes with formation of O-demethylation (M2) and hydroxylation products (M4 and M7) as prominent in vitro metabolites. Experiments with human cDNA-expressed P450 enzymes and P450 chemical inhibitors and correlation with P450 activities in individual human liver microsomes demonstrated that the oxidative metabolism of apixaban for formation of all metabolites was predominantly catalyzed by CYP3A4/5 with a minor contribution of CYP1A2 and CYP2J2 for formation of M2. The contribution of CYP2C8, 2C9, and 2C19 to metabolism of apixaban was less significant. In addition, a human absorption, distribution, metabolism, and excretion study showed that more than half of the dose was excreted as unchanged parent (f(m CYP) <0.5), thus significantly reducing the overall metabolic drug-drug interaction potential of apixaban. Together with a low clinical efficacious concentration and multiple clearance pathways, these results demonstrate that the metabolic drug-drug interaction potential between apixaban and coadministered drugs is low. PMID:19940026

  14. 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. PMID:27009433

  15. Nonclinical Pharmacokinetics, Disposition, and Drug-Drug Interaction Potential of a Novel d-Amino Acid Peptide Agonist of the Calcium-Sensing Receptor AMG 416 (Etelcalcetide).

    PubMed

    Subramanian, Raju; Zhu, Xiaochun; Kerr, Savannah J; Esmay, Joel D; Louie, Steven W; Edson, Katheryne Z; Walter, Sarah; Fitzsimmons, Michael; Wagner, Mylo; Soto, Marcus; Pham, Roger; Wilson, Sarah F; Skiles, Gary L

    2016-08-01

    AMG 416 (etelcalcetide) is a novel synthetic peptide agonist of the calcium-sensing receptor composed of a linear chain of seven d-amino acids (referred to as the d-amino acid backbone) with a d-cysteine linked to an l-cysteine via a disulfide bond. AMG 416 contains four basic d-arginine residues and is a +4 charged peptide at physiologic pH with a mol. wt. of 1048.3 Da. The pharmacokinetics (PK), disposition, and potential of AMG 416 to cause drug-drug interaction were investigated in nonclinical studies with two single (14)C-labels placed either at a potentially metabolically labile acetyl position or on the d-alanine next to d-cysteine in the interior of the d-amino acid backbone. After i.v. dosing, the PK and disposition of AMG 416 were similar in male and female rats. Radioactivity rapidly distributed to most tissues in rats with intact kidneys, and renal elimination was the predominant clearance pathway. No strain-dependent differences were observed. In bilaterally nephrectomized rats, minimal radioactivity (1.2%) was excreted via nonrenal pathways. Biotransformation occurred primarily via disulfide exchange with endogenous thiol-containing molecules in whole blood rather than metabolism by enzymes, such as proteases or cytochrome P450s; the d-amino acid backbone remained unaltered. A substantial proportion of the plasma radioactivity was covalently conjugated to albumin. AMG 416 presents a low risk for P450 or transporter-mediated drug-drug interactions because it showed no interactions in vitro. These studies demonstrated a (14)C label on either the acetyl or the d-alanine in the d-amino acid backbone would be appropriate for clinical studies. PMID:26895981

  16. Assessment of the mass balance recovery and metabolite profile of avibactam in humans and in vitro drug-drug interaction potential.

    PubMed

    Vishwanathan, Karthick; Mair, Stuart; Gupta, Anshul; Atherton, James; Clarkson-Jones, Jacqueline; Edeki, Timi; Das, Shampa

    2014-05-01

    Avibactam, a novel non-β-lactam β-lactamase inhibitor with activity against Ambler class A, class C, and some class D enzymes is being evaluated in combination with various β-lactam antibiotics to treat serious bacterial infections. The in vivo mass balance recovery and metabolite profile of [(14)C] avibactam (500 mg/1-h infusion) was assessed in six healthy male subjects, and a series of in vitro experiments evaluated the metabolism and drug-drug interaction potential of avibactam. In the mass balance study, measurement of plasma avibactam (using a validated liquid chromatography-tandem mass spectrometry method) and total radioactivity in plasma, whole blood, urine, and feces (using liquid scintillation counting) indicated that most of the avibactam was excreted unchanged in urine within 12 hours, with recovery complete (>97% of the administered dose) within 96 hours. Geometric mean avibactam renal clearance (158 ml/min) was greater than the product of unbound fraction of drug and glomerular filtration rate (109.5 ml/min), suggesting that active tubular secretion accounted for some renal elimination. There was no evidence of metabolism in plasma and urine, with unchanged avibactam the major component in both matrices. Avibactam demonstrated in vitro substrate potential for organic anion transporters 1 and 3 (OAT1 and OAT3) proteins expressed in human embryonic kidney 293 cells (Km > 1000 μM; >10-fold the Cmax of a therapeutic dose), which could account for the active tubular secretion observed in vivo. Avibactam uptake by OAT1 and OAT3 was inhibited by probenecid, a potent OAT1/OAT3 inhibitor. Avibactam did not interact with various other membrane transport proteins or cytochrome P450 enzymes in vitro, suggesting it has limited propensity for drug-drug interactions involving cytochrome P450 enzymes. PMID:24616266

  17. 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. PMID:25587128

  18. Interaction of Ethambutol with human organic cation transporters of the SLC22 family indicates potential for drug-drug interactions during antituberculosis therapy.

    PubMed

    Pan, Xiaolei; Wang, Li; Gründemann, Dirk; Sweet, Douglas H

    2013-10-01

    According to the 2012 WHO global tuberculosis (TB) report (http://apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf), the death rate for tuberculosis was over 1.4 million patients in 2011, with ∼9 million new cases diagnosed. Moreover, the frequency of comorbidity with human immunodeficiency virus (HIV) and with diabetes is on the rise, increasing the risk of these patients for experiencing drug-drug interactions (DDIs) due to polypharmacy. Ethambutol is considered a first-line antituberculosis drug. Ethambutol is an organic cation at physiological pH, and its major metabolite, 2,2'-(ethylenediimino)dibutyric acid (EDA), is zwitterionic. Therefore, we assessed the effects of ethambutol and EDA on the function of human organic cation transporter 1 (hOCT1), hOCT2, and hOCT3 and that of EDA on organic anion transporter 1 (hOAT1) and hOAT3. Potent inhibition of hOCT1- and hOCT2-mediated transport by ethambutol (50% inhibitory concentration [IC50] = 92.6 ± 10.9 and 253.8 ± 90.8 μM, respectively) was observed. Ethambutol exhibited much weaker inhibition of hOCT3 (IC50 = 4.1 ± 1.6 mM); however, significant inhibition (>80%) was observed at physiologically relevant concentrations in the gastrointestinal (GI) tract after oral dosing. EDA failed to exhibit any inhibitory effects that warranted further investigation. DDI analysis indicated a strong potential for ethambutol interaction on hOCT1 expressed in enterocytes and hepatocytes and on hOCT3 in enterocytes, which would alter absorption, distribution, and excretion of coadministered cationic drugs, suggesting that in vivo pharmacokinetic studies are necessary to confirm drug safety and efficacy. In particular, TB patients with coexisting HIV or diabetes might experience significant DDIs in situations of coadministration of ethambutol and clinical therapeutics known to be hOCT1/hOCT3 substrates (e.g., lamivudine or metformin). PMID:23917312

  19. Interaction of Ethambutol with Human Organic Cation Transporters of the SLC22 Family Indicates Potential for Drug-Drug Interactions during Antituberculosis Therapy

    PubMed Central

    Pan, Xiaolei; Gründemann, Dirk

    2013-01-01

    According to the 2012 WHO global tuberculosis (TB) report (http://apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf), the death rate for tuberculosis was over 1.4 million patients in 2011, with ∼9 million new cases diagnosed. Moreover, the frequency of comorbidity with human immunodeficiency virus (HIV) and with diabetes is on the rise, increasing the risk of these patients for experiencing drug-drug interactions (DDIs) due to polypharmacy. Ethambutol is considered a first-line antituberculosis drug. Ethambutol is an organic cation at physiological pH, and its major metabolite, 2,2′-(ethylenediimino)dibutyric acid (EDA), is zwitterionic. Therefore, we assessed the effects of ethambutol and EDA on the function of human organic cation transporter 1 (hOCT1), hOCT2, and hOCT3 and that of EDA on organic anion transporter 1 (hOAT1) and hOAT3. Potent inhibition of hOCT1- and hOCT2-mediated transport by ethambutol (50% inhibitory concentration [IC50] = 92.6 ± 10.9 and 253.8 ± 90.8 μM, respectively) was observed. Ethambutol exhibited much weaker inhibition of hOCT3 (IC50 = 4.1 ± 1.6 mM); however, significant inhibition (>80%) was observed at physiologically relevant concentrations in the gastrointestinal (GI) tract after oral dosing. EDA failed to exhibit any inhibitory effects that warranted further investigation. DDI analysis indicated a strong potential for ethambutol interaction on hOCT1 expressed in enterocytes and hepatocytes and on hOCT3 in enterocytes, which would alter absorption, distribution, and excretion of coadministered cationic drugs, suggesting that in vivo pharmacokinetic studies are necessary to confirm drug safety and efficacy. In particular, TB patients with coexisting HIV or diabetes might experience significant DDIs in situations of coadministration of ethambutol and clinical therapeutics known to be hOCT1/hOCT3 substrates (e.g., lamivudine or metformin). PMID:23917312

  20. A Rapid Study of Botanical Drug-Drug Interaction with Protein by Re-ligand Fishing using Human Serum Albumin-Functionalized Magnetic Nanoparticles.

    PubMed

    Qing, Lin-Sen; Xue, Ying; Ding, Li-Sheng; Liu, Yi-Ming; Liang, Jian; Liao, Xun

    2015-12-01

    A great many active constituents of botanical drugs bind to human serum albumin (HSA) reversibly with a dynamic balance between the free- and bound-forms in blood. The curative or side effect of a drug depends on its free-form level, which is always influenced by other drugs, combined dosed or multi-constituents of botanical drugs. This paper presented a rapid and convenient methodology to investigate the drug-drug interactions with HSA. The interaction of two steroidal saponins, dioscin and pseudo-protodioscin, from a botanical drug was studied for their equilibrium time and equilibrium amount by re-ligand fishing using HSA functionalized magnetic nanoparticles. A clear competitive situation was obtained by this method. The equilibrium was reached soon about 15 s at a ratio of 0.44: 1. Furthermore, the interaction of pseudo-protodioscin to total steroidal saponins from DAXXK was also studied. The operation procedures of this method were faster and more convenient compared with other methods reported. PMID:26882690

  1. Drug-drug interaction between oxycodone and adjuvant analgesics in blood-brain barrier transport and antinociceptive effect.

    PubMed

    Nakazawa, Yusuke; Okura, Takashi; Shimomura, Keita; Terasaki, Tetsuya; Deguchi, Yoshiharu

    2010-01-01

    To examine possible blood-brain barrier (BBB) transport interactions between oxycodone and adjuvant analgesics, we firstly screened various candidates in vitro using [(3)H]pyrilamine, a substrate of the oxycodone transporter, as a probe drug. The uptake of [(3)H]pyrilamine by conditionally immortalized rat brain capillary endothelial cells (TR-BBB13) was inhibited by antidepressants (amitriptyline, imipramine, clomipramine, amoxapine, and fluvoxamine), antiarrhythmics (mexiletine, lidocaine, and flecainide), and ketamine. On the other hand, antiepileptics (carbamazepine, phenytoin, and clonazepam) and corticosteroids (dexamethasone and prednisolone) did not inhibit [(3)H]pyrilamine uptake, with the exception of sodium valproate. The uptake of oxycodone was significantly inhibited in a concentration-dependent manner by amitriptyline, fluvoxamine and mexiletine with K(i) values of 13, 65, and 44 microM, respectively. These K(i) values are 5-300 times greater than the human therapeutic plasma concentrations. Finally, we evaluated in vivo interaction between oxycodone and amitriptyline in mice. Antinociceptive effects of oxycodone were increased by coadministration of amitriptyline. The oxycodone concentrations in plasma and brain were not changed by coadministration of amitriptyline. Overall, the results suggest that several adjuvant analgesics may interact with the BBB transport of oxycodone at relatively high concentrations. However, it is unlikely that there would be any significant interaction at therapeutically or pharmacologically relevant concentrations. PMID:19499573

  2. 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. PMID:26608671

  3. P-gp, MRP2 and OAT1/OAT3 mediate the drug-drug interaction between resveratrol and methotrexate.

    PubMed

    Jia, Yongming; Liu, Zhihao; Wang, Changyuan; Meng, Qiang; Huo, Xiaokui; Liu, Qi; Sun, Huijun; Sun, Pengyuan; Yang, Xiaobo; Ma, Xiaodong; Liu, Kexin

    2016-09-01

    The purpose of present study was to investigate the effect of resveratrol (Res) on altering methotrexate (MTX) pharmacokinetics and clarify the related molecular mechanism. Res significantly increased rat intestinal absorption of MTX in vivo and in vitro. Simultaneously, Res inhibited MTX efflux transport in MDR1-MDCK and MRP2-MDCK cell monolayers, suggesting that the target of drug interaction was MDR1 and MRP2 in the intestine during the absorption process. Furthermore, there was a significant decrease in renal clearance of MTX after simultaneous intravenous administration. Similarly, MTX uptake was markedly inhibited by Res in rat kidney slices and hOAT1/3-HEK293 cell, indicating that OAT1 and OAT3 were involved in the drug interaction in the kidney. Additionally, concomitant administration of Res decreased cytotoxic effects of MTX in hOAT1/3-HEK293 cells, and ameliorated nephrotoxicity caused by MTX in rats. Conversely, intestinal damage caused by MTX was not exacerbated after Res treatment. In conclusion, Res enhanced MTX absorption in intestine and decreased MTX renal elimination by inhibiting P-gp, MRP2, OAT1 and OAT3 in vivo and in vitro. Res improved MTX-induced renal damage without increasing intestinal toxicity. PMID:27377006

  4. 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. PMID:26195223

  5. Modeling of Rifampicin-Induced CYP3A4 Activation Dynamics for the Prediction of Clinical Drug-Drug Interactions from In Vitro Data

    PubMed Central

    Yamashita, Fumiyoshi; Sasa, Yukako; Yoshida, Shuya; Hisaka, Akihiro; Asai, Yoshiyuki; Kitano, Hiroaki; Hashida, Mitsuru; Suzuki, Hiroshi

    2013-01-01

    Induction of cytochrome P450 3A4 (CYP3A4) expression is often implicated in clinically relevant drug-drug interactions (DDI), as metabolism catalyzed by this enzyme is the dominant route of elimination for many drugs. Although several DDI models have been proposed, none have comprehensively considered the effects of enzyme transcription/translation dynamics on induction-based DDI. Rifampicin is a well-known CYP3A4 inducer, and is commonly used as a positive control for evaluating the CYP3A4 induction potential of test compounds. Herein, we report the compilation of in vitro induction data for CYP3A4 by rifampicin in human hepatocytes, and the transcription/translation model developed for this enzyme using an extended least squares method that can account for inherent inter-individual variability. We also developed physiologically based pharmacokinetic (PBPK) models for the CYP3A4 inducer and CYP3A4 substrates. Finally, we demonstrated that rifampicin-induced DDI can be predicted with reasonable accuracy, and that a static model can be used to simulate DDI once the blood concentration of the inducer reaches a steady state following repeated dosing. This dynamic PBPK-based DDI model was implemented on a new multi-hierarchical physiology simulation platform named PhysioDesigner. PMID:24086247

  6. Assessment of Disease-Related Therapeutic Protein Drug-Drug Interaction for Etrolizumab in Patients With Moderately to Severely Active Ulcerative Colitis.

    PubMed

    Wei, Xiaohui; Kenny, Jane R; Dickmann, Leslie; Maciuca, Romeo; Looney, Caroline; Tang, Meina T

    2016-06-01

    The efficacy and safety of etrolizumab, a humanized IgG1 mAb, were evaluated in patients with ulcerative colitis (UC) in a phase 2 study (EUCALYPTUS). The current study assessed the risk of therapeutic protein drug-drug interaction (TP-DDI) of etrolizumab on CYP3A activity in patients with UC. Literature review was performed to compare serum proinflammatory cytokine levels and pharmacokinetic (PK) parameters of CYP3A substrate drugs between patients with inflammatory bowel disease (IBD) and healthy subjects. Treatment effect of etrolizumab on CYP3A activity was evaluated by measuring colonic CYP3A4 mRNA expression and serum C-reactive protein (CRP) in EUCALYPTUS patients. Literature data suggested similar levels between IBD patients and healthy subjects for serum proinflammatory cytokines and PK parameters of CYP3A substrate drugs. Additionally, treatment with etrolizumab did not change colonic CYP3A4 mRNA expression or serum CRP levels in UC patients. In conclusion, our results indicate a low TP-DDI risk for etrolizumab in UC patients, particularly on medications metabolized by CYP3A. PMID:26412221

  7. Drug-Drug Interaction of Omeprazole With the HCV Direct-Acting Antiviral Agents Paritaprevir/Ritonavir and Ombitasvir With and Without Dasabuvir.

    PubMed

    Polepally, Akshanth R; Dutta, Sandeep; Hu, Beibei; Podsadecki, Thomas J; Awni, Walid M; Menon, Rajeev M

    2016-07-01

    Paritaprevir (administered with low-dose ritonavir), ombitasvir, and dasabuvir are direct-acting antiviral agents administered as combination regimens for the treatment of chronic hepatitis C virus infection. Drug-drug interactions between 2D (ombitasvir/paritaprevir/ritonavir) or 3D (ombitasvir/paritaprevir/ritonavir and dasabuvir) regimens and omeprazole, a CYP2C19 substrate and acid-reducing agent, were evaluated in 24 healthy volunteers. Subjects received omeprazole (40 mg once daily) on day 1 and days 20-24 and the 2D or 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily ± dasabuvir 250 mg twice daily) on days 6-24. Compared with omeprazole alone, coadministration with the 2D or 3D regimen decreased omeprazole geometric mean Cmax and AUCt values by 40% to 50%. Ombitasvir, dasabuvir, and ritonavir mean exposures showed <10% change, and paritaprevir mean exposures showed <20% change when the 2D or 3D regimen was administered with omeprazole compared with administration without omeprazole. Although no a priori dose adjustment is needed, a higher omeprazole dose should be considered if clinically indicated when coadministered with the 2D or 3D regimen. No dose adjustment is required for the 2D or 3D regimen when administered with omeprazole, other acid-reducing agents, or CYP2C19 inhibitors. PMID:27310328

  8. In Vitro Metabolism and Drug-Drug Interaction Potential of UTL-5g, a Novel Chemo- and Radioprotective Agent

    PubMed Central

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

    2014-01-01

    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. PMID:25249693

  9. 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. PMID:26945713

  10. A Strategy for assessing potential drug-drug interactions of a concomitant agent against a drug absorbed via an intestinal transporter in humans.

    PubMed

    Mizuno-Yasuhira, Akiko; Nakai, Yasuhiro; Gunji, Emi; Uchida, Saeko; Takahashi, Teisuke; Kinoshita, Kohnosuke; Jingu, Shigeji; Sakai, Soichi; Samukawa, Yoshishige; Yamaguchi, Jun-Ichi

    2014-09-01

    A strategy for assessing potential drug-drug interactions (DDIs) based on a simulated intestinal concentration is described. The proposed prediction method was applied to the DDI assessment of luseogliflozin, a novel antidiabetic drug, against miglitol absorbed via the intestinal sodium-glucose cotransporter 1 (SGLT1). The method involves four steps: collection of physicochemical and pharmacokinetic parameters of luseogliflozin for use in a computer simulation; evaluation of the validity of these parameters by verifying the goodness of fit between simulated and observed plasma profiles; simulation of the intestinal luseogliflozin concentration-time profile using the Advanced Compartment Absorption and Transit (ACAT) model in a computer program and estimation of the time spent above a value 10-fold higher than the IC50 value (TAIC) for SGLT1; and evaluation of the DDI potential of luseogliflozin by considering the percentage of TAIC against the miglitol Tmax (time for Cmax) value (TAIC/Tmax). An initial attempt to prove the validity of this method was performed in rats. The resulting TAIC/Tmax in rats was 32%, suggesting a low DDI potential of luseogliflozin against miglitol absorption. The validity was then confirmed using an in vivo interaction study in rats. In humans, luseogliflozin was expected to have no DDI potential against miglitol absorption, since the TAIC/Tmax in humans was lower than that in rats. This prediction was proven, as expected, in a clinical interaction study. In conclusion, the present strategy based on a simulation of the intestinal concentration-time profile using dynamic modeling would be useful for assessing the clinical DDI potential of a concomitant agent against drugs absorbed via an intestinal transporter. PMID:25005603

  11. Statin-Induced Cardioprotection Against Ischemia-Reperfusion Injury: Potential Drug-Drug Interactions. Lesson to be Learnt by Translating Results from Animal Models to the Clinical Settings.

    PubMed

    Birnbaum, Gilad D; Birnbaum, Itamar; Ye, Yumei; Birnbaum, Yochai

    2015-10-01

    Numerous interventions have been shown to limit myocardial infarct size in animal models; however, most of these interventions have failed to have a significant effect in clinical trials. One potential explanation for the lack of efficacy in the clinical setting is that in bench models, a single intervention is studied without the background of other interventions or modalities. This is in contrast to the clinical setting in which new medications are added to the "standard of care" treatment that by now includes a growing number of medications. Drug-drug interaction may lead to alteration, dampening, augmenting or masking the effects of the intended intervention. We use the well described model of statin-induced myocardial protection to demonstrate potential interactions with agents which are commonly concomitantly used in patients with stable coronary artery disease and/or acute coronary syndromes. These interactions could potentially explain the reduced efficacy of statins in the clinical trials compared to the animal models. In particular, caffeine and aspirin could attenuate the infarct size limiting effects of statins; morphine could delay the onset of protection or mask the protective effect in patients with ST elevation myocardial infarction, whereas other anti-platelet agents (dipyridamole, cilostazol and ticagrelor) may augment (or mask) the effect due to their favorable effects on adenosine cell reuptake and intracellular cAMP levels. We recommend that after characterizing the effects of new modalities in single intervention bench research, studies should be repeated in the background of standard-of-care medications to assure that the magnitude of the effect is not altered before proceeding with clinical trials. PMID:26303765

  12. Clinical Pharmacokinetic, Pharmacodynamic, and Drug-Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor.

    PubMed

    Devineni, Damayanthi; Polidori, David

    2015-10-01

    The sodium-glucose co-transporter 2 (SGLT2) inhibitors represent novel therapeutic approaches in the management of type 2 diabetes mellitus; they act on kidneys to decrease the renal threshold for glucose (RTG) and increase urinary glucose excretion (UGE). Canagliflozin is an orally active, reversible, selective SGLT2 inhibitor. Orally administered canagliflozin is rapidly absorbed achieving peak plasma concentrations in 1-2 h. Dose-proportional systemic exposure to canagliflozin has been observed over a wide dose range (50-1600 mg) with an oral bioavailability of 65 %. Canagliflozin is glucuronidated into two inactive metabolites, M7 and M5 by uridine diphosphate-glucuronosyltransferase (UGT) 1A9 and UGT2B4, respectively. Canagliflozin reaches steady state in 4 days, and there is minimal accumulation observed after multiple dosing. Approximately 60 % and 33 % of the administered dose is excreted in the feces and urine, respectively. The half-life of orally administered canagliflozin 100 or 300 mg in healthy participants is 10.6 and 13.1 h, respectively. No clinically relevant differences are observed in canagliflozin exposure with respect to age, race, sex, and body weight. The pharmacokinetics of canagliflozin remains unaffected by mild or moderate hepatic impairment. Systemic exposure to canagliflozin is increased in patients with renal impairment relative to those with normal renal function; however, the efficacy is reduced in patients with renal impairment owing to the reduced filtered glucose load. Canagliflozin did not show clinically relevant drug interactions with metformin, glyburide, simvastatin, warfarin, hydrochlorothiazide, oral contraceptives, probenecid, and cyclosporine, while co-administration with rifampin modestly reduced canagliflozin plasma concentrations and thus may necessitate an appropriate monitoring of glycemic control. Canagliflozin increases UGE and suppresses RTG in a dose-dependent manner, thereby lowering the plasma glucose

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

    PubMed Central

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

    2016-01-01

    The objective of this study was to determine incidence rate, type, and pattern of clinically relevant potential drug-drug interactions (pDDIs) in a large outpatient population of a developing country. A retrospective, descriptive cross-sectional study was conducted on outpatients’ prescriptions in Khorasan Razavi province, Iran, over 12 months. A list of 25 clinically relevant DDIs, which are likely to occur in the outpatient setting, was used as the reference. Most frequent clinically relevant pDDIs, most common drugs contributing to the pDDIs, and the pattern of pDDIs for each medical specialty were determined. Descriptive statistics were used to report the results. In total, out of 8,169,142 prescriptions, 6,096 clinically relevant pDDIs were identified. The most common identified pDDIs were theophyllines-quinolones, warfarin-nonsteroidal anti-inflammatory drugs, benzodiazepines-azole antifungal agents, and anticoagulants-thyroid hormones. The most common drugs contributing to the identified pDDIs were ciprofloxacin, theophylline, warfarin, aminophylline, alprazolam, levothyroxine, and selegiline. While the incidence rate of clinically relevant pDDIs in prescriptions of general practitioners, internists, and cardiologists was the highest, the average pDDI incidence per 10,000 prescriptions of pulmonologists, infectious disease specialists, and cardiologists was highest. Although a small proportion of the analyzed prescriptions contained drug pairs with potential for clinically relevant DDIs, a significant number of outpatients have been exposed to the adverse effects associated with these interactions. It is recommended that in addition to training physicians and pharmacists, other effective interventions such as computerized alerting systems and electronic prescribing systems be designed and implemented. PMID:27499793

  14. Pharmacokinetic drug-drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel-ethinyl estradiol in healthy subjects.

    PubMed

    Gan, Lu; Jiang, Xuemin; Mendonza, Anisha; Swan, Therese; Reynolds, Christine; Nguyen, Joanne; Pal, Parasar; Neelakantham, Srikanth; Dahlke, Marion; Langenickel, Thomas; Rajman, Iris; Akahori, Mizuki; Zhou, Wei; Rebello, Sam; Sunkara, Gangadhar

    2016-01-01

    LCZ696 is a novel angiotensin receptor neprilysin inhibitor in development for the treatment of cardiovascular diseases. Here, we assessed the potential for pharmacokinetic drug-drug interaction of LCZ696 (400 mg, single dose or once daily [q.d.]) when co-administered with omeprazole 40 mg q.d. (n = 28) or metformin 1000 mg q.d. (n = 27) or levonorgestrel-ethinyl estradiol 150/30 μg single dose (n = 24) in three separate open-label, single-sequence studies in healthy subjects. Pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan), metformin, and levonorgestrel-ethinyl estradiol were assessed. Omeprazole did not alter the AUCinf of sacubitril and pharmacokinetics of LBQ657; however, 7% decrease in the Cmax of sacubitril, and 11% and 13% decreases in AUCinf and Cmax of valsartan were observed. Co-administration of LCZ696 with metformin had no significant effect on the pharmacokinetics of LBQ657 and valsartan; however, AUCtau,ss and Cmax,ss of metformin were decreased by 23%. Co-administration of LCZ696 with levonorgestrel-ethinyl estradiol had no effect on the pharmacokinetics of ethinyl estradiol and LBQ657 or AUCinf of levonorgestrel. The Cmax of levonorgestrel decreased by 15%, and AUCtau,ss and Cmax,ss of valsartan decreased by 14% and 16%, respectively. Co-administration of LCZ696 with omeprazole, metformin, or levonorgestrel-ethinyl estradiol was not associated with any clinically relevant pharmacokinetic drug interactions. PMID:27119576

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

    PubMed

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

    2016-01-01

    The objective of this study was to determine incidence rate, type, and pattern of clinically relevant potential drug-drug interactions (pDDIs) in a large outpatient population of a developing country. A retrospective, descriptive cross-sectional study was conducted on outpatients' prescriptions in Khorasan Razavi province, Iran, over 12 months. A list of 25 clinically relevant DDIs, which are likely to occur in the outpatient setting, was used as the reference. Most frequent clinically relevant pDDIs, most common drugs contributing to the pDDIs, and the pattern of pDDIs for each medical specialty were determined. Descriptive statistics were used to report the results. In total, out of 8,169,142 prescriptions, 6,096 clinically relevant pDDIs were identified. The most common identified pDDIs were theophyllines-quinolones, warfarin-nonsteroidal anti-inflammatory drugs, benzodiazepines-azole antifungal agents, and anticoagulants-thyroid hormones. The most common drugs contributing to the identified pDDIs were ciprofloxacin, theophylline, warfarin, aminophylline, alprazolam, levothyroxine, and selegiline. While the incidence rate of clinically relevant pDDIs in prescriptions of general practitioners, internists, and cardiologists was the highest, the average pDDI incidence per 10,000 prescriptions of pulmonologists, infectious disease specialists, and cardiologists was highest. Although a small proportion of the analyzed prescriptions contained drug pairs with potential for clinically relevant DDIs, a significant number of outpatients have been exposed to the adverse effects associated with these interactions. It is recommended that in addition to training physicians and pharmacists, other effective interventions such as computerized alerting systems and electronic prescribing systems be designed and implemented. PMID:27499793

  16. Investigation of the impact of substrate selection on in vitro organic anion transporting polypeptide 1B1 inhibition profiles for the prediction of drug-drug interactions.

    PubMed

    Izumi, Saki; Nozaki, Yoshitane; Maeda, Kazuya; Komori, Takafumi; Takenaka, Osamu; Kusuhara, Hiroyuki; Sugiyama, Yuichi

    2015-02-01

    The risk assessment of organic anion transporting polypeptide (OATP) 1B1-mediated drug-drug interactions (DDIs) is an indispensable part of drug development. We previously reported that in vitro inhibitory potencies of several inhibitors on OATP1B1 depend on the substrates when prototypical substrates, estradiol-17β-glucuronide (E₂G), estrone-3-sulfate, and sulfobromophthalein were used as test substrates. The purpose of this study was to comprehensively investigate this substrate-dependent inhibition of OATP1B1 using clinically relevant OATP1B1 inhibitors and substrate drugs. Effects of cyclosporine A (CsA), rifampin, and gemfibrozil on OATP1B1-mediated uptake of 12 substrate drugs were examined in OATP1B1-expressing human embryonic kidney 293 cells. The Ki values (μM) for CsA varied from 0.0771 to 0.486 (6.3-fold), for rifampin from 0.358 to 1.23 (3.4-fold), and for gemfibrozil from 9.65 to 252 (26-fold). Except for the inhibition of torasemide uptake by CsA and that of nateglinide uptake by gemfibrozil, the Ki values were within 2.8-fold of those obtained using E₂G as a substrate. Preincubation potentiated the inhibitory effect of CsA on OATP1B1 with similar magnitude regardless of the substrates. R values calculated based on a static model showed some variation depending on the Ki values determined with various substrates, and such variability could have an impact on the DDI predictions particularly for a weak-to-moderate inhibitor (gemfibrozil). OATP1B1 substrate drugs except for torasemide and nateglinide, or E₂G as a surrogate, is recommended as an in vitro probe in the inhibition experiments, which will help mitigate the risk of false-negative DDI predictions potentially caused by substrate-dependent Ki variation. PMID:25414411

  17. Assessment of intestinal availability (FG) of substrate drugs of cytochrome p450s by analyzing changes in pharmacokinetic properties caused by drug-drug interactions.

    PubMed

    Hisaka, Akihiro; Nakamura, Mikiko; Tsukihashi, Ayako; Koh, Saori; Suzuki, Hiroshi

    2014-10-01

    In this study, we developed the drug-drug interaction (DDI) method as a new assessment technique of intestinal availability (F(G), the fraction of drug transferred from the intestinal enterocytes into the liver, escaping from intestinal metabolism) based on the clearance theory. This method evaluates F(G) from changes caused by DDIs in the area under the blood concentration-time curve and in the elimination half-life of victim drugs. Application of the DDI method to data from the literature revealed that the mean and S.D. of F(G) values for 20 substrate drugs of CYP3A was 0.56 ± 0.29, whereas that for 8 substrate drugs of CYP2C9, CYP2C19, and CYP2D6 was 0.86 ± 0.11. These results were consistent with the fact that intestinal metabolism is mediated predominantly by CYP3A. The DDI method showed reasonable correlations with the conventional i.v./p.o. method and the grape fruit juice (GFJ) method (coefficients of determination of 0.41 and 0.81, respectively). The i.v./p.o. method was more susceptible to fluctuations in the hepatic blood flow rate compared with the DDI and GFJ methods. The DDI method evaluates F(G) separating from the absorption ratio (F(A)) although it requires approximation of F(A). Since preciseness of approximation of F(A) does not greatly affect the evaluation of F(G) by the DDI method, we proposed a reasonable approximation method of F(A) for the evaluation of F(G) in the DDI method. The DDI method would be applicable to a broad range of situations in which various DDI data are utilizable. PMID:25061161

  18. Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: comparative pharmacokinetics and drug-drug interactions.

    PubMed

    Peters, Solange; Zimmermann, Stefan; Adjei, Alex A

    2014-09-01

    The development of orally active small molecule inhibitors of the epidermal growth factor receptor (EGFR) has led to new treatment options for non-small cell lung cancer (NSCLC). Patients with activating mutations of the EGFR gene show sensitivity to, and clinical benefit from, treatment with EGFR tyrosine kinase inhibitors (EGFR-TKls). First generation reversible ATP-competitive EGFR-TKls, gefitinib and erlotinib, are effective as first, second-line or maintenance therapy. Despite initial benefit, most patients develop resistance within a year, 50-60% of cases being related to the appearance of a T790M gatekeeper mutation. Newer, irreversible EGFR-TKls - afatinib and dacomitinib - covalently bind to and inhibit multiple receptors in the ErbB family (EGFR, HER2 and HER4). These agents have been mainly evaluated for first-line treatment but also in the setting of acquired resistance to first-generation EGFR-TKls. Afatinib is the first ErbB family blocker approved for patients with NSCLC with activating EGFR mutations; dacomitinib is in late stage clinical development. Mutant-selective EGFR inhibitors (AZD9291, CO-1686, HM61713) that specifically target the T790M resistance mutation are in early development. The EGFR-TKIs differ in their spectrum of target kinases, reversibility of binding to EGFR receptor, pharmacokinetics and potential for drug-drug interactions, as discussed in this review. For the clinician, these differences are relevant in the setting of polymedicated patients with NSCLC, as well as from the perspective of innovative anticancer drug combination strategies. PMID:25027951

  19. Pomalidomide: evaluation of cytochrome P450 and transporter-mediated drug-drug interaction potential in vitro and in healthy subjects.

    PubMed

    Kasserra, Claudia; Assaf, Mahmoud; Hoffmann, Matthew; Li, Yan; Liu, Liangang; Wang, Xiaomin; Kumar, Gondi; Palmisano, Maria

    2015-02-01

    Pomalidomide offers an alternative for patients with relapsed/refractory multiple myeloma who have exhausted treatment options with lenalidomide and bortezomib. Little is known about pomalidomide's potential for drug-drug interactions (DDIs); as pomalidomide clearance includes hydrolysis and cytochrome P450 (CYP450)-mediated hydroxylation, possible DDIs via CYP450 and drug-transporter proteins were investigated in vitro and in a clinical study. In vitro pomalidomide was neither an inducer nor inhibitor of CYP450, nor an inhibitor of transporter proteins P glycoprotein (P-gp), BCRP, OAT1, OAT3, OCT2, OATP1B1, and OATP1B3. Oxidative metabolism of pomalidomide was predominately mediated by CYP1A2 and CYP3A4, and pomalidomide was shown to be a P-gp substrate. In healthy males, co-administration of oral (4 mg) pomalidomide with ketoconazole (CYP3A/P-gp inhibitor) or carbamazepine (CYP3A/P-gp inducer) did not result in clinically relevant changes in pomalidomide exposure. Co-administration of pomalidomide with fluvoxamine (CYP1A2 inhibitor) in the presence of ketoconazole approximately doubled pomalidomide exposure. Pomalidomide appears to have low potential for clinically relevant DDI and is unlikely to affect the clinical exposure of other drugs. Avoid co-administration of strong CYP1A2 inhibitors unless medically necessary. Pomalidomide dose should be reduced by 50% if co-administered with strong CYP1A2 inhibitors and strong CYP3A/P-gp inhibitors. PMID:25159194

  20. 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. PMID:26522641

  1. 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. PMID:27298338

  2. 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

  3. Prevalence of drug-drug interactions upon addition of simeprevir- or sofosbuvir-containing treatment to medication profiles of patients with HIV and hepatitis C coinfection.

    PubMed

    Patel, Nimish; Nasiri, Mona; Koroglu, Arden; Amin, Ronish; McGuey, Liam; McNutt, Louise-Anne; Roman, Martha; Miller, Christopher

    2015-02-01

    The objectives were to (1) compare the frequency of contraindicated drug-drug interactions (XDDI) when simeprevir (SIM)- and sofosbuvir (SOF)-containing regimens are theoretically added to a patient's medication profile; (2) identify which hepatitis C (HCV) regimen is associated with the lowest frequency of XDDIs within different types of antiretroviral treatment (ART) regimens; and (3) determine the risk factors for XDDIs with each regimen. A cross-sectional study was performed among adult HIV/HCV-coinfected patients. Demographics, comorbidities, and medication lists were collected from medical records. Medication lists were entered into Lexi-Interact drug interaction software and XDDI before/after the addition of SIM- and SOF-containing therapy was documented. Classification and regression tree (CART) analyses identified breakpoints in continuous variables. Before the addition of any HCV therapy, XDDIs were present in 20% of the 335 included patients. After the addition of SIM-containing therapy, the frequency of XDDIs significantly increased to 88.4% (p<0.001). After adding SOF-containing therapy, the prevalence of XDDIs increased to 24.5% (p<0.001). The prevalence of XDDIs was significantly lower for SOF-containing HCV therapy within various types of ART regimens. Use of ≥7 non-HIV medications (CART breakpoint) was the only variable to predict XDDIs before the addition of any HCV therapy. Similarly, this was the only variable to predict XDDIs after the addition of SOF-containing therapy (PR: 4.80; 95% CI: 2.57-8.96, p<0.001). Variables independently associated with XDDIs after the addition of SIM-containing therapy were NNRTI regimen (prevalence ratio, PR: 1.62; 95% confidence interval, CI: 1.38-1.91, p<0.001), PI regimen (PR: 1.64; 95% CI: 1.40-1.93, p<0.001), and ≥7 non-HIV medications (PR: 1.06; 95% CI: 1.00-1.14, p=0.09). The addition of SOF-containing therapy was associated with a lower prevalence of XDDI than SIM-containing therapy. PMID:25432275

  4. Treatment optimization in patients co-infected with HIV and Mycobacterium tuberculosis infections: focus on drug-drug interactions with rifamycins.

    PubMed

    Regazzi, Mario; Carvalho, Anna Cristina; Villani, Paola; Matteelli, Alberto

    2014-06-01

    Tuberculosis (TB) and HIV continue to be two of the major causes of morbidity and mortality in the world, and together are responsible for the death of millions of people every year. There is overwhelming evidence to recommend that patients with TB and HIV co-infection should receive concomitant therapy of both conditions regardless of the CD4 cell count level. The principles for treatment of active TB disease in HIV-infected patients are the same as in HIV-uninfected patients. However, concomitant treatment of both conditions is complex, mainly due to significant drug-drug interactions between TB and HIV drugs. Rifamycins are potent inducers of the cytochrome P450 (CYP) pathway, leading to reduced (frequently sub-therapeutic) plasma concentrations of some classes of antiretrovirals. Rifampicin is also an inducer of the uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzymes and interferes with drugs, such as integrase inhibitors, that are metabolized by this metabolic pathway. Rifampicin is also an inducer of the adenosine triphosphate (ATP) binding cassette transporter P-glycoprotein, which may also lead to decreased bioavailability of concomitantly administered antiretrovirals. On the other side, rifabutin concentrations are affected by the antiretrovirals that induce or inhibit CYP enzymes. In this review, the pharmacokinetic interactions, and the relevant clinical consequences, of the rifamycins-rifampicin, rifabutin, and rifapentine-with antiretroviral drugs are reviewed and discussed. A rifampicin-based antitubercular regimen and an efavirenz-based antiretroviral regimen is the first choice for treatment of TB/HIV co-infected patients. Rifabutin is the preferred rifamycin to use in HIV-infected patients on a protease inhibitor-based regimen; however, the dose of rifabutin needs to be reduced to 150 mg daily. More information is required to select optimal treatment regimens for TB/HIV co-infected patients whenever efavirenz cannot be used and rifabutin

  5. Importance of multi-P450 inhibition in drug-drug interactions: evaluation of incidence, inhibition magnitude and prediction from in vitro data

    PubMed Central

    Isoherranen, Nina; Lutz, Justin D; Chung, Sophie P; Hachad, Houda; Levy, Rene H; Ragueneau-Majlessi, Isabelle

    2012-01-01

    Drugs that are mainly cleared by a single enzyme are considered more sensitive to drug-drug interactions (DDIs) than drugs cleared by multiple pathways. However, whether this is true when a drug cleared by multiple pathways is co-administered with an inhibitor of multiple P450 enzymes (multi-P450 inhibition) is not known. Mathematically, simultaneous equipotent inhibition of two elimination pathways that each contributes half of the drug clearance is equal to equipotent inhibition of a single pathway that clears the drug. However, simultaneous strong or moderate inhibition of two pathways by a single inhibitor is perceived as an unlikely scenario. The aim of this study was (i) to identify P450 inhibitors currently in clinical use that can inhibit more than one clearance pathway of an object drug in vivo, and (ii) to evaluate the magnitude and predictability of DDIs caused by these multi-P450 inhibitors. Multi-P450 inhibitors were identified using the Metabolism and Transport Drug Interaction Database™. A total of 38 multi-P450 inhibitors, defined as inhibitors that increased the AUC or decreased the clearance of probes of two or more P450’s, were identified. Seventeen (45 %) multi-P450 inhibitors were strong inhibitors of at least one P450 and an additional 12 (32 %) were moderate inhibitors of one or more P450s. Only one inhibitor (fluvoxamine) was a strong inhibitor of more than one enzyme. Fifteen of the multi-P450 inhibitors also inhibit drug transporters in vivo, but such data are lacking on many of the inhibitors. Inhibition of multiple P450 enzymes by a single inhibitor resulted in significant (>2-fold) clinical DDIs with drugs that are cleared by multiple pathways such as imipramine and diazepam while strong P450 inhibitors resulted in only weak DDIs with these object drugs. The magnitude of the DDIs between multi-P450 inhibitors and diazepam, imipramine and omeprazole could be predicted using in vitro data with similar accuracy as probe substrate

  6. Assessment of cytochrome P450-mediated drug-drug interaction potential of orteronel and exposure changes in patients with renal impairment using physiologically based pharmacokinetic modeling and simulation.

    PubMed

    Lu, Chuang; Suri, Ajit; Shyu, Wen Chyi; Prakash, Shimoga

    2014-12-01

    Orteronel is a nonsteroidal, selective inhibitor of 17,20-lyase that was recently in phase 3 clinical development as a treatment for castration-resistant prostate cancer. In humans, the primary clearance route for orteronel is renal excretion. Human liver microsomal studies indicated that orteronel weakly inhibits CYP1A2, 2C8, 2C9 and 2C19, with IC50 values of 17.8, 27.7, 30.8 and 38.8 µm, respectively, whereas orteronel does not inhibit CYP2B6, 2D6 or 3A4/5 (IC50  > 100 µm). Orteronel also does not exhibit time-dependent inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4/5. The results of a static model indicated an [I]/Ki ratio >0.1 for CYP1A2, 2C8, 2C9 and 2C19. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to assess the potential for drug-drug interactions (DDIs) between orteronel and theophylline, repaglinide, (S)-warfarin and omeprazole, which are sensitive substrates of CYP1A2, 2C8, 2C9 and 2C19, respectively. Simulation of the area under the plasma concentration-time curve (AUC) of these four CYP substrates in the presence and absence of orteronel revealed geometric mean AUC ratios <1.25. Therefore, in accordance with the 2012 US FDA Draft Guidance on DDIs, orteronel can be labeled a 'non-inhibitor' and further clinical DDI evaluation is not required. In PBPK models of moderate and severe renal impairment, the AUC of orteronel was predicted to increase by 52% and 83%, respectively. These results are in agreement with those of a clinical trial in which AUC increases of 38% and 87% were observed in patients with moderate and severe renal impairment, respectively. PMID:25264242

  7. 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

  8. 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. PMID:27317801

  9. 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

    2016-03-01

    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. PMID:26750564

  10. 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

  11. Pattern and associated factors of potential drug-drug interactions in both pre- and early post-hematopoietic stem cell transplantation stages at a referral center in the Middle East.

    PubMed

    Gholaminezhad, Safoora; Hadjibabaie, Molouk; Gholami, Kheirollah; Javadi, Mohammad Reza; Radfar, Mania; Karimzadeh, Iman; Ghavamzadeh, Ardeshir

    2014-11-01

    The aim of this study was to determine the pattern as well as associated factors of moderate and major potential drug-drug interactions (PDDIs) in both the pre- and early post-transplantation stages at a referral hematopoietic stem cell transplantation (HSCT) center. All adolescents and adults undergone HSCT within a 3-year period were screened retrospectively for potential moderate or severe PDDIs by the Lexi-Interact On-Desktop software. Among 384 patients, a total of 13,600 PDDIs were detected. The median (interquartile range) cumulative PDDIs burden was 41 (28). All (100 %) individuals experienced at least one PDDI. More than four fifths (81.8 %) of detected PDDIs were moderate. The predominant mechanism of PDDIs was pharmacokinetics (54.3 %). Interaction between sulfamethoxazole-trimethoprim and fluconazole was the most common PDDIs involving 95.3 % of the study population. More than three fifths (61.5 %) of detected PDDIs were caused by HSCT-related medications. No interaction was identified between two anticancer agents. Interactions of cyclophosphamide with phenytoin, busulfan with metronidazole, dexamethasone, or clarithromycin were the only detected PDDI between anticancer and non-anticancer medications. Type of HSCT and the numbers of administered medications were significantly associated with major PDDIs. The epidemiology, real clinical consequence, and economic burden of DDIs on patients undergone HSCT particularly around the transplantation period should be assessed further by prospective, multicenter studies. PMID:24906215

  12. Substrate-dependent drug-drug interactions between gemfibrozil, fluvastatin and other organic anion-transporting peptide (OATP) substrates on OATP1B1, OATP2B1, and OATP1B3.

    PubMed

    Noé, Johannes; Portmann, Renée; Brun, Marie-Elise; Funk, Christoph

    2007-08-01

    Hepatic uptake carriers of the organic anion-transporting peptide (OATP) family of solute carriers are more and more recognized as being involved in hepatic elimination of many drugs and potentially associated drug-drug interactions. The gemfibrozil-statin interaction was studied at the level of active hepatic uptake as a model for such drug-drug interactions. Active, temperature-dependent uptake of fluvastatin into primary human hepatocytes was shown. Multiple transporters are involved in this uptake as Chinese hamster ovary or HEK293 cells expressing either OATP1B1 (K(m) = 1.4-3.5 microM), OATP2B1 (K(m) = 0.7-0.8 microM), or OATP1B3 showed significant fluvastatin uptake relative to control cells. For OATP1B1 the inhibition by gemfibrozil was substrate-dependent as the transport of fluvastatin (IC(50) of 63 microM), pravastatin, simvastatin, and taurocholate was inhibited by gemfibrozil, whereas the transport of estrone-3-sulfate and troglitazone sulfate (both used at 3 microM) was not affected. The OATP1B1- but not OATP2B1-mediated transport of estrone-3-sulfate displayed biphasic saturation kinetics, with two distinct affinity components for estrone-3-sulfate (0.23 and 45 microM). Only the high-affinity component was inhibited by gemfibrozil. Recombinant OATP1B1-, OATP2B1-, and OATP1B3-mediated fluvastatin transport was inhibited to 97, 70, and 62% by gemfibrozil (200 microM), respectively, whereas only a small inhibitory effect by gemfibrozil (200 microM) on fluvastatin uptake into primary human hepatocytes was observed (27% inhibition). The results indicate that the in vitro engineered systems can not always predict the behavior in more complex systems such as freshly isolated primary hepatocytes. Therefore, selection of substrate, substrate concentration, and in vitro transport system are critical for the conduct of in vitro interaction studies involving individual liver OATP carriers. PMID:17470528

  13. Drug-drug interactions in inmates treated for human immunodeficiency virus and Mycobacterium tuberculosis infection or disease: an institutional tuberculosis outbreak.

    PubMed

    Spradling, P; Drociuk, D; McLaughlin, S; Lee, L M; Peloquin, C A; Gallicano, K; Pozsik, C; Onorato, I; Castro, K G; Ridzon, R

    2002-11-01

    The use of rifamycins is limited by drug interactions in human immunodeficiency virus (HIV)-infected persons who are receiving highly active antiretroviral therapy (HAART). During a tuberculosis (TB) outbreak at a prison housing HIV-infected inmates, rifabutin was used to treat 238 men (13 case patients and 225 contacts). Steady-state peak plasma rifabutin concentrations were obtained after rifabutin dosages were adjusted for men receiving single-interacting HAART (with either 1 protease inhibitor [PI] or efavirenz), multi-interacting HAART (with either 2 PIs or > or =1 PI with efavirenz), and for noninteracting HAART (>1 nucleoside reverse-transcriptase inhibitor or no HAART) without rifabutin dose adjustments. Low rifabutin concentrations occurred in 9% of those receiving noninteracting HAART, compared with 19% of those receiving single-interacting and 29% of those receiving multi-interacting HAART (chi2, 3.76; P=.05). Of 225 contacts treated with rifabutin-pyrazinamide, 158 (70%) completed treatment while incarcerated. Rifabutin-pyrazinamide therapy was difficult to implement, because of the need for dosage adjustments and expert clinical management. PMID:12384845

  14. 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

  15. Multidrug PLA-PEG filomicelles for concurrent delivery of anticancer drugs-The influence of drug-drug and drug-polymer interactions on drug loading and release properties.

    PubMed

    Jelonek, Katarzyna; Li, Suming; Kaczmarczyk, Bożena; Marcinkowski, Andrzej; Orchel, Arkadiusz; Musiał-Kulik, Monika; Kasperczyk, Janusz

    2016-08-20

    This study aimed to analyze the influence of drug-drug and drug-polymer interactions on drug loading and release properties of multidrug micelles. Three hydrophobic drugs-paclitaxel (Ptx), 17-AAG and rapamycin (Rap) were incorporated in poly(l-lactide)-poly(ethylene glycol) (PLA-PEG) filomicelles. Double loaded micelles containing Ptx and 17-AAG were used for the sake of comparison. (1)H NMR confirmed the effective incorporation of the various drugs in micelles, and HPLC allowed to determine the drug loading contents. FTIR was used to evaluate interactions between particular drugs and between drugs and copolymer. Ptx and 17-AAG present similar loading efficiencies in double loaded micelles probably due to interactions of drugs with each other and also with the copolymer. In contrast, unequal drug loading properties are observed for triple loaded micelles. Rapamycin shows very weak interactions with the copolymer, and displays the lowest loading efficiency. In vitro release of drugs from micelles was realized in pH 7.4 phosphate buffered saline at 37°C, and monitored by HPLC. Similar release profiles are observed for the three drugs: a strong burst followed by slower release. Nevertheless, Ptx release from micelles is significantly slower as compared to 17-AAG and Rap, probably due to interactions of NH and OH groups of Ptx with the carbonyl group of PLA. In vitro cytotoxicity of Ptx/17-AAG/Rap loaded micelles and a mixture of free drugs was determined. Drug loaded micelles exhibit advantageous effect of prolonged drug release and cytotoxic activity against Caco-2 cells, which makes them a promising solution for simultaneous drug delivery to solid tumors. Therefore, understanding of interactions within multidrug micelles should be a valuable approach for the development of concurrent delivery systems of anticancer drugs with tailored properties. PMID:27346726

  16. CYP3A4-based drug-drug interaction: CYP3A4 substrates' pharmacokinetic properties and ketoconazole dose regimen effect.

    PubMed

    Boulenc, Xavier; Nicolas, Olivier; Hermabessière, Stéphanie; Zobouyan, Isabelle; Martin, Valérie; Donazzolo, Yves; Ollier, Céline

    2016-02-01

    The aim of the study was to assess the magnitude of the CYP3A4 inhibitory effect of 2 dosing regimens of ketoconazole and the influence of the pharmacokinetic properties of the CYP3A4 substrate on the extent of the substrate exposure increase. For this purpose, a clinical study was conducted and PBPK modeling simulations were performed. A crossover study was conducted in healthy subjects. The study was designed to compare the effects of different regimens of reversible CYP3A4 inhibitors, i.e., ketoconazole 400 mg OD, ketoconazole 200 mg BID, on two CYP3A4 substrates, alprazolam and midazolam, reflecting different pharmacokinetic properties in terms of first-pass effect and elimination. In parallel, time-based simulations were performed using the Simcyp population-based Simulator to address the usefulness of modeling to assess interaction clinical study design with CYP3A4 substrates. Comparison of the OD versus BID regimens for ketoconazole showed an opposite trend for the 2 substrates: BID (200 mg) dosing regimen provided the maximal clearance inhibition for alprazolam, while it was OD (400 mg) dosing regimen for midazolam. However, these effects are moderate despite the well-known pharmacokinetic differences between these substrates, suggesting that these differences are not enough. In the other way round, these investigations show how two CYP3A4 substrates can be different without leading to a major impact of the ketoconazole dosing regimen. The clinical findings are consistent with the Simcyp predictions, in particular the opposite trend observed with midazolam and alprazolam and the ketoconazole dosing regimen. These clinical investigations showed the influence of the CYP3A4 substrates' pharmacokinetic properties and the relevance of ketoconazole dose regimen on the magnitude of the interaction ratios. In addition, PBPK Simcyp simulations demonstrated how they can be used to help clinical study design assessment to capture the maximum effect. PMID:25374256

  17. Pharmacokinetics and pharmacodynamics of propofol and fentanyl in patients undergoing abdominal aortic surgery - a study of pharmacodynamic drug-drug interactions.

    PubMed

    Wiczling, Paweł; Bieda, Krzysztof; Przybyłowski, Krzysztof; Hartmann-Sobczyńska, Roma; Borsuk, Agnieszka; Matysiak, Jan; Kokot, Zenon J; Sobczyński, Paweł; Grześkowiak, Edmund; Bienert, Agnieszka

    2016-07-01

    Propofol is routinely combined with opioid analgesics to ensure adequate anesthesia during surgery. The aim of the study was to assess the effect of fentanyl on the hypnotic effect of propofol and the possible clinical implications of this interaction. The pharmacokinetic/pharmacodynamic (PK/PD) data were obtained from 11 patients undergoing abdominal aortic surgery, classified as ASA III. Propofol was administered by a target-controlled infusion system. Fentanyl 2-3 µg/kg was given whenever insufficient analgesia occurred. The bispectral index (BIS) was used to monitor the depth of anesthesia. A population PK/PD analysis with a non-linear mixed-effect model (NONMEM 7.2 software) was conducted. Two-compartment models satisfactorily described the PK of propofol and fentanyl. The delay of the anesthetic effect in relation to PK was described by the effect compartment. The BIS was linked to propofol and fentanyl effect-site concentrations through an additive Emax model. Context-sensitive decrement times (CSDT) determined from the final model were used to assess the influence of fentanyl on the recovery after anesthesia. The population PK/PD model was successfully developed to describe simultaneously the time course and variability of propofol and fentanyl concentrations and BIS. Additive propofol-fentanyl interactions were observed and quantitated. The duration of the fentanyl infusion had minimal effect on CSDT when it was shorter than the duration of the propofol infusion. If the fentanyl infusion was longer than the propofol infusion, an almost two-fold increase in CSDT occurred. Additional doses of fentanyl administered after the cessation of the propofol infusion result in lower BIS values, and can prolong the time of recovery from anesthesia. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26990035

  18. 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

    2015-04-01

    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. PMID:25781223

  19. The Use of Transporter Probe Drug Cocktails for the Assessment of Transporter-Based Drug-Drug Interactions in a Clinical Setting-Proposal of a Four Component Transporter Cocktail.

    PubMed

    Ebner, Thomas; Ishiguro, Naoki; Taub, Mitchell E

    2015-09-01

    Probe drug cocktails are used clinically to assess the potential for drug-drug interactions (DDIs), and in particular, DDIs resulting from coadministration of substrates and inhibitors of cytochrome P450 enzymes. However, a probe drug cocktail has not been identified to assess DDIs involving inhibition of drug transporters. We propose a cocktail consisting of the following substrates to explore the potential for DDIs caused by inhibition of key transporters: digoxin (P-glycoprotein, P-gp), rosuvastatin (breast cancer resistance protein, BCRP; organic anion transporting polypeptides, OATP), metformin (organic cation transporter, OCT; multidrug and toxin extrusion transporters, MATE), and furosemide (organic anion transporter, OAT). Furosemide was evaluated in vitro, and is a substrate of OAT1 and OAT3, with Km values of 38.9 and 21.5 μM, respectively. Furosemide was also identified as a substrate of BCRP, OATP1B1, and OATP1B3. Furosemide inhibited BCRP (50% inhibition of drug transport: 170 μM), but did not inhibit OATP1B1, OATP1B3, OCT2, MATE1, and MATE2-K at concentrations below 300 μM, and P-gp at concentrations below 2000 μM. Conservative approaches for the estimation of the likelihood of in vivo DDIs indicate a remote chance of in vivo transporter inhibition by these probe drugs when administered at low single oral doses. This four component probe drug cocktail is therefore proposed for clinical evaluation. PMID:25981193

  20. Dynamic and Static Simulations of Fluvoxamine-Perpetrated Drug-Drug Interactions Using Multiple Cytochrome P450 Inhibition Modeling, and Determination of Perpetrator-Specific CYP Isoform Inhibition Constants and Fractional CYP Isoform Contributions to Victim Clearance.

    PubMed

    Iga, Katsumi

    2016-03-01

    Fluvoxamine-perpetrated drug-drug interactions (DDIs) of victims metabolized by multiple cytochrome P450 isoforms (CYP1A2, CYP2C19, and CYP3A4) were simulated using 2 compartment-based tube modeling, assuming a multiple inhibition-constant (Ki) model, as well as a previously reported single Ki model. Good fittings were obtained for all DDIs using consistent perpetrator-specific CYP isoform Kis and fractional CYP isoform contributions to victim clearance in concordance with literature information. Through these simulations, the following rules to predict DDI were derived. Overall enzymatic inhibitory activity calculated from static DDI data determines entirely dynamic DDIs. DDI-relevant time-dependent hepatic blood unbound perpetrator levels can be approximated to mean hepatic blood unbound perpetrator levels in any victim DDIs when a perpetrator is supplied consistently. Static and dynamic multiple CYP model-based simulations agree with one another. Fluvoxamine-perpetrated DDIs can be bridged to other perpetrator DDIs. The derived rules will allow simpler prediction of DDIs from in vivo DDI databases. Tens or hundreds of Ki gaps between in vitro and in vivo data could be reduced to within severalfold using the liver-microsome contamination model, thus suggesting that microsomes qualified with contamination would greatly improve prediction of DDIs from in vitro data. PMID:26886336

  1. Glucuronidation converts clopidogrel to a strong time-dependent inhibitor of CYP2C8: a phase II metabolite as a perpetrator of drug-drug interactions.

    PubMed

    Tornio, A; Filppula, A M; Kailari, O; Neuvonen, M; Nyrönen, T H; Tapaninen, T; Neuvonen, P J; Niemi, M; Backman, J T

    2014-10-01

    Cerivastatin and repaglinide are substrates of cytochrome P450 (CYP)2C8, CYP3A4, and organic anion-transporting polypeptide (OATP)1B1. A recent study revealed an increased risk of rhabdomyolysis in patients using cerivastatin with clopidogrel, warranting further studies on clopidogrel interactions. In healthy volunteers, repaglinide area under the concentration-time curve (AUC(0-∞)) was increased 5.1-fold by a 300-mg loading dose of clopidogrel and 3.9-fold by continued administration of 75 mg clopidogrel daily. In vitro, we identified clopidogrel acyl-β-D-glucuronide as a potent time-dependent inhibitor of CYP2C8. A physiologically based pharmacokinetic model indicated that inactivation of CYP2C8 by clopidogrel acyl-β-D-glucuronide leads to uninterrupted 60-85% inhibition of CYP2C8 during daily clopidogrel treatment. Computational modeling resulted in docking of clopidogrel acyl-β-D-glucuronide at the CYP2C8 active site with its thiophene moiety close to heme. The results indicate that clopidogrel is a strong CYP2C8 inhibitor via its acyl-β-D-glucuronide and imply that glucuronide metabolites should be considered potential inhibitors of CYP enzymes. PMID:24971633

  2. Methods and strategies for assessing uncontrolled drug-drug interactions in population pharmacokinetic analyses: results from the International Society of Pharmacometrics (ISOP) Working Group.

    PubMed

    Bonate, Peter L; Ahamadi, Malidi; Budha, Nageshwar; de la Peña, Amparo; Earp, Justin C; Hong, Ying; Karlsson, Mats O; Ravva, Patanjali; Ruiz-Garcia, Ana; Struemper, Herbert; Wade, Janet R

    2016-04-01

    The purpose of this work was to present a consolidated set of guidelines for the analysis of uncontrolled concomitant medications (ConMed) as a covariate and potential perpetrator in population pharmacokinetic (PopPK) analyses. This white paper is the result of an industry-academia-regulatory collaboration. It is the recommendation of the working group that greater focus be given to the analysis of uncontrolled ConMeds as part of a PopPK analysis of Phase 2/3 data to ensure that the resulting outcome in the PopPK analysis can be viewed as reliable. Other recommendations include: (1) collection of start and stop date and clock time, as well as dose and frequency, in Case Report Forms regarding ConMed administration schedule; (2) prespecification of goals and the methods of analysis, (3) consideration of alternate models, other than the binary covariate model, that might more fully characterize the interaction between perpetrator and victim drug, (4) analysts should consider whether the sample size, not the percent of subjects taking a ConMed, is sufficient to detect a ConMed effect if one is present and to consider the correlation with other covariates when the analysis is conducted, (5) grouping of ConMeds should be based on mechanism (e.g., PGP-inhibitor) and not drug class (e.g., beta-blocker), and (6) when reporting the results in a publication, all details related to the ConMed analysis should be presented allowing the reader to understand the methods and be able to appropriately interpret the results. PMID:26837775

  3. Inhibition of hepatic organic anion-transporting polypeptide by RNA interference in sandwich-cultured human hepatocytes: an in vitro model to assess transporter-mediated drug-drug interactions.

    PubMed

    Liao, Mingxiang; Raczynski, Arek R; Chen, Michael; Chuang, Bei-Ching; Zhu, Qing; Shipman, Rob; Morrison, Jodi; Lee, David; Lee, Frank W; Balani, Suresh K; Xia, Cindy Q

    2010-09-01

    Organic anion-transporting polypeptides (OATPs), members of the SLCO/SLC21 family, mediate the transport of various endo- and xenobiotics. In human liver, OATP1B1, 1B3, and 2B1 are located at the basolateral membrane of hepatocytes and are involved in hepatic drug uptake and biliary elimination. Clinically significant drug-drug interactions (DDIs) mediated by hepatic OATPs have drawn great attention from clinical practitioners and researchers. However, there are considerable challenges to prospectively understanding the extent of OATP-mediated DDIs because of the lack of specific OATP inhibitors or substrates and the limitations of in vitro tools. In the present study, a novel RNA interference knockdown sandwich-cultured human hepatocyte model was developed and validated. Quantitative polymerase chain reaction, microarray and immunoblotting analyses, along with uptake assays, illustrated that the expression and transport activity of hepatic OATPs were reduced by small interfering (siRNA) efficiently and specifically in this model. Although OATP siRNA decreased only 20 to 30% of the total uptake of cerivastatin into human hepatocytes, it caused a 50% reduction in cerivastatin metabolism, which was observed by monitoring the formation of the two major metabolites of cerivastatin. The results suggest that coadministration of a drug that is a hepatic OATP inhibitor could significantly alter the pharmacokinetic profile of cerivastatin in clinical studies. Further studies with this novel model demonstrated that OATP and cytochrome P450 have a synergistic effect on cerivastatin-gemfibrozil interactions. The siRNA knockdown sandwich-cultured human hepatocytes may provide a new powerful model for evaluating DDIs. PMID:20516252

  4. Solitary Inhibition of the Breast Cancer Resistance Protein Efflux Transporter Results in a Clinically Significant Drug-Drug Interaction with Rosuvastatin by Causing up to a 2-Fold Increase in Statin Exposure.

    PubMed

    Elsby, Robert; Martin, Paul; Surry, Dominic; Sharma, Pradeep; Fenner, Katherine

    2016-03-01

    The intestinal efflux transporter breast cancer resistance protein (BCRP) restricts the absorption of rosuvastatin. Of the transporters important to rosuvastatin disposition, fostamatinib inhibited BCRP (IC50 = 50 nM) and organic anion-transporting polypeptide 1B1 (OATP1B1; IC50 > 10 μM), but not organic anion transporter 3, in vitro, predicting a drug-drug interaction (DDI) in vivo through inhibition of BCRP only. Consequently, a clinical interaction study between fostamatinib and rosuvastatin was performed (and reported elsewhere). This confirmed the critical role BCRP plays in statin absorption, as inhibition by fostamatinib resulted in a significant 1.96-fold and 1.88-fold increase in rosuvastatin area under the plasma concentration-time curve (AUC) and Cmax, respectively. An in vitro BCRP inhibition assay, using polarized Caco-2 cells and rosuvastatin as probe substrate, was subsequently validated with literature inhibitors and used to determine BCRP inhibitory potencies (IC50) of the perpetrator drugs eltrombopag, darunavir, lopinavir, clopidogrel, ezetimibe, fenofibrate, and fluconazole. OATP1B1 inhibition was also determined using human embryonic kidney 293-OATP1B1 cells versus estradiol 17β-glucuronide. Calculated parameters of maximum enterocyte concentration [Igut max], maximum unbound hepatic inlet concentration, transporter fraction excreted value, and determined IC50 value were incorporated into mechanistic static equations to compute theoretical increases in rosuvastatin AUC due to inhibition of BCRP and/or OATP1B1. Calculated theoretical increases in exposure correctly predicted the clinically observed changes in rosuvastatin exposure and suggested intestinal BCRP inhibition (not OATP1B1) to be the mechanism underlying the DDIs with these drugs. In conclusion, solitary inhibition of the intestinal BCRP transporter can result in clinically significant DDIs with rosuvastatin, causing up to a maximum 2-fold increase in exposure, which may warrant

  5. Drug-drug interactions affecting fluoroquinolones.

    PubMed

    Wijnands, G J; Vree, T B; Janssen, T J; Guelen, P J

    1989-12-29

    In a three-week study, the metabolism of the bronchodilator theophylline and its major metabolites formed by C-8 oxidation (1,3-dimethyluric acid) and N-demethylation (3-methylxanthine and 1-methyluric acid) was investigated in two healthy volunteers. Metabolic studies were performed following intravenous infusion of a single 6 mg/kg dose of aminophylline. During Week 1, theophylline was given alone (blank period), and during Weeks 2 and 3 it was given during oral coadministration of ofloxacin and enoxacin, respectively. Dosage of each quinolone was 200 mg twice daily for four days, starting three days prior to the theophylline infusion. During enoxacin coadministration, elimination half-lives of theophylline increased from 8.7 to 17.4 hours and from 6.1 to 12.3 hours, respectively. Total body clearance of theophylline decreased in both volunteers, whereas renal clearance did not alter. From this it was concluded that the decreased elimination results from a reduced metabolic clearance. During enoxacin coadministration, the formation of the metabolites 1-methyluric acid and 3-methylxanthine clearly was decreased, whereas the formation of 1,3-dimethyluric acid was less affected compared with the blank period. Interference with theophylline disposition by enoxacin is based predominantly on inhibition of microsomal N-demethylation. Ofloxacin comedication did not cause a change in the plasma parameters or renal excretion of theophylline and its metabolites compared with the blank period. PMID:2603893

  6. Investigation of drug-drug interactions caused by human pregnane X receptor-mediated induction of CYP3A4 and CYP2C subfamilies in chimeric mice with a humanized liver.

    PubMed

    Hasegawa, Maki; Tahara, Harunobu; Inoue, Ryo; Kakuni, Masakazu; Tateno, Chise; Ushiki, Junko

    2012-03-01

    The induction of cytochrome P450 (P450) enzymes is one of the risk factors for drug-drug interactions (DDIs). To date, the human pregnane X receptor (PXR)-mediated CYP3A4 induction has been well studied. In addition to CYP3A4, the expression of CYP2C subfamily is also regulated by PXR, and the DDIs caused by the induction of CYP2C enzymes have been reported to have a major clinical impact. The purpose of the present study was to investigate whether chimeric mice with a humanized liver (PXB mice) can be a suitable animal model for investigating the PXR-mediated induction of CYP2C subfamily, together with CYP3A4. We evaluated the inductive effect of rifampicin (RIF), a typical human PXR ligand, on the plasma exposure to the four P450 substrate drugs (triazolam/CYP3A4, pioglitazone/CYP2C8, (S)-warfarin/CYP2C9, and (S)-(-)-mephenytoin/CYP2C19) by cassette dosing in PXB mice. The induction of several drug-metabolizing enzymes and transporters in the liver was also examined by measuring the enzyme activity and mRNA expression levels. Significant reductions in the exposure to triazolam, pioglitazone, and (S)-(-)-mephenytoin, but not to (S)-warfarin, were observed. In contrast to the in vivo results, all the four P450 isoforms, including CYP2C9, were elevated by RIF treatment. The discrepancy in the (S)-warfarin results between in vivo and in vitro studies may be attributed to the relatively small contribution of CYP2C9 to (S)-warfarin elimination in the PXB mice used in this study. In summary, PXB mice are a useful animal model to examine DDIs caused by PXR-mediated induction of CYP2C and CYP3A4. PMID:22126990

  7. 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. PMID:26460073

  8. Simulation of Metabolic Drug-Drug Interactions Perpetrated by Fluvoxamine Using Hybridized Two-Compartment Hepatic Drug-Pool-Based Tube Modeling and Estimation of In Vivo Inhibition Constants.

    PubMed

    Iga, Katsumi

    2015-10-01

    Co-administration of fluvoxamine (FLV) (perpetrator) and ramelteon (victim, high-clearance CYP1A2 substrate) reportedly showed a 130-fold increase in the area under blood-ramelteon-levels curve (AUCR), which is unpredictable by any method assuming the traditional well-stirred hepatic extraction (Eh ) model. Thus, in order to predict this drug interaction (DDI), a mathematical method that allows simulation of dynamic changes in blood victim levels in response to metabolic inhibition by a perpetrator, without the use of any specialized tools, was derived using hybridized two-compartment hepatic drug-pool-based tube modeling. Using this method, the ramelteon-victimized DDI could be simulated in comparison with other victim DDIs, assuming a consistent FLV dosing regimen. Despite large differences in AUCRs, CYP1A2 or CYP2C19 substrate-victimized DDIs resulted in equivalent inhibition constants (Ki , around 3 nM) and net enzymatic inhibitory activities calculated by eliminating hepatic availability increases for victims. Thus, the unusually large ramelteon DDI could be attributed to the Eh of ramelteon itself. This DDI risk could also be accurately predicted from Ki s estimated in the other CYP1A2 or CYP2C19-substrate interactions. Meanwhile, dynamic changes in blood perpetrator levels were demonstrated to have a small effect on DDI, thus suggesting the usefulness of a tube-based static method for DDI prediction. PMID:26099559

  9. 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. PMID:26577601

  10. Evaluation of Drug-Drug Interactions between Direct-Acting Anti-Hepatitis C Virus Combination Regimens and the HIV-1 Antiretroviral Agents Raltegravir, Tenofovir, Emtricitabine, Efavirenz, and Rilpivirine.

    PubMed

    Khatri, Amit; Dutta, Sandeep; Dunbar, Martin; Podsadecki, Thomas; Trinh, Roger; Awni, Walid; Menon, Rajeev

    2016-05-01

    The three direct-acting antiviral agent (3D) regimen is a novel combination of direct-acting antiviral agents (DAAs) that has proven effective for the treatment of hepatitis C virus (HCV) infection. Given the potential for coadministration in patients with human immunodeficiency virus infection, possible drug interactions with antiretroviral drugs must be carefully considered. Four phase 1, multiple-dose pharmacokinetic studies were conducted in healthy volunteers (n = 66). The 3D regimen of 150/100 mg daily paritaprevir/ritonavir, 25 mg daily ombitasvir, and 400 mg twice-daily dasabuvir was administered alone or in combination with 200 mg daily of emtricitabine and 300 mg daily of tenofovir disoproxil fumarate (tenofovir DF), 25 mg daily of rilpivirine, or 400 mg of raltegravir twice daily. A 2-DAA regimen of 150/100 mg daily paritaprevir/ritonavir and 400 mg of dasabuvir twice daily was also studied in combination with efavirenz/emtricitabine/tenofovir DF at 600/200/300 mg daily, respectively (Atripla; Bristol-Myers Squibb). Pharmacokinetic parameters were determined from plasma drug concentrations. No clinically significant drug interactions were observed (≤32% change in exposure) between the 3D regimen and that of emtricitabine plus tenofovir DF. Raltegravir exposure was increased up to 134% when the drug was coadministered with the 3D regimen. Although coadministration with rilpivirine was well tolerated in healthy volunteers, observed elevations in rilpivirine exposures may increase the potential for adverse drug reactions. Concomitant use of the 2-DAA regimen and efavirenz/emtricitabine/tenofovir DF was discontinued owing to poor tolerability and adverse events. No dose adjustment is required during coadministration of raltegravir, tenofovir DF, or emtricitabine with the 3D regimen. Rilpivirine is not recommended and efavirenz is contraindicated for coadministration with the 3D regimen. PMID:26953200

  11. 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'…

  12. 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.

  13. Kondo versus indirect exchange: Role of lattice and actual range of RKKY interactions in real materials

    NASA Astrophysics Data System (ADS)

    Allerdt, Andrew; Büsser, C. A.; Martins, G. B.; Feiguin, A. E.

    2015-02-01

    Magnetic impurities embedded in a metal interact via an effective Ruderman-Kittel-Kasuya-Yosida (RKKY) coupling mediated by the conduction electrons, which is commonly assumed to be long ranged, with an algebraic decay in the interimpurity distance. However, they can also form a Kondo screened state that is oblivious to the presence of other impurities. We study the competition mechanisms between both effects on the square and cubic lattices by introducing an exact mapping onto an effective one-dimensional problem that we can solve with the density matrix renormalization group method. We show a dramatic departure from the conventional RKKY theory, that can be attributed to the dimensionality and different densities of states, as well as the quantum nature of the magnetic moments. In particular, for dimension d >1 , Kondo physics dominates even at short distances, while the ferromagnetic RKKY state is energetically unfavorable. Our findings can have clear implications in the interpretation of experiments and for tailoring the magnetic properties of surfaces.

  14. 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.

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

    DOE PAGESBeta

    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; et al

    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

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

    PubMed

    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

    2015-09-01

    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

  17. 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

  18. 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; Orr, Galya; Geiger, Franz M.; Haynes, Christy L.; Pedersen, Joel A.

    2015-07-24

    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. 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.

  19. Kondo versus indirect exchange: the role of the lattice and the actual range of RKKY interactions in real materials

    NASA Astrophysics Data System (ADS)

    Allerdt, Andrew; Feiguin, Adrian; Busser, Carlos; Martins, George

    2015-03-01

    Magnetic impurities embedded in a metal interact via an effective Ruderman-Kittel-Kasuya-Yosida (RKKY) coupling mediated by the conduction electrons, which is commonly assumed to be long ranged, with an algebraic decay in the inter-impurity distance. However, they can also form a Kondo screened state that is oblivious to the presence of other impurities. We study the competition mechanisms between both effects on the square and cubic lattices by introducing an exact mapping onto an effective one-dimensional problem that we can solve with the density matrix renormalization group method (DMRG). We show a dramatic departure from the conventional RKKY theory, that can be attributed to the dimensionality and different densities of states, as well as the quantum nature of the magnetic moments. In particular, for dimension d > 1 , Kondo physics dominates even at short distances, while the ferromagnetic RKKY state is energetically unfavorable. Our findings can have clear implications in the interpretation of experiments and for tailoring the magnetic properties of surfaces.

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

    PubMed

    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. PMID:27267283

  1. Synthesis of stable isotope labelled internal standards for drug-drug interaction (DDI) studies.

    PubMed

    Atzrodt, J; Blankenstein, J; Brasseur, D; Calvo-Vicente, S; Denoux, M; Derdau, V; Lavisse, M; Perard, S; Roy, S; Sandvoss, M; Schofield, J; Zimmermann, J

    2012-09-15

    The syntheses of stable isotope labelled internal standards of important CYP-isoform selective probes, like testosterone 1, diclofenac 3, midazolam 5, and dextromethorphan 7, as well as their corresponding hydroxylated metabolites 6β-hydroxytestosterone 2, 4'-hydroxydiclofenac 4, 1'-hydroxymidazolam 6 and dextrorphan 8 are reported. Microwave-enhanced H/D-exchange reactions applying either acid, base, or homogeneous and heterogeneous transition metal catalysis, or combinations thereof proved to be highly efficient for direct deuterium labelling of the above mentioned probes. Compared to conventional stepwise synthetic approaches, the combination of H/D exchange and biotransformation provides the potential for considerable time- and cost savings, in particular for the synthesis of the stable isotope labelled internal standards of 4'-hydroxydiclofenac 4 and 1'-hydroxymidazolam 6. PMID:22890009

  2. Metformin and cimetidine: Physiologically based pharmacokinetic modelling to investigate transporter mediated drug-drug interactions.

    PubMed

    Burt, H J; Neuhoff, S; Almond, L; Gaohua, L; Harwood, M D; Jamei, M; Rostami-Hodjegan, A; Tucker, G T; Rowland-Yeo, K

    2016-06-10

    Metformin is used as a probe for OCT2 mediated transport when investigating possible DDIs with new chemical entities. The aim of the current study was to investigate the ability of physiologically-based pharmacokinetic (PBPK) models to simulate the effects of OCT and MATE inhibition by cimetidine on metformin kinetics. PBPK models were developed, incorporating mechanistic kidney and liver sub-models for metformin (OCT and MATE substrate) and a mechanistic kidney sub-model for cimetidine. The models were used to simulate inhibition of the MATE1, MATE2-K, OCT1 and OCT2 mediated transport of metformin by cimetidine. Assuming competitive inhibition and using cimetidine Ki values determined in vitro, the predicted metformin AUC ratio was 1.0 compared to an observed value of 1.46. The observed AUC ratio could only be recovered with this model when the cimetidine Ki for OCT2 was decreased 1000-fold or the Ki's for both OCT1 and OCT2 were decreased 500-fold. An alternative description of metformin renal transport by OCT1 and OCT2, incorporating electrochemical modulation of the rate of metformin uptake together with 8-18-fold decreases in cimetidine Ki's for OCTs and MATEs, allowed recovery of the extent of the observed effect of cimetidine on metformin AUC. While the final PBPK model has limitations, it demonstrates the benefit of allowing for the complexities of passive permeability combined with active cellular uptake modulated by an electrochemical gradient and active efflux. PMID:27019345

  3. Influence of gold(I) complexes involving adenine derivatives on major drug-drug interaction pathway.

    PubMed

    Dvořák, Zdeněk; Novotná, Aneta; Vančo, Ján; Trávníček, Zdeněk

    2013-12-01

    A series of considerably anti-inflammatory active gold(I) mixed-ligand complexes, involving the benzyl-substituted derivatives of N6-benzyladenine (HLn) and triphenylphosphine (PPh3) as ligands and having the general formula [Au(Ln)(PPh3)]·xH2O (1-4; n=1-4 and x=0-1), was evaluated for the ability to influence the expression of CYP1A1/2 and CYP3A4 and transcriptional activity of glucocorticoid (GR) and aryl hydrocarbon (AhR) receptors in primary human hepatocytes and HepG2 cells. In both tests, evaluating the ability of the complexes to modulate the expression of CYP1A1, CYP1A2 and CYP3A4 in primary human hepatocytes and influence the transcriptional activity of AhR and GR in the reporter cell lines, no negative influence on the major drug-metabolizing cytochrome P450 isoenzymes and their signaling pathway (through GR and AhR receptors) was observed. These positive findings revealed another substantial evidence that could lead to utilization of the complexes as effective and relatively safe drugs for the treatment of hard-to-treat inflammation-related diseases, such as rheumatoid arthritis, comparable or even better than clinically used gold-containing drug Auranofin. PMID:24157406

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

    PubMed

    Patel, Apurv; Dodiya, Hitesh; Shelate, Pragna; Shastri, Divyesh; 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

  5. 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

  6. [Analgesics in geriatric patients. Adverse side effects and interactions].

    PubMed

    Gosch, Markus

    2015-07-01

    Pain is a widespread symptom in clinical practice. Older adults and chronically ill patients are particularly affected. In multimorbid geriatric patients, pharmacological pain treatment is an extension of a previously existing multimedication. Besides the efficacy of pain treatment, drug side effects and drug-drug interactions have to be taken into account to minimize the health risk for these patients. Apart from the number of prescriptions, the age-related pharmacokinetic and pharmacodynamic changes significantly increase the risk among older adults. The use of non-steroidal anti-inflammatory drugs (NSAID) is widespread but NSAIDs have the highest risk of adverse drug reactions and drug interactions. In particular, the gastrointestinal, cardiovascular, renal and coagulation systems are affected. Apart from the known toxic effect on the liver (in high doses), paracetamol (acetaminophen) has similar risks although to a lesser degree. According to current data, metamizol is actually better than its reputation suggests. The risk of potential drug interactions seems to be low. Apart from the risk of sedation in combination with other drugs, tramadol and other opioids can induce the serotonin syndrome. Among older adults, especially in the case of polypharmacy, an individualized approach should be considered instead of sticking to the pain management recommended by the World Health Organization (WHO) in order to minimize drug-drug interactions and adverse drug reactions. PMID:26152872

  7. 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. PMID:26413799

  8. The Self Actualized Reader.

    ERIC Educational Resources Information Center

    Marino, Michael; Moylan, Mary Elizabeth

    A study examined the commonalities that "voracious" readers share, and how their experiences can guide parents, teachers, and librarians in assisting children to become self-actualized readers. Subjects, 25 adults ranging in age from 20 to 67 years, completed a questionnaire concerning their reading histories and habits. Respondents varied in…

  9. Drug Interactions

    PubMed Central

    Tong Logan, Angela; Silverman, Andrew

    2012-01-01

    One of the most clinically significant complications related to the use of pharmacotherapy is the potential for drug-drug or drug-disease interactions. The gastrointestinal system plays a large role in the pharmacokinetic profile of most medications, and many medications utilized in gastroenterology have clinically significant drug interactions. This review will discuss the impact of alterations of intestinal pH, interactions mediated by phase I hepatic metabolism enzymes and P-glycoprotein, the impact of liver disease on drug metabolism, and interactions seen with commonly utilized gastrointestinal medications. PMID:22933873

  10. 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

  11. In Vitro and In Vivo Mechanistic Studies toward Understanding the Role of 1-Aminobenzotriazole in Rat Drug-Drug Interactions.

    PubMed

    Boily, Marc-Olivier; Chauret, Nathalie; Laterreur, Julie; Leblond, François A; Boudreau, Chantal; Duquet, Marie-Claude; Lévesque, Jean-François; Ste-Marie, Line; Pichette, Vincent

    2015-12-01

    1-Aminobenzotriazole (ABT) is regularly used in vivo as a nonspecific and irreversible cytochrome P450 inhibitor to elucidate the role of metabolism on the pharmacokinetic profile of xenobiotics. However, few reports have considered the recent findings that ABT can alter drug absorption or have investigated the possible differential inhibition of ABT on intestinal and hepatic metabolism. To address these uncertainties, pharmacokinetic studies under well controlled and defined ABT pretreatment conditions (50 mg/kg, 1 hour ABT i.v. and 16 hours ABT p.o.) were conducted prior to the oral administration of metoprolol, a permeable P450 probe that undergoes extensive intestinal and hepatic metabolism. The pharmacokinetic profile of metoprolol was affected differently by the two ABT pretreatments. An increase in area under the curve of 16-fold with ABT p.o. and 6.5-fold with ABT i.v. was observed compared with control. Based on in vitro studies, this difference could not be attributed to a differential inhibition of intestinal and hepatic metabolism. In the ABT i.v. pretreatment group, the increase in area under the curve was also associated with a prolonged time at maximal concentration (24-fold versus control), suggesting a delay in absorption. This was further confirmed by the administration of a charcoal meal, which resulted in a 7-fold increase in stomach weights in the 1-hour ABT pretreated groups compared with the untreated or 16-hour ABT pretreated rats. Based on these results, we recommend pretreating rats with ABT p.o. 16 hours before the administration of a test compound to preserve the inhibitory effect on intestinal and hepatic metabolism and avoid the confounding effect on drug absorption. PMID:26438628

  12. Inhaled loxapine and intramuscular lorazepam in healthy volunteers: a randomized placebo-controlled drug-drug interaction study.

    PubMed

    Spyker, Daniel A; Cassella, James V; Stoltz, Randall R; Yeung, Paul P

    2015-12-01

    Pharmacodynamic effects and safety of single-dose inhaled loxapine administered via the Staccato(®) system and intramuscular (IM) lorazepam in combination versus each agent alone were compared in a randomized, double-blind, crossover study in healthy volunteers. Subjects received: inhaled loxapine 10 mg + IM lorazepam 1 mg; inhaled loxapine 10 mg + IM placebo; IM lorazepam 1 mg + Staccato placebo in random order, each separated by a 3-day washout. Primary endpoints were maximum effect (minimum value) and area under the curve (AUC) from baseline to 2 h post treatment for respirations/min and pulse oximetry. Least-squares means (90% confidence interval [CI]) for concomitant treatment versus each agent alone were derived and equivalence (no difference) confirmed if the 90% CI was within 0.8-1.25. Blood pressure (BP), heart rate (HR), sedation (100-mm visual analog scale), and adverse events (AEs) were recorded. All 18 subjects (mean age, 20.4 years; 61% male) completed the study. There was no difference between inhaled loxapine + IM lorazepam and either agent alone on respiration or pulse oximetery during the 12-h postdose period, confirmed by 90% CIs for AUC and C min ratios. BP and HR were no different for inhaled loxapine + IM lorazepam and each agent alone over a 12-h postdose period. Although the central nervous system sedative effects were observed for each treatment in healthy volunteers, the effect was greater following concomitant lorazepam 1 mg IM + inhaled loxapine 10 mg administration. There were no deaths, serious AEs, premature discontinuations due to AEs, or treatment-related AEs. PMID:27022468

  13. Boron nitride nanotube as a delivery system for platinum drugs: Drug encapsulation and diffusion coefficient prediction.

    PubMed

    Khatti, Zahra; Hashemianzadeh, Seyed Majid

    2016-06-10

    Molecular dynamics (MD) simulation has been applied to investigate a drug delivery system based on boron nitride nanotubes, particularly the delivery of platinum-based anticancer drugs. For this propose, the behavior of carboplatin drugs inserted in boron nitride nanotubes (BNNT) as a carrier was studied. The diffusion rate of water molecules and carboplatin was investigated inside functionalized and pristine boron nitride nanotubes. The penetration rate of water and drug in functionalized BNNT was higher than that in pristine BNNT due to favorable water-mediated hydrogen bonding in hydroxyl edge-functionalized BNNT. Additionally, the encapsulation of multiple carboplatin drugs inside functionalized boron nitride nanotubes with one to five drug molecules confined inside the nanotube cavity was examined. At high drug loading, the hydrogen bond formation between adjacent drugs and the non-bonded van der Waals interaction between carboplatin and functionalized BNNT inner surface were found to be influential in drug displacement within the functionalized BNNT cavity for higher drug-loading capacity. PMID:27084121

  14. 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 element in a metaphysical…

  15. [Assessment of actual benefits of new drugs by the Transparency Committee].

    PubMed

    Le Jeunne, C

    2008-01-01

    When a drug has been granted a marketing authorization, if the pharmaceutical company wants it to be covered by the National Health Insurance, the company has to submit a file with all the studies concerning the drug, especially drug-drug comparative studies, to be assessed by the Transparency Committee. Drugs are assessed on two criteria: actual or expected benefit (AB) and improvement in actual benefit (IAB). Actual benefit mainly takes into account the severity of the disease concerned, the level of efficacy relative to known side effects (risk-benefit ratio), and the place the drug is intended to take in the therapeutic strategy. At the end of the assessment, AB is considered as important, moderate, poor or insufficient (to justify inclusion of the drug on the list of products to be reimbursed). After actual benefit is determined, improvement of actual benefit is assessed, comparing the estimated benefit of this drug with one of drugs with the same indication that is already reimbursed, to assess whether this drug will improve the patient's disease. This can be assessed by direct comparison (two drugs compared in the same clinical trial) or by indirect comparison (separate studies with the same design). There are four levels of added value, from I (major improvement) to IV (minor improvement). Level V represents no improvement. This second assessment is always relative to another drug. It never provides an absolute score. However, IAB is very important for pharmaceutical companies, because it is a fundamental criterion to determine the price of the drug, which is discussed with the Economic Committee of Health Products in a final phase. Actual benefit and improvement in actual benefit are allocated for each indication of a drug. PMID:18401307

  16. 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.

  17. A pocket aide-memoire on drug interactions.

    PubMed

    Stockley, I H

    1975-04-01

    A pocket size "slide-rule" type device designed to be used by physicians, pharmacists and nurses as a memory aid on potential drug-drug interactions is described. Color-coded symbols on the device indicate both the type and clinical significance of the potential interactions involving 56 drugs or groups of drugs. PMID:1130413

  18. [Antidepressives and antidepressive interactions with other drugs].

    PubMed

    Zavrsnik, Davorka; Spirtović, Selma; Becić, Fahir

    2006-01-01

    During the therapy with antidepressive agents, for the reason of its duration, numerous drug-drug interactions may occur. Antidepressive agents inhibit P450 enzyme activity and interfere with other drug metabolism. Many interactions are acceptable from the clinical point of view, and some are seriously dangerous indicating a need for their better knowledge. The aim of this work is to point out the possible interactions between antidepressive agents and other drugs. PMID:16425539

  19. 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

  20. [Pharmacokinetic interactions of telaprevir with other drugs].

    PubMed

    Berenguer Berenguer, Juan; González-García, Juan

    2013-07-01

    Telaprevir is a new direct-acting antiviral drug for the treatment of hepatitis C virus (HCV) infection and is both a substrate and an inhibitor of cytochrome P450 (CYP450) isoenzymes. With the introduction of this new drug, assessment of drug-drug interactions has become a key factor in the evaluation of patients under treatment for HCV infection. During the treatment of this infection, many patients require other drugs to mitigate the adverse effects of anti-HCV drugs and to control other comorbidities. Moreover, most patients coinfected with HIV and HCV require antiretroviral therapy during treatment for HCV. Physicians should therefore be familiar with the pharmacokinetic properties of direct-acting antivirals for HCV treatment and their potential drug-drug interactions. The present article reviews the available information to date on the interactions of telaprevir with other drugs and provides recommendations for daily clinical practice. PMID:24063902

  1. Moral Reasoning in Hypothetical and Actual Situations.

    ERIC Educational Resources Information Center

    Sumprer, Gerard F.; Butter, Eliot J.

    1978-01-01

    Results of this investigation suggest that moral reasoning of college students, when assessed using the DIT format, is the same whether the dilemmas involve hypothetical or actual situations. Subjects, when presented with hypothetical situations, become deeply immersed in them and respond as if they were actual participants. (Author/BEF)

  2. Factors Related to Self-Actualization.

    ERIC Educational Resources Information Center

    Hogan, H. Wayne; McWilliams, Jettie M.

    1978-01-01

    Provides data to further support the notions that females score higher in self-actualization measures and that self-actualization scores correlate inversely to the degree of undesirability individuals assign to their heights and weights. Finds that, contrary to predictions, greater androgyny was related to lower, not higher, self-actualization…

  3. 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. PMID:26956546

  4. Drug-Drug Interaction Studies of Paliperidone and Divalproex Sodium Extended-Release Tablets in Healthy Participants and Patients with Psychiatric Disorders.

    PubMed

    Remmerie, Bart; Ariyawansa, Jay; De Meulder, Marc; Coppola, Danielle; Berwaerts, Joris

    2016-06-01

    The objective of these 2 phase 1, open-label, 2-treatment, single-sequence studies was to evaluate the effect of repeated oral doses of divalproex sodium extended-release (ER) on the pharmacokinetics (PK) of a single dose of paliperidone ER in healthy participants (study 1), and the effect of multiple doses of paliperidone ER on the steady-state PK of valproic acid (VPA) in patients with psychiatric disorders (study 2), respectively. In study 1 healthy participants received, in a fixed sequential order, treatment A, paliperidone ER 12 mg (day 1); treatment B, VPA 1000 mg (2 × 500 mg divalproex sodium ER) once daily (days 5 to 18) and paliperidone ER 12 mg (day 15). In study 2 patients received treatment A, VPA (days 1-7); treatment B, VPA + paliperidone ER 12 mg (days 8-12). Divalproex sodium ER doses (study 2) were individualized such that systemic therapeutic VPA exposure from prior treatment was maintained on entry into the study. PK assessments were performed at prespecified time points (paliperidone days 1 and 15 [study 1]; VPA days 7 and 12 [study 2]). The oral bioavailability of paliperidone was increased by an estimated 51% (Cmax ) and 51%-52% (AUCs) when coadministered with divalproex sodium ER. No effect on the steady-state plasma concentration of VPA was observed following repeated coadministration with paliperidone ER: the 90%CI around the VPA exposure ratios for the 2 treatments was within the 80%-125% bioequivalence criteria for Cmax,ss and AUCτ . Both VPA and paliperidone ER were well tolerated, and no new safety concerns were identified. PMID:26412032

  5. Sandwich-Cultured Hepatocytes: An In Vitro Model to Evaluate Hepatobiliary Transporter-Based Drug Interactions and Hepatotoxicity

    PubMed Central

    Swift, Brandon; Pfeifer, Nathan D.; Brouwer, Kim L.R.

    2011-01-01

    Sandwich-cultured hepatocytes (SCH) are a powerful in vitro tool that can be utilized to study hepatobiliary drug transport, species differences in drug transport, transport protein regulation, drug-drug interactions, and hepatotoxicity. This review provides an up-to-date summary of the SCH model, including a brief history of, and introduction to, the use of SCH, as well as methodology to evaluate hepatobiliary drug disposition. A summary of the literature that has utilized this model to examine the interplay between drug metabolizing enzymes and transport proteins, drug-drug interactions at the transport level, and hepatotoxicity as a result of altered hepatic transport also is provided. PMID:20109035

  6. 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

  7. Teratogenic drugs and their drug interactions with hormonal contraceptives.

    PubMed

    Ahn, M R; Li, L; Shon, J; Bashaw, E D; Kim, M-J

    2016-09-01

    The US Food and Drug Administration (FDA) Guidance for Industry-Drug Interaction Studies, recommends that a potential human teratogen needs to be studied in vivo for effects on contraceptive steroids.(1) This article highlights the need to evaluate the drug-drug interactions (DDIs) between drugs with teratogenic potential and hormonal contraceptives (HCs) during drug development. It also addresses the FDA's effort of communicating DDI findings in product labels to mitigate the risk of unintended pregnancy. PMID:27090193

  8. 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.

  9. Pharmacokinetics and interactions of headache medications, part I: introduction, pharmacokinetics, metabolism and acute treatments.

    PubMed

    Sternieri, Emilio; Coccia, Ciro Pio Rosario; Pinetti, Diego; Ferrari, Anna

    2006-12-01

    Recent progress in the treatment of primary headaches has made available specific, effective and safe medications for these disorders, which are widely spread among the general population. One of the negative consequences of this undoubtedly positive progress is the risk of drug-drug interactions. This review is the first in a two-part series on pharmacokinetic drug-drug interactions of headache medications. Part I addresses acute treatments. Part II focuses on prophylactic treatments. The overall aim of this series is to increase the awareness of physicians, either primary care providers or specialists, regarding this topic. Pharmacokinetic drug-drug interactions of major severity involving acute medications are a minority among those reported in literature. The main drug combinations to avoid are: i) NSAIDs plus drugs with a narrow therapeutic range (i.e., digoxin, methotrexate, etc.); ii) sumatriptan, rizatriptan or zolmitriptan plus monoamine oxidase inhibitors; iii) substrates and inhibitors of CYP2D6 (i.e., chlorpromazine, metoclopramide, etc.) and -3A4 (i.e., ergot derivatives, eletriptan, etc.), as well as other substrates or inhibitors of the same CYP isoenzymes. The risk of having clinically significant pharmacokinetic drug-drug interactions seems to be limited in patients with low frequency headaches, but could be higher in chronic headache sufferers with medication overuse. PMID:17125411

  10. 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 §...

  11. 50 CFR 253.16 - Actual cost.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 50 Wildlife and Fisheries 11 2013-10-01 2013-10-01 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 §...

  12. 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)

  13. 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)

  14. 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)

  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. Racial Discrimination in Occupations: Perceived and Actual.

    ERIC Educational Resources Information Center

    Turner, Castellano B.; Turner, Barbara F.

    The relationship between the actual representation of Blacks in certain occupations and individual perceptions of the occupational opportunity structure were examined. A scale which rated the degree of perceived discrimination against Blacks in 21 occupations was administered to 75 black male, 70 black female, 1,429 white male and 1,457 white…

  17. 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,…

  18. 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.

  19. 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.

  20. 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.

  1. 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...

  2. 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...

  3. 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...

  4. 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...

  5. 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...

  6. 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

  7. What Galvanic Vestibular Stimulation Actually Activates

    PubMed Central

    Curthoys, Ian S.; MacDougall, Hamish Gavin

    2012-01-01

    In a recent paper in Frontiers Cohen et al. (2012) asked “What does galvanic vestibular stimulation actually activate?” and concluded that galvanic vestibular stimulation (GVS) causes predominantly otolithic behavioral responses. In this Perspective paper we show that such a conclusion does not follow from the evidence. The evidence from neurophysiology is very clear: galvanic stimulation activates primary otolithic neurons as well as primary semicircular canal neurons (Kim and Curthoys, 2004). Irregular neurons are activated at lower currents. The answer to what behavior is activated depends on what is measured and how it is measured, including not just technical details, such as the frame rate of video, but the exact experimental context in which the measurement took place (visual fixation vs total darkness). Both canal and otolith dependent responses are activated by GVS. PMID:22833733

  8. MODIS Solar Diffuser: Modelled and Actual Performance

    NASA Technical Reports Server (NTRS)

    Waluschka, Eugene; Xiong, Xiao-Xiong; Esposito, Joe; Wang, Xin-Dong; Krebs, Carolyn (Technical Monitor)

    2001-01-01

    The Moderate Resolution Imaging Spectroradiometer (MODIS) instrument's solar diffuser is used in its radiometric calibration for the reflective solar bands (VIS, NTR, and SWIR) ranging from 0.41 to 2.1 micron. The sun illuminates the solar diffuser either directly or through a attenuation screen. The attenuation screen consists of a regular array of pin holes. The attenuated illumination pattern on the solar diffuser is not uniform, but consists of a multitude of pin-hole images of the sun. This non-uniform illumination produces small, but noticeable radiometric effects. A description of the computer model used to simulate the effects of the attenuation screen is given and the predictions of the model are compared with actual, on-orbit, calibration measurements.

  9. 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.

  10. [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. PMID:20554088

  11. Literature Based Drug Interaction Prediction with Clinical Assessment Using Electronic Medical Records: Novel Myopathy Associated Drug Interactions

    PubMed Central

    Subhadarshini, Abhinita; Karnik, Shreyas D.; Li, Xiaochun; Hall, Stephen D.; Jin, Yan; Callaghan, J. Thomas; Overhage, Marcus J.; Flockhart, David A.; Strother, R. Matthew; Quinney, Sara K.; Li, Lang

    2012-01-01

    Drug-drug interactions (DDIs) are a common cause of adverse drug events. In this paper, we combined a literature discovery approach with analysis of a large electronic medical record database method to predict and evaluate novel DDIs. We predicted an initial set of 13197 potential DDIs based on substrates and inhibitors of cytochrome P450 (CYP) metabolism enzymes identified from published in vitro pharmacology experiments. Using a clinical repository of over 800,000 patients, we narrowed this theoretical set of DDIs to 3670 drug pairs actually taken by patients. Finally, we sought to identify novel combinations that synergistically increased the risk of myopathy. Five pairs were identified with their p-values less than 1E-06: loratadine and simvastatin (relative risk or RR = 1.69); loratadine and alprazolam (RR = 1.86); loratadine and duloxetine (RR = 1.94); loratadine and ropinirole (RR = 3.21); and promethazine and tegaserod (RR = 3.00). When taken together, each drug pair showed a significantly increased risk of myopathy when compared to the expected additive myopathy risk from taking either of the drugs alone. Based on additional literature data on in vitro drug metabolism and inhibition potency, loratadine and simvastatin and tegaserod and promethazine were predicted to have a strong DDI through the CYP3A4 and CYP2D6 enzymes, respectively. This new translational biomedical informatics approach supports not only detection of new clinically significant DDI signals, but also evaluation of their potential molecular mechanisms. PMID:22912565

  12. 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

  13. Food-Drug Interactions

    PubMed Central

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

    2011-01-01

    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. PMID:22043389

  14. 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.

  15. Can we (actually) assess global risk?

    NASA Astrophysics Data System (ADS)

    Di Baldassarre, Giuliano

    2013-04-01

    The evaluation of the dynamic interactions of the different components of global risk (e.g. hazard, exposure, vulnerability or resilience) is one of the main challenges in risk assessment and management. In state-of-the-art approaches for the analysis of risk, natural and socio-economic systems are typically treated separately by using different methods. In flood risk studies, for instance, physical scientists typically focus on the study of the probability of flooding (i.e. hazard), while social scientists mainly examine the exposure, vulnerability or resilience to flooding. However, these different components are deeply interconnected. Changes in flood hazard might trigger changes in vulnerability, and vice versa. A typical example of these interactions is the so-called "levee effect", whereby heightening levees to reduce the probability of flooding often leads to increase the potential adverse consequences of flooding as people often perceive that flood risk was completely eliminated once the levee was raised. These interconnections between the different components of risk remain largely unexplored and poorly understood. This lack of knowledge is of serious concern as it limits our ability to plan appropriate risk prevention measures. To design flood control structures, for example, state-of-the-art models can indeed provide quantitative assessments of the corresponding risk reduction associated to the lower probability of flooding. Nevertheless, current methods cannot estimate how, and to what extent, such a reduction might trigger a future increase of the potential adverse consequences of flooding (the aforementioned "levee effect"). Neither can they evaluate how the latter might (in turn) lead to the requirement of additional flood control structures. Thus, while many progresses have been made in the static assessment of flood risk, more inter-disciplinary research is required for the development of methods for dynamic risk assessment, which is very much

  16. 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. PMID:26265050

  17. 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

  18. Hepatitis C Virus Direct-Acting Antiviral Drug Interactions and Use in Renal and Hepatic Impairment.

    PubMed

    Hill, Lucas

    2015-01-01

    Direct-acting antiviral (DAA) drugs exhibit considerable variability in mechanisms of metabolism and the extent to which they are substrates, inhibitors, or inducers of cytochrome P450 enzymes or P-glycoprotein and other drug transporters. Thus, potential drug-drug interactions with other commonly used therapies also vary, as do the effects of renal and hepatic impairment on DAA drug exposure. Drug-drug interaction profiles and use in cases of renal or hepatic impairment are reviewed for the DAAs simeprevir; sofosbuvir; ledipasvir; the fixed-dose combination regimen of paritaprevir, ritonavir, and ombitasvir plus dasabuvir; and the investigational drugs daclatasvir and asunaprevir. This article summarizes a presentation by Lucas Hill, PharmD, at the IAS-USA continuing education program held in Chicago, Illinois, in October 2014. PMID:26200709

  19. Drug Interaction Alert Override Rates in the Meaningful Use Era

    PubMed Central

    Bryant, A.D.; Fletcher, G.S.

    2014-01-01

    Summary Background Interruptive drug interaction alerts may reduce adverse drug events and are required for Stage I Meaningful Use attestation. For the last decade override rates have been very high. Despite their widespread use in commercial EHR systems, previously described interventions to improve alert frequency and acceptance have not been well studied. Objectives (1) To measure override rates of inpatient medication alerts within a commercial clinical decision support system, and assess the impact of local customization efforts. (2) To compare override rates between drug-drug interaction and drug-allergy interaction alerts, between attending and resident physicians, and between public and academic hospitals. (3) To measure the correlation between physicians’ individual alert quantities and override rates as an indicator of potential alert fatigue. Methods We retrospectively analyzed physician responses to drug-drug and drug-allergy interaction alerts, as generated by a common decision support product in a large teaching hospital system. Results (1) Over four days, 461 different physicians entered 18,354 medication orders, resulting in 2,455 visible alerts; 2,280 alerts (93%) were overridden. (2) The drug-drug alert override rate was 95.1%, statistically higher than the rate for drug-allergy alerts (90.9%) (p < 0.001). There was no significant difference in override rates between attendings and residents, or between hospitals. (3) Physicians saw a mean of 1.3 alerts per day, and the number of alerts per physician was not significantly correlated with override rate (R2 = 0.03, p = 0.41). Conclusions Despite intensive efforts to improve a commercial drug interaction alert system and to reduce alerting, override rates remain as high as reported over a decade ago. Alert fatigue does not seem to contribute. The results suggest the need to fundamentally question the premises of drug interaction alert systems. PMID:25298818

  20. 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. PMID:21725841

  1. 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. PMID:27105861

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

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ..., and water damage risks incurred when property is actually located in the United States and marine... 26 Internal Revenue 10 2014-04-01 2013-04-01 true Actual United States risks. 1.953-2 Section 1... coverage as “.825% plus .3% fire, etc. risks plus .12% water risks = 1.245%”, a reasonable basis exists...

  3. 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)

  4. 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…

  5. From Self-Awareness to Self-Actualization

    ERIC Educational Resources Information Center

    Cangemi, Joseph P.; Englander, Meryl R.

    1974-01-01

    Highest priority of education is to help students utilize as much of their talent as is possible. Third Force psychologists would interpret this as becoming self-actualized. Self-awareness is required for psychological growth. Without self-awareness there can be no growth, no mental hygiene, and no self-actualization. (Author)

  6. 12 CFR 1806.203 - Selection Process, actual award amounts.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 7 2010-01-01 2010-01-01 false Selection Process, actual award amounts. 1806... OF THE TREASURY BANK ENTERPRISE AWARD PROGRAM Awards § 1806.203 Selection Process, actual award... round: (1) To select Applicants not previously selected, using the calculation and selection...

  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. 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…

  9. Perceived and Actual Student Support Needs in Distance Education.

    ERIC Educational Resources Information Center

    Visser, Lya; Visser, Yusra Laila

    2000-01-01

    This study sought to determine the academic, affective, and administrative support expectations of distance education students, and to compare actual expectations of distance education students with the instructor's perceptions of such expectations. Results demonstrated divergence between perceived and actual expectations of student support in…

  10. Gebrauchstexte im Fremdsprachenunterricht ("Actual" Texts in Foreign Language Teaching)

    ERIC Educational Resources Information Center

    Ziegesar, Detlef von

    1976-01-01

    Presents for analysis actual texts and texts specially written for teaching, arriving at a basis for a typology of actual texts. Defines teaching aims using such texts, and develops, from a TV program, a teaching unit used in a Karlsruhe school. (Text is in German.) (IFS/WGA)

  11. Self-Actualizing Men and Women: A Comparison Study.

    ERIC Educational Resources Information Center

    Hall, Eleanor G.; Hansen, Jan B.

    1997-01-01

    The self-actualization of 167 women who lived in the Martha Cook (MC) dormitory of the University of Michigan (1950-1970) was compared to that of a group of Ivy League men researched in another study. In addition, two groups of MC women were compared to each other to identify differences which might explain why some self-actualized while other did…

  12. SELF-ACTUALIZATION AND THE UTILIZATION OF TALENT.

    ERIC Educational Resources Information Center

    FRENCH, JOHN R.P.; MILLER, DANIEL R.

    THIS STUDY ATTEMPTED (1) TO DEVELOP A THEORY OF THE CAUSES AND CONSEQUENCES OF SELF-ACTUALIZATION AS RELATED TO THE UTILIZATION OF TALENT, (2) TO FIT THE THEORY TO EXISTING DATA, AND (3) TO PLAN ONE OR MORE RESEARCH PROJECTS TO TEST THE THEORY. TWO ARTICLES ON IDENTITY AND MOTIVATION AND SELF-ACTUALIZATION AND SELF-IDENTITY THEORY REPORTED THE…

  13. 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)

  14. 26 CFR 1.962-3 - Treatment of actual distributions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 10 2013-04-01 2013-04-01 false Treatment of actual distributions. 1.962-3... TAX (CONTINUED) INCOME TAXES (CONTINUED) Controlled Foreign Corporations § 1.962-3 Treatment of actual... a foreign corporation. (ii) Treatment of section 962 earnings and profits under § 1.959-3....

  15. 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…

  16. Pharmacokinetic and pharmacodynamic drug interactions between antiretrovirals and oral contraceptives.

    PubMed

    Tittle, Victoria; Bull, Lauren; Boffito, Marta; Nwokolo, Nneka

    2015-01-01

    More than 50 % of women living with HIV in low- and middle-income countries are of reproductive age, but there are limitations to the administration of oral contraception for HIV-infected women receiving antiretroviral therapy due to drug-drug interactions caused by metabolism via the cytochrome P450 isoenzymes and glucuronidation. However, with the development of newer antiretrovirals that use alternative metabolic pathways, options for contraception in HIV-positive women are increasing. This paper aims to review the literature on the pharmacokinetics and pharmacodynamics of oral hormonal contraceptives when given with antiretroviral agents, including those currently used in developed countries, older ones that might still be used in salvage regimens, or those used in resource-limited settings, as well as newer drugs. Nucleos(t)ide reverse transcriptase inhibitors (NRTIs), the usual backbone to most combined antiretroviral treatments (cARTs) are characterised by a low potential for drug-drug interactions with oral contraceptives. On the other hand non-NRTIs (NNRTIs) and protease inhibitors (PIs) may interact with oral contraceptives. Of the NNRTIs, efavirenz and nevirapine have been demonstrated to cause drug-drug interactions; however, etravirine and rilpivirine appear safe to use without dose adjustment. PIs boosted with ritonavir are not recommended to be used with oral contraceptives, with the exception of boosted atazanavir which should be used with doses of at least 35 µg of estrogen. Maraviroc, an entry inhibitor, is safe for co-administration with oral contraceptives, as are the integrase inhibitors (INIs) raltegravir and dolutegravir. However, the INI elvitegravir, which is given in combination with cobicistat, requires a dose of estrogen of at least 30 µg. Despite the growing evidence in this field, data are still lacking in terms of large cohort studies, randomised trials and correlations to real clinical outcomes, such as pregnancy rates, in women

  17. [Comparison of four drug interaction screening programs].

    PubMed

    Ing Lorenzini, K; Reutemann, B; Samer, C F; Guignard, B; Bonnabry, P; Dayer, P; Perrier, A; Desmeules, J

    2012-10-17

    Adverse drug events (ADE) are a major public health issue, with drug-drug interactions (DDI) being one of well-recognized causes of ADE that could be preventable by the use of DDI screening software. We compared the ability of four programs to detect clinically important DDI. We tested 62 drug pairs with and 12 drug pairs without clinically important DDI. Lexi-Interact and Epocrates were the most sensitive (95%) compared to the Compendium and Theriaque (80 and 73%, respectively). The Compendium and Theriaque also showed the lowest negative predictive value. All programs showed high specificity and positive predictive value. The qualitative assessment showed the best performances for Compendium and Lexi-Interact. The last one seems to be the best screening program, but the Compendium is in French and is freely available. PMID:23198652

  18. Safety of patients--actual problem of modern medicine (review).

    PubMed

    Tsintsadze, Neriman; Samnidze, L; Beridze, T; Tsintsadze, M; Tsintsadze, Nino

    2011-09-01

    Safety of patients is actual problem of up-to-date medicine. The current successful treatment of various sicknesses is achieved by implementation in clinical practice such medical preparations (medications), which are characterized with the high therapeutic activity, low toxicity and prolonged effects. In spite of evidence of the pharmacotherapeutical advances, the frequency of complications after medication has grown - that is why the safety of patients is the acute actual problem of medicine and ecological state of human population today. PMID:22156680

  19. 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

  20. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions.

    PubMed

    Shitara, Yoshihisa; Sugiyama, Yuichi

    2006-10-01

    3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely used for the treatment of hypercholesterolemia. Their efficacy in preventing cardiovascular events has been shown by a large number of clinical trials. However, myotoxic side effects, sometimes severe, including myopathy or rhabdomyolysis, are associated with the use of statins. In some cases, such toxicity is associated with pharmacokinetic alterations. In this review, the pharmacokinetic aspects and physicochemical properties of statins are reviewed in order to understand the mechanism governing their pharmacokinetic alterations. Among the statins, simvastatin, lovastatin and atorvastatin are metabolized by cytochrome P450 3A4 (CYP3A4) while fluvastatin is metabolized by CYP2C9. Cerivastatin is subjected to 2 metabolic pathways mediated by CYP2C8 and 3A4. Pravastatin, rosuvastatin and pitavastatin undergo little metabolism. Their plasma clearances are governed by the transporters involved in the hepatic uptake and biliary excretion. Also for other statins, which are orally administered as open acid forms (i.e. fluvastatin, cerivastatin and atorvastatin), hepatic uptake transporter(s) play important roles in their clearances. Based on such information, pharmacokinetic alterations of statins can be predicted following coadministration of other drugs or in patients with lowered activities in drug metabolism and/or transport. We also present a quantitative analysis of the effect of some factors on the pharmacokinetics of statins based on a physiologically based pharmacokinetic model. To avoid a pharmacokinetic alteration, we need to have information about the metabolizing enzyme(s) and transporter(s) involved in the pharmacokinetics of statins and, along with such information, model-based prediction is also useful. PMID:16714062

  1. In Silico Predictions and In Vivo Results of Drug-Drug Interactions by Ketoconazole and Verapamil on AZD1305, a Combined Ion Channel Blocker and a Sensitive CYP3A4 Substrate.

    PubMed

    Johansson, Susanne; Löfberg, Boel; Aunes, Maria; Lunde, Helen; Frison, Lars; Edvardsson, Nils; Cullberg, Marie

    2016-09-01

    The objectives were to estimate and compare, in silico and in vivo, the effects of a strong and a moderate CYP3A4 inhibitor on AZD1305 pharmacokinetics. In silico, simulations were performed with the computer software Simcyp, and the predicted outcome was compared with the results observed in healthy male subjects. In silico, the geometric mean plasma exposure of AZD1305 + ketoconazole showed a 7.1-fold higher AUC and a 4.4-fold higher Cmax compared with AZD1305 alone. Coadministration with verapamil gave a 1.9-fold higher AUC and a 1.7-fold higher Cmax compared with AZD1305 alone. In vivo, the plasma exposure of AZD1305 + ketoconazole showed a 7.7-fold higher AUC and a 4.8 -fold higher Cmax compared with AZD1305 alone. Coadministration with verapamil gave a 2.2-fold higher AUC and a 2.0-fold higher Cmax compared with AZD1305 alone. The mean maximum QTcF increase from baseline was 407, 487, and 437 milliseconds for AZD1305, alone and in combination with verapamil or ketoconazole, respectively. Simcyp predicted the effects of ketoconazole and verapamil on the sensitive CYP3A4 substrate AZD1305 pharmacokinetics well. Both the in vivo study and the Simcyp predictions suggest a contraindication for strong CYP3A4 inhibitors and AZD1305 when given in combination. PMID:27627192

  2. 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.

  3. Self-Actualization: The Heart and Soul of a Potential-Based Life Skills Program for a Child with Multiple Disabilities

    ERIC Educational Resources Information Center

    Croft, Gillian; Boyer, Wanda; Hett, Geoffrey

    2009-01-01

    Although every child with disabilities may come to self-actualization by different means and measurements it is, nevertheless, an important goal. The child with disabilities may be guided toward her goal of self-actualization by being encouraged to find her individual strengths and capacities, and by being assisted to successfully interact with…

  4. 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

  5. Large-scale identification and analysis of suppressive drug interactions.

    PubMed

    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

    2014-04-24

    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

  6. 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. PMID:22423518

  7. Experimental philosophy of actual and counterfactual free will intuitions.

    PubMed

    Feltz, Adam

    2015-11-01

    Five experiments suggested that everyday free will and moral responsibility judgments about some hypothetical thought examples differed from free will and moral responsibility judgments about the actual world. Experiment 1 (N=106) showed that free will intuitions about the actual world measured by the FAD-Plus poorly predicted free will intuitions about a hypothetical person performing a determined action (r=.13). Experiments 2-5 replicated this result and found the relations between actual free will judgments and free will judgments about hypothetical determined or fated actions (rs=.22-.35) were much smaller than the differences between them (ηp(2)=.2-.55). These results put some pressure on theoretical accounts of everyday intuitions about freedom and moral responsibility. PMID:26126174

  8. A Flawed Argument Against Actual Infinity in Physics

    NASA Astrophysics Data System (ADS)

    Perez Laraudogoitia, Jon

    2010-12-01

    In “Nonconservation of Energy and loss of Determinism II. Colliding with an Open Set” (2010) Atkinson and Johnson argue in favour of the idea that an actual infinity should be excluded from physics, at least in the sense that physical systems involving an actual infinity of component elements should not be admitted. In this paper I show that the argument Atkinson and Johnson use is erroneous and that an analysis of the situation considered by them is possible without requiring any type of rejection of the idea of infinity.

  9. Pilot Eye Scanning under Actual Single Pilot Instrument Flight

    NASA Astrophysics Data System (ADS)

    Rinoie, Kenichi; Sunada, Yasuto

    Operations under single pilot instrument flight rules for general aviation aircraft is known to be one of the most demanding pilot tasks. Scanning numerous instruments plays a key role for perception and decision-making during flight. Flight experiments have been done by a single engine light airplane to investigate the pilot eye scanning technique for IFR flights. Comparisons between the results by an actual flight and those by a PC-based flight simulator are made. The experimental difficulties of pilot eye scanning measurements during the actual IFR flight are discussed.

  10. Comparison of simulated and actual wind shear radar data products

    NASA Technical Reports Server (NTRS)

    Britt, Charles L.; Crittenden, Lucille H.

    1992-01-01

    Prior to the development of the NASA experimental wind shear radar system, extensive computer simulations were conducted to determine the performance of the radar in combined weather and ground clutter environments. The simulation of the radar used analytical microburst models to determine weather returns and synthetic aperture radar (SAR) maps to determine ground clutter returns. These simulations were used to guide the development of hazard detection algorithms and to predict their performance. The structure of the radar simulation is reviewed. Actual flight data results from the Orlando and Denver tests are compared with simulated results. Areas of agreement and disagreement of actual and simulated results are shown.

  11. 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:…

  12. 26 CFR 513.8 - Addressee not actual owner.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... CONVENTIONS IRELAND Withholding of Tax § 513.8 Addressee not actual owner. (a) If any person with an address in Ireland who receives a dividend from a United States corporation with respect to which United... such reduced rate of 15 percent, such recipient in Ireland will withhold an additional amount of...

  13. Remote sensing estimates of actual evapotranspiration in an irrigation district

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Accurate estimates of the spatial distribution of actual evapotranspiration (AET) are useful in hydrology, but can be difficult to obtain. Remote sensing provides a potential capability for routinely monitoring AET by combining remotely sensed surface temperature and vegetation cover observations w...

  14. Self Actualization of Females in an Experimental Orientation Program

    ERIC Educational Resources Information Center

    Vander Wilt, Robert B.; Klocke, Ronald A.

    1971-01-01

    An alternative to the traditional orientation program was developed that forced students to consider their physical and psychological outer limits. Students were confronted in a new and unique way that contributed to the self actualization process of the female portion of the group. (Author/BY)

  15. Actual Leisure Participation of Norwegian Adolescents with Down Syndrome

    ERIC Educational Resources Information Center

    Dolva, Anne-Stine; Kleiven, Jo; Kollstad, Marit

    2014-01-01

    This article reports the actual participation in leisure activities by a sample of Norwegian adolescents with Down syndrome aged 14. Representing a first generation to grow up in a relatively inclusive context, they live with their families, attend mainstream schools, and are part of common community life. Leisure information was obtained in…

  16. Research into Students' Perceptions of Preferred and Actual Learning Environment.

    ERIC Educational Resources Information Center

    Hattie, John A.; And Others

    Measures of both preferred and actual classroom and school environment were administered to 1,675 secondary school students in New South Wales (Australia). Shortened versions of the My Class Inventory, Classroom Environment Scale, and Individualized Classroom Environment Questionnaire, as well as the Quality of School Life questionnaire were…

  17. 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…

  18. 40 CFR 74.22 - Actual SO2 emissions rate.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ....6 for natural gas For other fuels, the combustion source must specify the SO2 emissions factor. (c... (CONTINUED) SULFUR DIOXIDE OPT-INS Allowance Calculations for Combustion Sources § 74.22 Actual SO2 emissions rate. (a) Data requirements. The designated representative of a combustion source shall submit...

  19. What Does the Force Concept Inventory Actually Measure?

    ERIC Educational Resources Information Center

    Huffman, Douglas; Heller, Patricia

    1995-01-01

    The Force Concept Inventory (FCI) is a 29-question, multiple-choice test designed to assess students' Newtonian and non-Newtonian conceptions of force. Presents an analysis of FCI results as one way to determine what the inventory actually measures. (LZ)

  20. 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…

  1. 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…

  2. Study on Tire-attached Energy Harvester for Low-speed Actual Vehicle Driving

    NASA Astrophysics Data System (ADS)

    Zhang, Y.; Zheng, R.; Kaizuka, T.; Su, D.; Nakano, K.

    2015-12-01

    This study reports a tire-attached energy harvester, in which a cantilever beam pasted piezoelectric film and magnets with the same polarity are fabricated as a bistable vibrating system, for low-speed actual-vehicle driving. As the wheel rotates, the energy harvester is subjected to the noise produced from the interaction between the paved road and the rotating tire, and tangentially gravitational force as a periodic input can be applied to achieve the occurrence of stochastic resonance. Stochastic resonance can significantly stimulate the response of the bistable vibrating system, and therefore enhance the energy harvesting efficiency.

  3. Actual curriculum development practices instrument: Testing for factorial validity

    NASA Astrophysics Data System (ADS)

    Foi, Liew Yon; Bakar, Kamariah Abu; Hamzah, Mohd Sahandri Gani; Alwi, Nor Hayati

    2014-09-01

    The Actual Curriculum Development Practices Instrument (ACDP-I) was developed and the factorial validity of the ACDP-I was tested (n = 107) using exploratory factor analysis procedures in the earlier work of [1]. Despite the ACDP-I appears to be content and construct valid instrument with very high internal reliability qualities for using in Malaysia, the accumulated evidences are still needed to provide a sound scientific basis for the proposed score interpretations. Therefore, the present study addresses this concern by utilising the confirmatory factor analysis to further confirm the theoretical structure of the variable Actual Curriculum Development Practices (ACDP) and enrich the psychometrical properties of ACDP-I. Results of this study have practical implication to both researchers and educators whose concerns focus on teachers' classroom practices and the instrument development and validation process.

  4. 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.

  5. 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.

  6. Northrop Triga facility decommissioning plan versus actual results

    SciTech Connect

    Gardner, F.W.

    1986-01-01

    This paper compares the Triga facility decontamination and decommissioning plan to the actual results and discusses key areas where operational activities were impacted upon by the final US Nuclear Regulatory Commission (NRC)-approved decontamination and decommissioning plan. Total exposures for fuel transfer were a factor of 4 less than planned. The design of the Triga reactor components allowed the majority of the components to be unconditionally released.

  7. 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

  8. Perceived accessibility versus actual physical accessibility of healthcare facilities.

    PubMed

    Sanchez, J; Byfield, G; Brown, T T; LaFavor, K; Murphy, D; Laud, P

    2000-01-01

    This study addressed how healthcare clinics perceive themselves in regard to accessibility for persons with spinal cord injuries (SCI). All 40 of the clinics surveyed reported that they were wheelchair accessible; however, there was significant variability in the number of sites that actually met the guidelines of the Americans with Disability Act. In general, a person using a wheelchair could enter the building, the examination room, and the bathroom. The majority of sites did not have an examination table that could be lowered to wheelchair level. Most reported limited experience in working with persons with (SCI), yet they claimed to be able to assist with difficult transfers. Only one site knew about autonomic dysreflexia. Problems of accessibility appeared to be seriously compounded by the clinics' perception of how they met physical accessibility guidelines without consideration of the actual needs of persons with SCI. This study addressed the perception of accessibility as reported by clinic managers versus actual accessibility in healthcare clinics in a Midwestern metropolitan area for persons using wheelchairs. PMID:10754921

  9. 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. PMID:18039565

  10. Drug Interactions in Dermatology: What the Dermatologist Should Know

    PubMed Central

    Coondoo, Arijit; Chattopadhyay, Chandan

    2013-01-01

    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. PMID:23918993

  11. 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. PMID:23918993

  12. Acute-onset rhabdomyolysis secondary to sitagliptin and atorvastatin interaction.

    PubMed

    Khan, Muhammad Waqas; Kurian, Saji; Bishnoi, Rohit

    2016-01-01

    Rhabdomyolysis is a serious medical condition in which the skeletal muscle tissue gets damaged and breaks down at rapid rates, potentially leading to death if not managed early on. Rhabdomyolysis in adults has several etiologies such as crush injuries, prolonged immobilization, strenuous exercise, hormonal or metabolic causes, infections, and drug-drug interactions. We present a case report of the interaction of two drugs that are used commonly in the general population. We here discuss a case of a 60-year-old female who presented to the hospital with complaints of generalized weakness, muscle aches, and atypical chest pain for a week after her primary care physician started her on sitagliptin while she was already on atorvastatin. After review of literature, this is the second known case of such an interaction causing acute breakdown of skeletal musculature. PMID:27199569

  13. 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. PMID:26033842

  14. 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.

  15. Time experiences, self-actualizing values, and creativity.

    PubMed

    Yonge, G D

    1975-12-01

    The Personal Orientation Inventory (POI), the Inventory of Temporal Experiences (ITE), and the Adjective Check List (ACL) were administered to 80 subjects. Sixteen scores were derived from the POI, 4 from the ITE and a Creativity score for the ACL. The resulting intercorrelations were interpreted in the light of the theories of Maslow and Hugenholtz which postulate a convergence of self-actualization, creativity, and certain experiences of time. The present study presents some evidence for the expected convergence and contributes to the construct validity of several of the variables studied. PMID:1202191

  16. 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.

  17. Interferometric measurement of actual oblique astigmatism of ophthalmic lenses

    NASA Astrophysics Data System (ADS)

    Wihardjo, Erning

    1995-03-01

    A technique for measuring oblique astigmatism error of ophthalmic lenses is described. The technique is based on a Mach-Zehnder interferometer, which allows us to simulate the actual conditions of the eye. The effects of the lens power, the pupilary aperture size and the viewing distance in calculating a projected pupil zone on the lens are discussed. The projected pupil size on the lens affects the measurement result of the oblique astigmatism error. Conversion of the interferogram to astigmatism error in diopters is given.

  18. 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.

  19. Actual Versus Predicted Cardiovascular Demands in Submaximal Cycle Ergometer Testing

    PubMed Central

    HOEHN, AMANDA M.; MULLENBACH, MEGAN J.; FOUNTAINE, CHARLES J.

    2015-01-01

    The Astrand-Rhyming cycle ergometer test (ARCET) is a commonly administered submaximal test for estimating aerobic capacity. Whereas typically utilized in clinical populations, the validity of the ARCET to predict VO2max in a non-clinical population, especially female, is less clear. Therefore, the purpose of this study was to determine the accuracy of the ARCET in a sample of healthy and physically active college students. Subjects (13 females, 10 males) performed a maximal cycle ergometer test to volitional exhaustion to determine VO2max. At least 48 hours later, subjects performed the ARCET protocol. Predicted VO2max was calculated following the ARCET format using the age corrected factor. There was no significant difference (p=.045) between actual (41.0±7.97 ml/kg/min) and predicted VO2max (40.3±7.58 ml/kg/min). When split for gender there was a significant difference between actual and predicted VO2 for males, (45.1±7.74 vs. 42.7±8.26 ml/kg/min, p=0.029) but no significant difference observed for females, (37.9±6.9 vs. 38.5±6.77 ml/kg/min, p=0.675). The correlation between actual and predicted VO2 was r=0.84, p<0.001 with an SEE= 4.3 ml/kg/min. When split for gender, the correlation for males was r=0.94, p<0.001, SEE=2.72 ml/kg/min; for females, r=0.74, p=0.004, SEE=4.67 ml/kg/min. The results of this study indicate that the ARCET accurately estimated VO2max in a healthy college population of both male and female subjects. Implications of this study suggest the ARCET can be used to assess aerobic capacity in both fitness and clinical settings where measurement via open-circuit spirometry is either unavailable or impractical. PMID:27182410

  20. Radioactive Doses - Predicted and Actual - and Likely Health Effects.

    PubMed

    Nagataki, S; Takamura, N

    2016-04-01

    Five years have passed since the nuclear accident at Fukushima Daiichi Nuclear Power Stations on 11 March 2011. Here we refer to reports from international organisations as sources of predicted values obtained from environmental monitoring and dose estimation models, and reports from various institutes in Japan are used as sources of individual actual values. The World Health Organization, based on information available up to 11 September 2011 (and published in 2012), reported that characteristic effective doses in the first year after the accident, to all age groups, were estimated to be in the 10-50 mSv dose band in example locations in evacuation areas. Estimated characteristic thyroid doses to infants in Namie Town were within the 100-200 mSv dose band. A report from the United Nations Scientific Committee on the Effects of Atomic Radiation published in 2014 shows that the effective dose received by adults in evacuation areas during the first year after the accident was 1.1-13 mSv. The absorbed dose to the thyroid in evacuated settlements was 7.2-35 mSv in adults and 15-83 mSv in 1-year-old infants. Individual external radiation exposure in the initial 4 months after the accident, estimated by superimposing individual behaviour data on to a daily dose rate map, was less than 3 mSv in 93.9% of residents (maximum 15 mSv) in evacuation areas. Actual individual thyroid equivalent doses were less than 15 mSv in 98.8% of children (maximum 25 mSv) in evacuation areas. When uncertainty exists in dose estimation models, it may be sensible to err on the side of caution, and final estimated doses are often much greater than actual radiation doses. However, overestimation of the dose at the time of an accident has a great influence on the psychology of residents. More than 100 000 residents have not returned to the evacuation areas 5 years after the Fukushima accident because of the social and mental effects during the initial period of the disaster. Estimates of

  1. 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.…

  2. 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.

  3. 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. PMID:20371254

  4. Actual leisure participation of Norwegian adolescents with Down syndrome.

    PubMed

    Dolva, Anne-Stine; Kleiven, Jo; Kollstad, Marit

    2014-02-01

    This article reports the actual participation in leisure activities by a sample of Norwegian adolescents with Down syndrome aged 14. Representing a first generation to grow up in a relatively inclusive context, they live with their families, attend mainstream schools, and are part of common community life. Leisure information was obtained in individual, structured parent interviews, and added to existing longitudinal data from a project following the sample. Generally, the leisure activity may be viewed as varying along a continuum-reaching from formal, organized, and assisted activity participation outside home, to informal, self-organized, and independent participation at home. Formal leisure activities were either organized "for all" or "adapted for disabled." The adolescents' leisure appears as active and social. However, social participation largely involved parents and family, while socializing with other adolescents mainly took place within formal activities adapted for disabled. Clearly, formal and informal activities provide rather different opportunities for social encounters and assistance. PMID:24515503

  5. 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

  6. Retrieved actual ET using SEBS model from Landsat-5 TM data for irrigation area of Australia

    NASA Astrophysics Data System (ADS)

    Ma, Weiqiang; Hafeez, Mohsin; Rabbani, Umair; Ishikawa, Hirohiko; Ma, Yaoming

    2012-11-01

    The idea of ground-based evapotranspiration (ET) is of the most interesting for land-atmosphere interactions, such as water-saving irrigation, the performance of irrigation systems, crop water deficit, drought mitigation strategies and accurate initialization of climate prediction models especially in arid and semiarid catchments where water shortage is a critical problem. The recent year's drought in Australia and concerns about climate change has prominent the need to manage water resources more sustainably especially in the Murrumbidgee catchment which utilizes bulk water for food security and production. This paper discusses the application of a Surface Energy Balance System (SEBS) model based on Landsat-5 TM data and field observations has been used and tested for deriving ET over Coleambally Irrigation Area (CIA), located in the southwest of NSW, Australia. 16 Landsat-5 TM scenes were selected covering the time period of 2009, 2010 and 2011 for estimating the actual ET in CIA. To do the validation the used methodology, the ground-measured ET was compared to the Landsat-5 TM retrieved actual ET results for CIA. The derived ET value over CIA is much closer to the field measurement. From the remote sensing results and observations, the root mean square error (RMSE) is 0.74 and the mean APD is 7.5%. The derived satellite remote sensing values belong to reasonable range.

  7. Official recommendations and actual practice in physiotherapy: managing troubles of physical performance.

    PubMed

    Parry, Ruth Helen

    2005-01-01

    This paper explores relations between official written recommendations for physiotherapists and actual practice. It does so by presenting and discussing findings from a conversation analytic study of 74 physiotherapy treatment sessions video-recorded in four English hospitals. Various practices are described by which therapists address troubles of ongoing or recent physical performance by patients during phases of sessions that are occupied with therapists' instructions in treatment activities and patients' physical responses. Divergence between practice and official guidance can be observed, particularly regarding recommendations that therapists always be unambiguous and clear in their communication with patients. Also, there seem to be conflicting demands between maintaining performance of physical treatment activities, whilst also spending time giving patients information and explanation about troubles of performance, and checking their understanding (as is recommended). There are also conflicting demands between individual recommendations. These observations inform a discussion of the wider challenges involved in formulating relevant, appropriate official guidance on communication practice. I argue that the difficulties of auditing actual conduct against official recommendations on interaction should be acknowledged, and that recommendations should be explicitly tentative and broad. Conversation analytic studies can provide resources and understandings to complement and augment such official guidance. PMID:16808720

  8. 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

  9. 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. PMID:26036354

  10. 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

  11. 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

  12. Gender, smiling, and witness credibility in actual trials.

    PubMed

    Nagle, Jacklyn E; Brodsky, Stanley L; Weeter, Kaycee

    2014-01-01

    It has been acknowledged that females exhibit more smiling behaviors than males, but there has been little attention to this gender difference in the courtroom. Although both male and female witnesses exhibit smiling behaviors, there has been no research examining the subsequent effect of gender and smiling on witness credibility. This study used naturalistic observation to examine smiling behaviors and credibility in actual witnesses testifying in court. Raters assessed the smiling behaviors and credibility (as measured by the Witness Credibility Scale) of 32 male and female witnesses testifying in trials in a mid-sized Southern city. "Credibility raters" rated the perceived likeability, trustworthiness, confidence, knowledge, and overall credibility of the witnesses using the Witness Credibility Scale. "Smile raters" noted smiling frequency and types, including speaking/expressive and listening/receptive smiles. Gender was found to affect perceived trustworthiness ratings, in which male witnesses were seen as more trustworthy than female witnesses. No significant differences were found in the smiling frequency for male and female witnesses. However, the presence of smiling was found to contribute to perceived likeability of a witness. Smiling female witnesses were found to be more likeable than smiling male and non-smiling female witnesses. PMID:24634058

  13. 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.

  14. A comprehensive approach to actual polychlorinated biphenyls environmental contamination.

    PubMed

    Risso, F; Magherini, A; Ottonelli, M; Magi, E; Lottici, S; Maggiolo, S; Garbarino, M; Narizzano, R

    2016-05-01

    Worldwide polychlorinated biphenyls (PCBs) pollution is due to complex mixtures with high number of congeners, making the determination of total PCBs in the environment an open challenge. Because the bulk of PCBs production was made of Aroclor mixtures, this analysis is usually faced by the empirical mixture identification via visual inspection of the chromatogram. However, the identification reliability is questionable, as patterns in real samples are strongly affected by the frequent occurrence of more than one mixture. Our approach is based on the determination of a limited number of congeners chosen to enable objective criteria for Aroclor identification, summing up the advantages of congener-specific analysis with the ones of total PCBs determination. A quantitative relationship is established between congeners and any single mixture, or mixtures combination, leading to the identification of the actual contamination composition. The approach, due to its generality, allows the use of different sets of congeners and any technical mixture, including the non-Aroclor ones. The results confirm that PCB environmental pollution in northern Italy is based on Aroclor. Our methodology represents an important tool to understand the source and fate of the PCBs contamination. PMID:26805927

  15. 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. PMID:26306163

  16. 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

  17. Lack of a pharmacokinetic interaction between trastuzumab and carboplatin in the presence of docetaxel: results from a phase Ib study in patients with HER2-positive metastatic or locally advanced inoperable solid tumors.

    PubMed

    Eppler, Stephen; Gordon, Michael S; Redfern, Charles H; Trudeau, Caroline; Xu, Na; Han, Kelong; Lum, Bert L

    2015-04-01

    The objective of this study was to evaluate the potential for a pharmacokinetic (PK) drug-drug interaction (DDI) between trastuzumab and carboplatin and to evaluate the potential effect of trastuzumab on the electrocardiogram QT interval. Here, we report the results of the PK DDI assessment and an interim safety analysis. Patients with metastatic or locally advanced, inoperable, human epidermal growth factor receptor 2-positive cancer received docetaxel and carboplatin on cycle 1, day 1 and then on day 1 of each subsequent 3-weekly treatment cycle. Trastuzumab was administered by intravenous infusion, with an accelerated loading dose on cycle 1, day 2 and cycle 1, day 8, and then a maintenance dose on day 1 of each subsequent 3-weekly treatment cycle. Blood was collected at various time points to assess free (unbound) plasma carboplatin and serum trastuzumab PK. The study enrolled 59 patients. Carboplatin concentrations in the presence and absence of trastuzumab were similar, as demonstrated by the geometric mean ratios for PK parameters, which were close to 1.0 (no effect). The observed trastuzumab concentrations were similar to the values predicted by population PK modelling on the basis of a prediction-corrected visual predictive check, computed using the actual sampling time. In this interim safety analysis, 84.5% of patients had experienced adverse events of grade three or higher, the most common of which were hematologic and as expected. The results suggest that there is no clinically relevant PK DDI between carboplatin and trastuzumab. The safety profile of trastuzumab plus carboplatin and docetaxel was consistent with the known safety profile of this combination. PMID:25643049

  18. 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.

  19. Are presolar dust grains from novae actually from supernovae?

    NASA Astrophysics Data System (ADS)

    Nittler, L. R.; Hoppe, P.

    2005-05-01

    Meteorites contain presolar stardust grains that formed in prior generations of stars and exhibit large isotopic anomalies reflecting the nuclear processes that occurred in their individual parent stars. RGB and AGB stars and supernovae are well established as sources of many of these grains. Novae have been proposed as sources for a few SiC and graphite grains with low 12}C/{13C and 14}N/{15N ratios and unusual Si isotopic ratios (Amari et al., ApJ, 551, 1065). We have found three SiC grains from the Murchison meteorite with C and N isotopic ratios similar to the previously-reported putative nova grains. However, the isotopic signatures of Si, Ca, Al and Ti in one of the grains (334-2) clearly indicate a supernova origin, especially excess 28Si correlated with excess 44Ca. The latter signature is attributable to in situ decay of (half-life=50yr) 44Ti. Another 13C- and 15N-rich grain (151-4) has a large 47Ti enrichment. This signature is not expected for nova nucleosynthesis. Thus, the new isotopic data raise the possibility that the grains previously reported to have formed in novae actually formed in supernovae, and that novae have not left a record in the presolar grain populations that have been so far studied. Moreover, the results in grain 334-2 indicate that supernovae contain regions highly enriched in both 13C and 15N. This is not predicted by current models but may bear on the cosmic origin of 15N. This work was funded in part by NASA.

  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. Comparison of predicted and actual consequences of missense mutations.

    PubMed

    Miosge, Lisa A; Field, Matthew A; Sontani, Yovina; Cho, Vicky; Johnson, Simon; Palkova, Anna; Balakishnan, Bhavani; Liang, Rong; Zhang, Yafei; Lyon, Stephen; Beutler, Bruce; Whittle, Belinda; Bertram, Edward M; Enders, Anselm; Goodnow, Christopher C; Andrews, T Daniel

    2015-09-15

    Each person's genome sequence has thousands of missense variants. Practical interpretation of their functional significance must rely on computational inferences in the absence of exhaustive experimental measurements. Here we analyzed the efficacy of these inferences in 33 de novo missense mutations revealed by sequencing in first-generation progeny of N-ethyl-N-nitrosourea-treated mice, involving 23 essential immune system genes. PolyPhen2, SIFT, MutationAssessor, Panther, CADD, and Condel were used to predict each mutation's functional importance, whereas the actual effect was measured by breeding and testing homozygotes for the expected in vivo loss-of-function phenotype. Only 20% of mutations predicted to be deleterious by PolyPhen2 (and 15% by CADD) showed a discernible phenotype in individual homozygotes. Half of all possible missense mutations in the same 23 immune genes were predicted to be deleterious, and most of these appear to become subject to purifying selection because few persist between separate mouse substrains, rodents, or primates. Because defects in immune genes could be phenotypically masked in vivo by compensation and environment, we compared inferences by the same tools with the in vitro phenotype of all 2,314 possible missense variants in TP53; 42% of mutations predicted by PolyPhen2 to be deleterious (and 45% by CADD) had little measurable consequence for TP53-promoted transcription. We conclude that for de novo or low-frequency missense mutations found by genome sequencing, half those inferred as deleterious correspond to nearly neutral mutations that have little impact on the clinical phenotype of individual cases but will nevertheless become subject to purifying selection. PMID:26269570

  2. Comparison of predicted and actual consequences of missense mutations

    PubMed Central

    Miosge, Lisa A.; Field, Matthew A.; Sontani, Yovina; Cho, Vicky; Johnson, Simon; Palkova, Anna; Balakishnan, Bhavani; Liang, Rong; Zhang, Yafei; Lyon, Stephen; Beutler, Bruce; Whittle, Belinda; Bertram, Edward M.; Enders, Anselm; Goodnow, Christopher C.; Andrews, T. Daniel

    2015-01-01

    Each person’s genome sequence has thousands of missense variants. Practical interpretation of their functional significance must rely on computational inferences in the absence of exhaustive experimental measurements. Here we analyzed the efficacy of these inferences in 33 de novo missense mutations revealed by sequencing in first-generation progeny of N-ethyl-N-nitrosourea–treated mice, involving 23 essential immune system genes. PolyPhen2, SIFT, MutationAssessor, Panther, CADD, and Condel were used to predict each mutation’s functional importance, whereas the actual effect was measured by breeding and testing homozygotes for the expected in vivo loss-of-function phenotype. Only 20% of mutations predicted to be deleterious by PolyPhen2 (and 15% by CADD) showed a discernible phenotype in individual homozygotes. Half of all possible missense mutations in the same 23 immune genes were predicted to be deleterious, and most of these appear to become subject to purifying selection because few persist between separate mouse substrains, rodents, or primates. Because defects in immune genes could be phenotypically masked in vivo by compensation and environment, we compared inferences by the same tools with the in vitro phenotype of all 2,314 possible missense variants in TP53; 42% of mutations predicted by PolyPhen2 to be deleterious (and 45% by CADD) had little measurable consequence for TP53-promoted transcription. We conclude that for de novo or low-frequency missense mutations found by genome sequencing, half those inferred as deleterious correspond to nearly neutral mutations that have little impact on the clinical phenotype of individual cases but will nevertheless become subject to purifying selection. PMID:26269570

  3. 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

  4. Pharmacokinetics and interactions of headache medications, part II: prophylactic treatments.

    PubMed

    Sternieri, Emilio; Coccia, Ciro Pio Rosario; Pinetti, Diego; Guerzoni, Simona; Ferrari, Anna

    2006-12-01

    The present part II review highlights pharmacokinetic drug-drug interactions (excluding those of minor severity) of medications used in prophylactic treatment of the main primary headaches (migraine, tension-type and cluster headache). The principles of pharmacokinetics and metabolism, and the interactions of medications for acute treatment are examined in part I. The overall goal of this series of two reviews is to increase the awareness of physicians, primary care providers and specialists regarding pharmacokinetic drug-drug interactions (DDIs) of headache medications. The aim of prophylactic treatment is to reduce the frequency of headache attacks using beta-blockers, calcium-channel blockers, antidepressants, antiepileptics, lithium, serotonin antagonists, corticosteroids and muscle relaxants, which must be taken daily for long periods. During treatment the patient often continues to take symptomatic drugs for the attack, and may need other medications for associated or new-onset illnesses. DDIs can, therefore, occur. As a whole, DDIs of clinical relevance concerning prophylactic drugs are a limited number. Their effects can be prevented by starting the treatment with low dosages, which should be gradually increased depending on response and side effects, while frequently monitoring the patient and plasma levels of other possible coadministered drugs with a narrow therapeutic range. Most headache medications are substrates of CYP2D6 (e.g., beta-blockers, antidepressants) or CYP3A4 (e.g., calcium-channel blockers, selective serotonin re-uptake inhibitors, corticosteroids). The inducers and, especially, the inhibitors of these isoenzymes should be carefully coadministered. PMID:17125412

  5. 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)

  6. The BCI competition. III: Validating alternative approaches to actual BCI problems.

    PubMed

    Blankertz, Benjamin; Müller, Klaus-Robert; Krusienski, Dean J; Schalk, Gerwin; Wolpaw, Jonathan R; Schlögl, Alois; Pfurtscheller, Gert; Millán, José del R; Schröder, Michael; Birbaumer, Niels

    2006-06-01

    A brain-computer interface (BCI) is a system that allows its users to control external devices with brain activity. Although the proof-of-concept was given decades ago, the reliable translation of user intent into device control commands is still a major challenge. Success requires the effective interaction of two adaptive controllers: the user's brain, which produces brain activity that encodes intent, and the BCI system, which translates that activity into device control commands. In order to facilitate this interaction, many laboratories are exploring a variety of signal analysis techniques to improve the adaptation of the BCI system to the user. In the literature, many machine learning and pattern classification algorithms have been reported to give impressive results when applied to BCI data in offline analyses. However, it is more difficult to evaluate their relative value for actual online use. BCI data competitions have been organized to provide objective formal evaluations of alternative methods. Prompted by the great interest in the first two BCI Competitions, we organized the third BCI Competition to address several of the most difficult and important analysis problems in BCI research. The paper describes the data sets that were provided to the competitors and gives an overview of the results. PMID:16792282

  7. 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.

  8. 45 CFR 73.735-904 - Resolution of apparent or actual conflicts of interest.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 45 Public Welfare 1 2011-10-01 2011-10-01 false Resolution of apparent or actual conflicts of... ADMINISTRATION STANDARDS OF CONDUCT Reporting Financial Interests § 73.735-904 Resolution of apparent or actual... disqualification is employed to resolve an apparent or actual conflict of interest, the disqualified employee...

  9. 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 SYSTEM TRUTH IN LENDING (REGULATION Z) Pt. 226, App. M2 Appendix M2 to Part 226—Actual Repayment Disclosures (a) Calculating actual...

  10. 7 CFR 400.51 - Availability of actual production history program.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... History § 400.51 Availability of actual production history program. An Actual Production History (APH) Coverage Program is offered under the provisions contained in the following regulations: 7 CFR part 457... 7 Agriculture 6 2012-01-01 2012-01-01 false Availability of actual production history program....

  11. 7 CFR 400.51 - Availability of actual production history program.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... History § 400.51 Availability of actual production history program. An Actual Production History (APH) Coverage Program is offered under the provisions contained in the following regulations: 7 CFR part 457... 7 Agriculture 6 2014-01-01 2014-01-01 false Availability of actual production history program....

  12. 7 CFR 400.51 - Availability of actual production history program.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... History § 400.51 Availability of actual production history program. An Actual Production History (APH) Coverage Program is offered under the provisions contained in the following regulations: 7 CFR part 457... 7 Agriculture 6 2013-01-01 2013-01-01 false Availability of actual production history program....

  13. 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…

  14. 7 CFR 400.51 - Availability of actual production history program.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... History § 400.51 Availability of actual production history program. An Actual Production History (APH) Coverage Program is offered under the provisions contained in the following regulations: 7 CFR part 457... 7 Agriculture 6 2011-01-01 2011-01-01 false Availability of actual production history program....

  15. 7 CFR 400.55 - Qualification for actual production history coverage program.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 6 2010-01-01 2010-01-01 false Qualification for actual production history coverage... Production History § 400.55 Qualification for actual production history coverage program. (a) The approved... history is certified and T or D-Yields are not provided in the actuarial documents, (2) If actual...

  16. 7 CFR 400.51 - Availability of actual production history program.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... History § 400.51 Availability of actual production history program. An Actual Production History (APH) Coverage Program is offered under the provisions contained in the following regulations: 7 CFR part 457... 7 Agriculture 6 2010-01-01 2010-01-01 false Availability of actual production history program....

  17. 26 CFR 1.544-6 - Constructive ownership as actual ownership.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 7 2014-04-01 2013-04-01 true Constructive ownership as actual ownership. 1.544... ownership as actual ownership. (a) General rules. (1) Stock constructively owned by a person by reason of... individual, shall be considered as actually owned by such person for the purpose of again applying such...

  18. 48 CFR 52.222-32 - Davis-Bacon Act-Price Adjustment (Actual Method).

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Adjustment (Actual Method). 52.222-32 Section 52.222-32 Federal Acquisition Regulations System FEDERAL... Provisions and Clauses 52.222-32 Davis-Bacon Act—Price Adjustment (Actual Method). As prescribed in 22.407(g), insert the following clause: Davis-Bacon Act—Price Adjustment (Actual Method) (DEC 2001) (a) The...

  19. 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... (actual method). Public comments are particularly invited on: Whether this collection of information is... comments identified by Information Collection 9000- 0154, Davis Bacon Act--Price Adjustment (Actual...

  20. 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

  1. Pharmacokinetic interactions of cimetidine 1987.

    PubMed

    Somogyi, A; Muirhead, M

    1987-05-01

    The number of studies on drug interactions with cimetidine has increased at a rapid rate over the past 5 years, with many of the interactions being solely pharmacokinetic in origin. Very few studies have investigated the clinical relevance of such pharmacokinetic interactions by measuring pharmacodynamic responses or clinical endpoints. Apart from pharmacokinetic studies, invariably conducted in young, healthy subjects, there have been a large number of in vitro and in vivo animal studies, case reports, clinical observations and general reviews on the subject, which is tending to develop an industry of its own accord. Nevertheless, where specific mechanisms have been considered, these have undoubtedly increased our knowledge on the way in which humans eliminate xenobiotics. There is now sufficient information to predict the likelihood of a pharmacokinetic drug-drug interaction with cimetidine and to make specific clinical recommendations. Pharmacokinetic drug interactions with cimetidine occur at the sites of gastrointestinal absorption and elimination including metabolism and excretion. Cimetidine has been found to reduce the plasma concentrations of ketoconazole, indomethacin and chlorpromazine by reducing their absorption. In the case of ketoconazole the interaction was clinically important. Cimetidine does not inhibit conjugation mechanisms including glucuronidation, sulphation and acetylation, or deacetylation or ethanol dehydrogenation. It binds to the haem portion of cytochrome P-450 and is thus an inhibitor of phase I drug metabolism (i.e. hydroxylation, dealkylation). Although generally recognised as a nonspecific inhibitor of this type of metabolism, cimetidine does demonstrate some degree of specificity. To date, theophylline 8-oxidation, tolbutamide hydroxylation, ibuprofen hydroxylation, misonidazole demethylation, carbamazepine epoxidation, mexiletine oxidation and steroid hydroxylation have not been shown to be inhibited by cimetidine in humans but

  2. Alka Seltzer Poppers: An Interactive Exploration.

    ERIC Educational Resources Information Center

    Sarquis, A. M.; Woodward, L. M.

    1999-01-01

    Using questioning strategies to involve students in actually doing and analyzing experimental design can offer useful insights to instructors and students alike. Describes an interactive exploration of Alka Seltzer. (CCM)

  3. Drug Interactions: What You Should Know

    MedlinePlus

    ... you still have questions after reading the drug product label, ask your doctor or pharmacist for more information ... not take the place of reading the actual product label. Back to top Drug Interaction Information Category Drug ...

  4. [The interactions between natural products and OATP1B1].

    PubMed

    Shi, Mei-zhi; Liu, Yu; Bian, Jia-lin; Jin, Meng; Gui, Chun-shan

    2015-07-01

    Organic anion transporting polypeptide 1B1 (OATP1B1) is an important liver-specific uptake transporter, which mediates transport of numerous endogenous substances and drugs from blood into hepatocytes. To identify and investigate potential modulators of OATP1B1 from natural products, the effect of 21 frequently used natural compounds and extracts on OATP1B1-mediated fluorescein methotrexate transport was studied by using Chinese hamster ovary cells stably expressing OATP1B1 (CHO-OATP1B1) in 96-well plates. This method could be used for the screening of large compound libraries. Our studies showed that some flavonoids (e.g., quercetin, quercitrin, rutin, chrysanthemum flavonoids and mulberrin) and triterpenoids (e.g., glycyrrhetinic acid and glycyrrhizic acid) were inhibitors of OATP1B1 with IC50 values less than 16 µmol · L(-1). The IC50 value of glycyrrhetinic acid on OATP1B1 was comparable to its blood concentration in clinics, indicating an OATPlB1-mediated drug-drug interaction could occur. Structure-activity relationship analysis showed that flavonoids had much higher inhibitory activity than their glycosides. Furthermore, the type and length of saccharides had a significant effect on their activity. In addition, we used OATP1B1 substrates fluvastatin and rosuvastatin as probe drugs to investigate the substrate-dependent effect of several natural compounds on the function of OATP1B1 in vitro. Our results demonstrated that the effect of these natural products on the function of OATPlB1 was substrate-dependent. In summary, this study would be conducive to predicting and avoiding potential OATP1B1-mediated drug-drug and drug-food interactions and thus provide the experimental basis and guidance for rational drug use. PMID:26552146

  5. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models.

    PubMed

    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 . PMID:27167132

  6. Drug Interactions and Antiretroviral Drug Monitoring

    PubMed Central

    Foy, Matthew; Sperati, C. John; Lucas, Gregory M.

    2014-01-01

    Due to the improved longevity afforded by combination antiretroviral therapy (cART), HIV-infected individuals are developing several non-AIDS related comorbid conditions. Consequently, medical management of the HIV-infected population is increasingly complex, with a growing list of potential drug-drug interactions (DDIs). This article reviews some of the most relevant and emerging potential interactions between antiretroviral medications and other agents. The most common DDIs are those involving protease inhibitors or non-nucleoside reverse transcriptase inhibitors which alter the cytochrome P450 enzyme system and/or drug transporters such as p-glycoprotein. Of note are the new agents for the treatment of chronic hepatitis C virus infection. These new classes of drugs and others drugs which are increasingly used in this patient population represent a significant challenge with regard to achieving the goals of effective HIV suppression and minimization of drug-related toxicities. Awareness of DDIs and a multidisciplinary approach are imperative in reaching these goals. PMID:24950731

  7. Clinically relevant drug interactions between anticancer drugs and psychotropic agents.

    PubMed

    Yap, K Y-L; Tay, W L; Chui, W K; Chan, A

    2011-01-01

    Drug interactions are commonly seen in the treatment of cancer patients. Psychotropics are often indicated for these patients since they may also suffer from pre-existing psychological disorders or experience insomnia and anxiety associated with cancer therapy. Thus, the risk of anticancer drug (ACD)-psychotropic drug-drug interactions (DDIs) is high. Drug interactions were compiled from the British National Formulary (53rd edn), Lexi-Comp's Drug Information Handbook (15th edn), Micromedex (v5.1), Hansten & Horn's Drug Interactions (2000) and Drug Interaction Facts (2008 edn). Product information of the individual drugs, as well as documented literature on ACD-psychotropic interactions from PubMed and other databases was also incorporated. This paper identifies clinically important ACD-psychotropic DDIs that are frequently observed. Pharmacokinetic DDIs were observed for tyrosine kinase inhibitors, corticosteroids and antimicrotubule agents due to their inhibitory or inductive effects on cytochrome P450 isoenzymes. Pharmacodynamic DDIs were identified for thalidomide with central nervous system depressants, procarbazine with antidepressants, myelosuppressive ACDs with clozapine and anthracyclines with QT-prolonging psychotropics. Clinicians should be vigilant when psychotropics are prescribed concurrently with ACDs. Close monitoring of plasma drug levels should be carried out to avoid toxicity in the patient, as well as to ensure adequate chemotherapeutic and psychotropic coverage. PMID:20030690

  8. 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

  9. Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions.

    PubMed

    Backman, Janne T; Filppula, Anne M; Niemi, Mikko; Neuvonen, Pertti J

    2016-01-01

    During the last 10-15 years, cytochrome P450 (CYP) 2C8 has emerged as an important drug-metabolizing enzyme. CYP2C8 is highly expressed in human liver and is known to metabolize more than 100 drugs. CYP2C8 substrate drugs include amodiaquine, cerivastatin, dasabuvir, enzalutamide, imatinib, loperamide, montelukast, paclitaxel, pioglitazone, repaglinide, and rosiglitazone, and the number is increasing. Similarly, many drugs have been identified as CYP2C8 inhibitors or inducers. In vivo, already a small dose of gemfibrozil, i.e., 10% of its therapeutic dose, is a strong, irreversible inhibitor of CYP2C8. Interestingly, recent findings indicate that the acyl-β-glucuronides of gemfibrozil and clopidogrel cause metabolism-dependent inactivation of CYP2C8, leading to a strong potential for drug interactions. Also several other glucuronide metabolites interact with CYP2C8 as substrates or inhibitors, suggesting that an interplay between CYP2C8 and glucuronides is common. Lack of fully selective and safe probe substrates, inhibitors, and inducers challenges execution and interpretation of drug-drug interaction studies in humans. Apart from drug-drug interactions, some CYP2C8 genetic variants are associated with altered CYP2C8 activity and exhibit significant interethnic frequency differences. Herein, we review the current knowledge on substrates, inhibitors, inducers, and pharmacogenetics of CYP2C8, as well as its role in clinically relevant drug interactions. In addition, implications for selection of CYP2C8 marker and perpetrator drugs to investigate CYP2C8-mediated drug metabolism and interactions in preclinical and clinical studies are discussed. PMID:26721703

  10. Interactions between photodegradation components

    PubMed Central

    2012-01-01

    Background The interactions of p-cresol photocatalytic degradation components were studied by response surface methodology. The study was designed by central composite design using the irradiation time, pH, the amount of photocatalyst and the p-cresol concentration as variables. The design was performed to obtain photodegradation % as actual responses. The actual responses were fitted with linear, two factor interactions, cubic and quadratic model to select an appropriate model. The selected model was validated by analysis of variance which provided evidences such as high F-value (845.09), very low P-value (<.0.0001), non-significant lack of fit, the coefficient of R-squared (R2 = 0.999), adjusted R-squared (Radj2 = 0.998), predicted R-squared (Rpred2 = 0.994) and the adequate precision (95.94). Results From the validated model demonstrated that the component had interaction with irradiation time under 180 min of the time while the interaction with pH was above pH 9. Moreover, photocatalyst and p-cresol had interaction at minimal amount of photocatalyst (< 0.8 g/L) and 100 mg/L p-cresol. Conclusion These variables are interdependent and should be simultaneously considered during the photodegradation process, which is one of the advantages of the response surface methodology over the traditional laboratory method. PMID:22967885

  11. 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

  12. 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.

  13. [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. PMID:10875058

  14. 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

  15. Iatrogenic cushing syndrome secondary to a probable interaction between voriconazole and budesonide.

    PubMed

    Jones, Whitney; Chastain, Cody A; Wright, Patty W

    2014-07-01

    Oral budesonide is commonly used for the management of Crohn's disease given its high affinity for glucocorticoid receptors and low systemic activity due to extensive first-pass metabolism through hepatic cytochrome P450 (CYP) 3A4. Voriconazole, a second-generation triazole antifungal agent, is both a substrate and potent inhibitor of CYP isoenzymes, specifically CYP2C19, CYP2C9, and CYP3A4; thus, the potential for drug-drug interactions with voriconazole is high. To our knowledge, drug-drug interactions between voriconazole and corticosteroids have not been specifically reported in the literature. We describe a 48-year-old woman who was receiving oral budesonide 9 mg/day for the management of Crohn's disease and was diagnosed with fluconazole-resistant Candida albicans esophagitis; oral voriconazole 200 mg every 12 hours for 3 weeks was prescribed for treatment. Because the patient experienced recurrent symptoms of dysphagia, a second 3-week course of voriconazole therapy was taken. Seven weeks after originally being prescribed voriconazole, she came to her primary care clinic with elevated blood pressure, lower extremity edema, and weight gain; she was prescribed a diuretic and evaluated for renal dysfunction. At a follow-up visit 6 weeks later with her specialty clinic, the patient's blood pressure was elevated, and her physical examination was notable for moon facies, posterior cervical fat pad prominence, and lower extremity pitting edema. Iatrogenic Cushing syndrome due to a drug-drug interaction between voriconazole and budesonide was suspected, and voriconazole was discontinued. Budesonide was continued as previously prescribed for her Crohn's disease. On reevaluation 2 months later, the patient's Cushingoid features had markedly regressed. To our knowledge, this is the first published case report of iatrogenic Cushing syndrome due to a probable interaction between voriconazole and oral budesonide. In patients presenting with Cushingoid features who

  16. 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

  17. 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

  18. 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

  19. A Researcher's Dilemma: A Comparison of Estimated versus Actual College G.P.A.

    ERIC Educational Resources Information Center

    Herman, William E.; Nelson, Gena C.

    2009-01-01

    This study compared college student reported grade point averages (GPA) with actual GPA as recorded at the Registrar's Office to determine the accuracy of student reported GPA. Results indicated that, on average, students reported slightly higher GPA than their actual GPA. Additionally, females were virtually as accurate as males and students with…

  20. 48 CFR 52.222-32 - Davis-Bacon Act-Price Adjustment (Actual Method).

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... ACQUISITION REGULATION (CONTINUED) CLAUSES AND FORMS SOLICITATION PROVISIONS AND CONTRACT CLAUSES Text of... work. For each labor classification, the difference between the actual wage and benefit rates (combined... classification, the difference between the actual wage and benefit rates (combined) paid and the wage and...

  1. Characteristics of the Self-Actualized Person: Visions from the East and West.

    ERIC Educational Resources Information Center

    Chang, Raylene; Page, Richard C.

    1991-01-01

    Compares and contrasts the ways that Chinese Taoism and Zen Buddhism view the development of human potential with the ways that the self-actualization theories of Rogers and Maslow describe the human potential movement. Notes many similarities between the ways that Taoism, Zen Buddhism, and the self-actualization theories of Rogers and Maslow…

  2. 45 CFR 73.735-904 - Resolution of apparent or actual conflicts of interest.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Resolution of apparent or actual conflicts of interest. 73.735-904 Section 73.735-904 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION STANDARDS OF CONDUCT Reporting Financial Interests § 73.735-904 Resolution of apparent or actual conflicts of interest....

  3. Self-Actualizations and Experience with Zen Meditation: Is a Learning Period Necessary for Meditation?

    ERIC Educational Resources Information Center

    Compton, William C.; Becker, Gordon M.

    1983-01-01

    Investigated the relationship between the practice of Zen meditation and a measure of self-actualization in experienced (N=36) and inexperienced (N=34) meditator groups. Analysis of data showed that a learning period (or selection period) exists for Zen meditation during which there is no increase in group self-actualization. (LLL)

  4. 41 CFR 301-11.300 - When is actual expense reimbursement warranted?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 41 Public Contracts and Property Management 4 2011-07-01 2011-07-01 false When is actual expense reimbursement warranted? 301-11.300 Section 301-11.300 Public Contracts and Property Management Federal Travel Regulation System TEMPORARY DUTY (TDY) TRAVEL ALLOWANCES ALLOWABLE TRAVEL EXPENSES 11-PER DIEM EXPENSES Actual Expense § 301-11.300 When...

  5. 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 Regulation System TEMPORARY DUTY (TDY) TRAVEL ALLOWANCES ALLOWABLE TRAVEL EXPENSES 11-PER DIEM EXPENSES Actual Expense § 301-11.300 When...

  6. 49 CFR 24.301 - Payment for actual reasonable moving and related expenses.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... mobile home, but may be eligible for a payment for moving personal property from the mobile home. (b... 49 Transportation 1 2011-10-01 2011-10-01 false Payment for actual reasonable moving and related... Related Expenses § 24.301 Payment for actual reasonable moving and related expenses. (a) General. (1)...

  7. 26 CFR 1.544-6 - Constructive ownership as actual ownership.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Constructive ownership as actual ownership. 1.544... ownership as actual ownership. (a) General rules. (1) Stock constructively owned by a person by reason of... reason of the application of the option rule provided in section 544(a)(3) shall be considered...

  8. 26 CFR 1.318-4 - Constructive ownership as actual ownership; exceptions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 4 2010-04-01 2010-04-01 false Constructive ownership as actual ownership... Constructive ownership as actual ownership; exceptions. (a) In general. Section 318(a)(5)(A) provides that... B are beneficiaries of a trust and the trust has an option to buy stock from A, B is...

  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. 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…

  11. 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...

  12. 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...

  13. 26 CFR 1.6041-5 - Information as to actual owner.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 13 2010-04-01 2010-04-01 false Information as to actual owner. 1.6041-5 Section 1.6041-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Information Returns § 1.6041-5 Information as to actual owner. When...

  14. 26 CFR 1.6041-5 - Information as to actual owner.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 13 2012-04-01 2012-04-01 false Information as to actual owner. 1.6041-5 Section 1.6041-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Information Returns § 1.6041-5 Information as to actual...

  15. 26 CFR 1.6041-5 - Information as to actual owner.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 13 2013-04-01 2013-04-01 false Information as to actual owner. 1.6041-5 Section 1.6041-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Information Returns § 1.6041-5 Information as to actual...

  16. 40 CFR 63.5335 - How do I determine the actual HAP loss?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... (CONTINUED) National Emission Standards for Hazardous Air Pollutants for Leather Finishing Operations... information and procedures you must use to determine the actual HAP loss from your leather finishing operation. By the fifteenth of each month, you must determine the actual HAP loss in pounds from your...

  17. Evaluating Empathy in Interviewing: Comparing Self-Report with Actual Behavior.

    ERIC Educational Resources Information Center

    Tamburrino, Marijo B.; And Others

    1993-01-01

    A study compared medical students' self-assessments of patient interview behavior with external ratings of actual interviews. Focus was on behaviors reflecting empathy. Results suggest the self-report questionnaire is not an adequate measure of actual interviewing skills. (MSE)

  18. 30 CFR 1206.180 - How do I determine an actual processing allowance?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 3 2013-07-01 2013-07-01 false How do I determine an actual processing allowance? 1206.180 Section 1206.180 Mineral Resources OFFICE OF NATURAL RESOURCES REVENUE, DEPARTMENT OF THE INTERIOR NATURAL RESOURCES REVENUE PRODUCT VALUATION Indian Gas Processing Allowances § 1206.180 How do I determine an actual processing...

  19. 27 CFR 19.35 - Application of effective tax rate (Actual).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... tax rate (Actual). 19.35 Section 19.35 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX... Rates § 19.35 Application of effective tax rate (Actual). Any proprietor who does not apply effective... tax rate for each batch of distilled spirits in the processing account on which credit against tax...

  20. Correlates of Counselor Self-Actualization and Client-Perceived Facilitativeness

    ERIC Educational Resources Information Center

    Selfridge, Fred F.; Vander Kolk, Charles

    1976-01-01

    Client ratings of the abilities of 33 school counselors to communicate the core facilitative conditions of empathy, regard, congruence, and trust are compared to the counselors' scores on a measure of self-actualization. Results support the contention that there exists a strong relationship between self-actualization and counselor effectiveness as…

  1. 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.

  2. 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. PMID:3196077

  3. Utility of population pharmacokinetic modeling in the assessment of therapeutic protein-drug interactions.

    PubMed

    Chow, Andrew T; Earp, Justin C; Gupta, Manish; Hanley, William; Hu, Chuanpu; Wang, Diane D; Zajic, Stefan; Zhu, Min

    2014-05-01

    Assessment of pharmacokinetic (PK) based drug-drug interactions (DDI) is essential for ensuring patient safety and drug efficacy. With the substantial increase in therapeutic proteins (TP) entering the market and drug development, evaluation of TP-drug interaction (TPDI) has become increasingly important. Unlike for small molecule (e.g., chemical-based) drugs, conducting TPDI studies often presents logistical challenges, while the population PK (PPK) modeling may be a viable approach dealing with the issues. A working group was formed with members from the pharmaceutical industry and the FDA to assess the utility of PPK-based TPDI assessment including study designs, data analysis methods, and implementation strategy. This paper summarizes key issues for consideration as well as a proposed strategy with focuses on (1) PPK approach for exploratory assessment; (2) PPK approach for confirmatory assessment; (3) importance of data quality; (4) implementation strategy; and (5) potential regulatory implications. Advantages and limitations of the approach are also discussed. PMID:24272952

  4. [Drug Interactions and Pharmacokinetics of Psychotropic Drugs].

    PubMed

    Suzuki, Eiji

    2015-01-01

    Pharmacokinetics is the field dedicated to investigating the absorption, distribution, metabolism and excretion of drugs. Absorption of drugs is affected when they are taken together with a meal. Depending on the drug, the area under the concentration curve is affected by whether a medication is taken before or after a meal. Combined use of drugs with a high plasma protein binding fraction may be dangerous, since drug efficacy is impacted by efficiency, which in turn is affected by the degree to which it binds to proteins. Even more significant is the issue of "drug/drug" interactions that arise due to inhibition of the cytochrome P450 (CYP) hepatic microsomal enzyme system. Some antidepressants, such as paroxetine and fluvoxamine, are strong inhibitors of the CYP system. In the case of a medication that depends on renal clearance for elimination, caution is required when taking such a drug if it influences renal function. When a medicinal effect changes, pharmacodynamic changes must also be considered. PMID:26514046

  5. Do CS-US Pairings Actually Matter? A Within-Subject Comparison of Instructed Fear Conditioning with and without Actual CS-US Pairings

    PubMed Central

    Raes, An K.; De Houwer, Jan; De Schryver, Maarten; Brass, Marcel; Kalisch, Raffael

    2014-01-01

    Previous research showed that instructions about CS-US pairings can lead to fear of the CS even when the pairings are never presented. In the present study, we examined whether the experience of CS-US pairings adds to the effect of instructions by comparing instructed conditioning with and without actual CS-US pairings in a within-subject design. Thirty-two participants saw three fractals as CSs (CS+1, CS+2, CS−) and received electric shocks as USs. Before the start of a so-called training phase, participants were instructed that both CS+1 and CS+2 would be followed by the US, but only CS+1 was actually paired with the US. The absence of the US after CS+2 was explained in such a way that participants would not doubt the instructions about the CS+2-US relation. After the training phase, a test phase was carried out. In this phase, participants expected the US after both CS+s but none of the CS+s was actually paired with the US. During test, self-reported fear was initially higher for CS+1 than for CS+2, which indicates that the experience of actual CS-US pairings adds to instructions about these pairings. On the other hand, the CS+s elicited similar skin conductance responses and US expectancies. Theoretical and clinical implications are discussed. PMID:24465447

  6. Drug-resin drug interactions in patients with delayed gastric emptying: What is optimal time window for drug administration?

    PubMed

    Camilleri, M

    2016-08-01

    Most drug-drug interactions involve overlap or competition in drug metabolic pathways. However, there are medications, typically resins, whose function is to bind injurious substances such as bile acids or potassium within the digestive tract. The objective of this article is to review the functions of the stomach and the kinetics of emptying of different food forms or formulations to make recommendations on timing of medication administration in order to avoid intragastric drug interactions. Based on the profiles and kinetics of emptying of liquid nutrients and homogenized solids, a window of 3 h between administration of a resin drug and another 'target' medication would be expected to allow a median of 80% of medications with particle size <1 mm to empty from the stomach and, hence, avoid potential interaction such as binding of the 'target' medication within the stomach. PMID:26987693

  7. The nonrelativistic limit of (central-extended) Poincare group and some consequences for quantum actualization

    SciTech Connect

    Ardenghi, Juan S.; Castagnino, M.; Campoamor-Stursberg, R.

    2009-10-15

    The nonrelativistic limit of the centrally extended Poincare group is considered and their consequences in the modal Hamiltonian interpretation of quantum mechanics are discussed [O. Lombardi and M. Castagnino, Stud. Hist. Philos. Mod. Phys 39, 380 (2008); J. Phys, Conf. Ser. 128, 012014 (2008)]. Through the assumption that in quantum field theory the Casimir operators of the Poincare group actualize, the nonrelativistic limit of the latter group yields to the actualization of the Casimir operators of the Galilei group, which is in agreement with the actualization rule of previous versions of modal Hamiltonian interpretation [Ardenghi et al., Found. Phys. (submitted)].

  8. 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. PMID:24933175

  9. From potential donor to actual donation: does socioeconomic position affect living kidney donation? A systematic review of the evidence.

    PubMed

    Bailey, Phillippa; Tomson, Charles; Risdale, Saira; Ben-Shlomo, Yoav

    2014-11-15

    Evidence from Europe, Australia and the United States demonstrates that socioeconomically deprived individuals with advanced chronic kidney disease are less likely to receive a living kidney transplant compared with less deprived individuals. This systematic review focuses on how socioeconomic position (SEP) may influence hypothetical and actual living kidney donors and where appropriate, summarizes the quantitative evidence.In the general population, a higher SEP appears to be associated with an increased 'hypothetical' willingness to be a living kidney donor but with marked heterogeneity in the absolute differences (I = 95.9%, P < 0.001). In a commercial setting, lower SEP motivates people to donate. Outside of this setting, there is no evidence of discordance in the SEP of donors and recipients that would suggest undisclosed financial exchange. There is evidence for a complex interaction between SEP and other variables, such as ethnicity, sex, and the national economic climate. Some evidence suggests that measures to remove financial disincentives to donation are associated with an increase in living donation rates. Future research needs to study how SEP impacts the potential donor population from willingness to donate, progression through donor assessment to actual donor nephrectomy. PMID:25250649

  10. Indicated and actual mass inventory measurements for an inverted U-tube steam generator

    SciTech Connect

    Loomis, G.G.; Plessinger, M.P.; Boucher, T.J.

    1986-01-01

    Results from an experimental investigation of actual versus indicated secondary liquid level in a steam generator at steaming conditions are presented. The experimental investigation was performed in two different small scale U-tube-in-shell steam generators at typical pressurized water reactor operating conditions (5-7 MPa; saturated) in the Semiscale facility. During steaming conditions, the indicated secondary liquid level was found to vary considerably from the actual ''bottled-up'' liquid level. These difference between indicated and actual liquid level are related to the frictional pressure drop associated with the two-phase steaming condition in the riser. Data from a series of bottle-up experiments (Simultaneously, the primary heat source and secondary feed and steam are terminated) are tabulated and the actual liquid level is correlated to the indicated liquid level.

  11. Analysis of Non-Standard Lightning Impulse Voltage for Actual Substation and Generation Circuit

    NASA Astrophysics Data System (ADS)

    Okabe, Shigemitsu; Koutou, Masanori; Yuasa, Sadayuki; Suzuki, Toshiyuki; Rokunohe, Toshiaki; Yamagiwa, Tokio

    Evaluation of lightning surge waveforms that actually enter into substations is important when investigating the test voltage of electric power equipment. The standard lightning impulse waveform (1.2/50μs) is used for factory tests. However, the actual lightning surge waveforms in actual substations are complex waveforms in which various different oscillations are superimposed. Investigation of insulation characteristics of equipment against the complex waveforms and the standard one has significant importance. We analyzed these waveforms entering actual substations with respect to the insulation characteristics of gas insulated switchigear (GIS). From the results, we defined four types of non-standard lightning impulse waveforms. Then non-standard lightning impulse voltage is generated by an equipment circuit which is consisted of an impulse generator (IG), R, L and C is analyzed with EMTP. Voltage time characteristics were evaluated from the obtained impulse voltages.

  12. 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...

  13. 25 CFR 700.153 - Actual reasonable moving and related expenses-residential moves.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ..., dismantling, removing, reassembling and reinstalling relocated household appliances, and other personal... subpart, a certified eligible head of household is entitled to actual reasonable expenses for— (a... mileage allowance schedules of the household and personal property from the acquired site to...

  14. 25 CFR 700.153 - Actual reasonable moving and related expenses-residential moves.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ..., dismantling, removing, reassembling and reinstalling relocated household appliances, and other personal... subpart, a certified eligible head of household is entitled to actual reasonable expenses for— (a... mileage allowance schedules of the household and personal property from the acquired site to...

  15. 25 CFR 700.153 - Actual reasonable moving and related expenses-residential moves.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ..., dismantling, removing, reassembling and reinstalling relocated household appliances, and other personal... subpart, a certified eligible head of household is entitled to actual reasonable expenses for— (a... mileage allowance schedules of the household and personal property from the acquired site to...

  16. 25 CFR 700.153 - Actual reasonable moving and related expenses-residential moves.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ..., dismantling, removing, reassembling and reinstalling relocated household appliances, and other personal... subpart, a certified eligible head of household is entitled to actual reasonable expenses for— (a... mileage allowance schedules of the household and personal property from the acquired site to...

  17. 25 CFR 700.153 - Actual reasonable moving and related expenses-residential moves.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ..., dismantling, removing, reassembling and reinstalling relocated household appliances, and other personal... subpart, a certified eligible head of household is entitled to actual reasonable expenses for— (a... mileage allowance schedules of the household and personal property from the acquired site to...

  18. 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)

  19. 40 CFR Appendix C to Part 72 - Actual 1985 Yearly SO2 Emissions Calculation

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... PROGRAMS (CONTINUED) PERMITS REGULATION Pt. 72, App. C Appendix C to Part 72—Actual 1985 Yearly SO2... = (coal SO2 emissions) + (oil SO2 emissions) (in tons) If gas is the only fuel, gas emissions...

  20. Life extension of elevated-temperature reactors considering actual operating conditions

    SciTech Connect

    Ziada, H.H.

    1993-01-01

    Many reactors have experienced operating conditions less severe than those specified in the design. Their actual operating conditions may involve fewer or less severe transients, lower operating temperatures, or a combination of these. Thus the actual operating conditions become important considerations in efforts to extend the life of reactor components. If the number of transients experienced is fewer than the number specified in the design, the actual transients must be reconstructed to determine extended life. When operating temperature is below 800 [degrees]F, fatigue damage becomes the controlling factor in life assessment. At operating temperatures above 800 [degrees]F (e.g., breeder reactors), creep damage becomes another controlling factor because residual stresses have a longer time for relaxation, a fact that will reduce creep damage. This study presents an approach to assessing the life of breeder reactor components when the actual transients are fewer in number than those specified in the design. It also discusses the sensitivity of creep-fatigue damage in such factors when actual operating temperatures and the actual severity of transients fall below the design specifications.

  1. Life extension of elevated-temperature reactors considering actual operating conditions

    SciTech Connect

    Ziada, H.H.

    1993-01-01

    Many reactors have experienced operating conditions less severe than those specified in the design. Their actual operating conditions may involve fewer or less severe transients, lower operating temperatures, or a combination of these. Thus the actual operating conditions become important considerations in efforts to extend the life of reactor components. If the number of transients experienced is fewer than the number specified in the design, the actual transients must be reconstructed to determine extended life. When operating temperature is below 800 {degrees}F, fatigue damage becomes the controlling factor in life assessment. At operating temperatures above 800 {degrees}F (e.g., breeder reactors), creep damage becomes another controlling factor because residual stresses have a longer time for relaxation, a fact that will reduce creep damage. This study presents an approach to assessing the life of breeder reactor components when the actual transients are fewer in number than those specified in the design. It also discusses the sensitivity of creep-fatigue damage in such factors when actual operating temperatures and the actual severity of transients fall below the design specifications.

  2. Clinical learning environments (actual and expected): perceptions of Iran University of Medical Sciences nursing students

    PubMed Central

    Bigdeli, Shoaleh; Pakpour, Vahid; Aalaa, Maryam; Shekarabi, Robabeh; Sanjari, Mahnaz; Haghani, Hamid; Mehrdad, Neda

    2015-01-01

    Background: Educational clinical environment has an important role in nursing students' learning. Any difference between actual and expected clinical environment will decrease nursing students’ interest in clinical environments and has a negative correlation with their clinical performance. Methods: This descriptive cross-sectional study is an attempt to compare nursing students' perception of the actual and expected status of clinical environments in medical-surgical wards. Participants of the study were 127 bachelor nursing students of Iran University of Medical Sciences in the internship period. Data gathering instruments were a demographic questionnaire (including sex, age, and grade point average), and the Clinical Learning Environment Inventory (CLEI) originally developed by Professor Chan (2001), in which its modified Farsi version (Actual and Preferred forms) consisting 42 items, 6 scales and 7 items per scale was used. Descriptive and inferential statistics (t-test, paired t-test, ANOVA) were used for data analysis through SPSS version 16. Results: The results indicated that there were significant differences between the preferred and actual form in all six scales. In other word, comparing with the actual form, the mean scores of all items in the preferred form were higher. The maximum mean difference was in innovation and the highest mean difference was in involvement scale. Conclusion: It is concluded that nursing students do not have a positive perception of their actual clinical teaching environment and this perception is significantly different from their perception of their expected environment. PMID:26034726

  3. Pralatrexate Monitoring Using a Commercially Available Methotrexate Assay to Avoid Potential Drug Interactions.

    PubMed

    McPherson, Jordan P; Vrontikis, Alaina; Sedillo, Courtney; Halwani, Ahmad S; Gilreath, Jeffrey A

    2016-02-01

    Pralatrexate (PDX) is a folate antagonist structurally similar to methotrexate (MTX). Unlike MTX, it is currently not known whether PDX exhibits delayed clearance and heightened toxicity in the setting of fluid overload. A specific serum assay for PDX is not commercially available. To our knowledge, we report the first case using an MTX serum assay as a surrogate for PDX concentrations to avoid a potential drug-drug interaction with pralatrexate. We describe a 76-year-old man with refractory cutaneous T-cell lymphoma who began therapy with weekly PDX 15 mg/m(2) intravenous infusions on days 1, 8, and 15 of a 28-day cycle. He subsequently developed mucositis, a moderate right-sided pleural effusion, and peripheral edema over the next 5 weeks. Aggressive diuresis with furosemide was initiated, which was then withheld the day before his next PDX dose to avoid a potential drug-drug interaction between PDX and furosemide. His baseline MTX/PDX concentration (measured prior to administration of the cycle 2, week 2 PDX dose) was less than 0.20 μmol/L (i.e., undetectable). After PDX administration, his 1-hour peak MTX/PDX concentration increased to 0.58 μmol/L. Aggressive diuresis was withheld until his MTX/PDX concentration was undetectable, 43.5 hours later. PDX is more potent than MTX and displays similar pharmacokinetic properties. PDX concentrations using the serum MTX assay reflect lower values than those reported from PDX-specific assays in clinical studies. Because PDX is approved by the U.S. Food and Drug Administration for the treatment of uncommon malignancies, it is unlikely that a specific assay will be commercially developed. We propose that the MTX serum assay has merit for use in determining when to reinstate possible interacting drug therapies such as loop diuretics. PMID:26809959

  4. Stability behaviour of antiretroviral drugs and their combinations. 3: Characterization of interaction products of emtricitabine and tenofovir disoproxil fumarate by mass spectrometry.

    PubMed

    Kurmi, Moolchand; Singh, Dilip Kumar; Tiwari, Shristy; Sharma, Parul; Singh, Saranjit

    2016-09-01

    The present study investigated drug-drug interaction behaviour of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) under solid state stability test conditions. Six interaction products were separated and detected by high performance liquid chromatography coupled to photodiode array detector (HPLC-PDA) using C18 column. The same were characterized using LC-high resolution mass spectrometry (LC-HRMS), LC-multi stage mass spectrometry (LC-MS(n)) and online hydrogen/deuterium (H/D) exchange studies. The interaction pathway among the two drugs was outlined based on the elucidated structures. Four of the six interaction products were also formed in marketed tablets containing FTC and TDF (along with efavirenz (EFV)) that were kept without packing under accelerated condition of 40°C/75% RH till 6 months. PMID:27344633

  5. PERCEIVED AND ACTUAL QUALITY OF LIFE WITH ULCERATIVE COLITIS: A COMPARISON OF MEDICALLY AND SURGICALLY TREATED PATIENTS

    PubMed Central

    Waljee, Akbar K.; Higgins, Peter DR; Waljee, Jennifer F.; Tujios, Shannan R; Saxena, Aditi; Brown, Lindsay Kennedy; Chaudhary, Meghana N; Morris, Arden M.

    2015-01-01

    Purpose Patients with chronic Ulcerative Colitis (UC) often refuse colectomy despite data indicating that it might improve quality of life. We hypothesized that perceived utility values are different for patients living with UC compared to UC patients after total proctocolectomy. Our aims were to compare the perceived utility assigned by UC patients with and without a colectomy to standardized chronic UC and post-colectomy scenarios, and to compare the utility of actual health states among groups. Methods We surveyed patients in a tertiary referral center from 3 groups including non-UC, UC patients without colectomy, and UC patients who were post-colectomy. We measured the Time-Trade-Off utilities of subjects for standardized scenarios describing moderate UC and a post-colectomy state. Among all UC patients (with and without colectomy), we measured Time-Trade-Off utility for their own health state. Results Responses were obtained from 150 patients per group (n=450). The non-UC patients regarded UC and colectomy scenarios equally (0.92), which was similar to UC patients without colectomy (0.90 and 0.91). Post-colectomy patients strongly preferred the colectomy scenario to the UC scenario (0.86 vs. 0.92, p<0.001). The median utility of UC patients without colectomy for their actual health state was higher than that of post-colectomy patients (0.96 and 0.92, p<0.05). Patients with more social support were more likely to have undergone colectomy compared with patients with little social support (OR=1.20 per dependent/supporter). Conclusions Patients living with UC prefer their actual health state to a perceived UC scenario or a post-colectomy scenario. Patients who have undergone colectomy equate the quality of life in their actual state with that in a post-colectomy scenario and prefer each to a perceived chronic UC state. Given the variety of preferences and the importance of social support, opportunities to interact with UC patients who have previously undergone

  6. Estimation of Regional-Scale Actual Evapotranspiration in Okayama prefecture in Japan using Complementary Relationship

    NASA Astrophysics Data System (ADS)

    Moroizumi, T.; Yamamoto, M.; Miura, T.

    2008-12-01

    It is important to estimate accurately a water balance in watershed for proposing a reuse of water resources and a proper settlement of water utilization. Evapotranspiration (ET) is an important factor of water balance. Therefore, it is needed to estimate accurately the actual ET. The objective of this study is to estimate accurately monthly actual ET in Yoshii, Asahi, and Takahashi River watersheds in Okayama prefecture from 1999 to 2000. The monthly actual ET was calculated by a Morton and a modified Brutsaert and Stricker (B&S) method, using Automated Meteorological Data Acquisition Systems (AMeDAS) in the basin. The actual ET was estimated using land covers which were classified in 11 categories. The land covers includes the effects of albedo. The actual ET was related to the elevation at each AMeDAS station. Using this relationship, the actual ET at the 1 or 5 km grid-interval mesh in the basin was calculated, and finally, the distribution of actual ET was mapped. The monthly ET estimated by the modified B&S method were smaller than that by Morton method which showed a same tendency as the Penman potential ET (PET). The annual values of Morton"fs ET, modified B&S"fs ET, and PET were estimated as 796, 645, and 800 mm, respectively. The ET by the modified B&S was larger in hilly and mountainous areas than in settlement or city. In general, it was a reasonable result because city or settlement areas were covered with concrete and asphalt and the ET was controlled.

  7. Systems pharmacology to investigate the interaction of berberine and other drugs in treating polycystic ovary syndrome.

    PubMed

    Wang, Yu; Fu, Xin; Xu, Jing; Wang, Qiuhong; Kuang, Haixue

    2016-01-01

    Polycystic ovary syndrome (PCOS) is a common multifactorial endocrine disorder among women of childbearing age. PCOS has various and heterogeneous clinical features apart from its indefinite pathogenesis and mechanism. Clinical drugs for PCOS are multifarious because it only treats separate symptoms. Berberine is an isoquinoline plant alkaloid with numerous biological activities, and it was testified to improve some diseases related to PCOS in animal models and in humans. Systems pharmacology was utilized to predict the potential targets of berberine related to PCOS and the potential drug-drug interaction base on the disease network. In conclusion, berberine is a promising polypharmacological drug for treating PCOS, and for enhancing the efficacy of clinical drugs. PMID:27306862

  8. Systems pharmacology to investigate the interaction of berberine and other drugs in treating polycystic ovary syndrome

    PubMed Central

    Wang, Yu; Fu, Xin; Xu, Jing; Wang, Qiuhong; Kuang, Haixue

    2016-01-01

    Polycystic ovary syndrome (PCOS) is a common multifactorial endocrine disorder among women of childbearing age. PCOS has various and heterogeneous clinical features apart from its indefinite pathogenesis and mechanism. Clinical drugs for PCOS are multifarious because it only treats separate symptoms. Berberine is an isoquinoline plant alkaloid with numerous biological activities, and it was testified to improve some diseases related to PCOS in animal models and in humans. Systems pharmacology was utilized to predict the potential targets of berberine related to PCOS and the potential drug-drug interaction base on the disease network. In conclusion, berberine is a promising polypharmacological drug for treating PCOS, and for enhancing the efficacy of clinical drugs. PMID:27306862

  9. Comparison of actual and predicted energy savings in Minnesota gas-heated single-family homes

    SciTech Connect

    Hirst, E.; Goeltz, R.

    1984-03-01

    Data available from a recent evaluation of a home energy audit program in Minnesota are sufficient to allow analysis of the actual energy savings achieved in audited homes and of the relationship between actual and predicted savings. The program, operated by Northern States Power in much of the southern half of the state, is part of Minnesota's version of the federal Residential Conservation Service. NSP conducted almost 12 thousand RCS audits between April 1981 (when the progam began) and the end of 1982. The data analyzed here, available for 346 homes that obtained an NSP energy audit, include monthly natural gas bills from October 1980 through April 1983; heating degree day data matched to the gas bills; energy audit reports; and information on household demographics, structure characteristics, and recent conservation actions from mail and telephone surveys. The actual reduction in weather-adjusted natural gas use between years 1 and 3 averaged 19 MBtu across these homes (11% of preprogram consumption); the median value of the saving was 16 MBtu/year. The variation in actual saving is quite large: gas consumption increased in almost 20% of the homes, while gas consumption decreased by more than 50 MBtu/year in more than 10% of the homes. These households reported an average expenditure of almost $1600 for the retrofit measures installed in their homes; the variation in retrofit cost, while large, was not as great as the variation in actual natural gas savings.

  10. Powerful Interactions

    ERIC Educational Resources Information Center

    Dombro, Amy Laura; Jablon, Judy R.; Stetson, Charlotte

    2011-01-01

    Interactions are the daily exchanges in words and gestures one has with others. As a teacher, the interactions he/she has with young children can make a positive difference in their lives. A teacher's powerful interactions with children play an important role in their emotional well-being and learning. Powerful interactions are not the same as…

  11. Evaluation of knowledge of Health care professionals on warfarin interactions with drug and herb medicinal in Central Saudi Arabia

    PubMed Central

    Al-Arifi, Mohamed N.; Wajid, Syed; Al-Manie, Nawaf K.; Al-Saker, Faisal M.; Babelgaith, Salmeen D.; Asiri, Yousif A.; Sales, Ibrahim

    2016-01-01

    Objectives: To evaluate health care professionals’ knowledge on warfarin interactions with drugs and herbs. Methods: A self-administered questionnaire was developed to assess health care professionals’ knowledge on warfarin interactions with drug and herb. Respondents were asked to classify 15 drugs that may effect on warfarin action as “enhance”, “inhibit “, “no effect”. The study sample involved health care professionals (physicians, pharmacists and nurses) from king Salman hospital, Saudi Arabia. Results: About 92.2% of health care professionals identified warfarin interactions with aspirin, 4.4% for warfarin and fluoxetine. Warfarin and cardiac agents (atenolol) was correctly identified by 11.1% of respondents. In warfarin –herb interactions section, the majority of respondents (66.7%) identified the interaction between green tea and warfarin. Approximately one-third of respondents (n=33) correctly classified warfarin interactions with cardamom. No significant difference was found between the health care professionals (p=0.49) for warfarin-drug interactions knowledge score and p= 0.52 for warfarin- herb interactions knowledge score. Conclusion: This study suggests that health care professionals’ knowledge of warfarin- drug-herb interactions was inadequate. Therefore, health care professionals should receive more education programs about drug-drug/herb interactions to provide appropriate patient counseling and optimal therapeutic outcomes. PMID:27022381

  12. 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.

  13. 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.

  14. Preferred-actual learning environment spaces and earth science outcomes in Taiwan

    NASA Astrophysics Data System (ADS)

    Chang, Chun-Yen; Hsiao, Chien-Hua; Barufaldi, James P.

    2006-05-01

    This study examines the possibilities of differential impacts on students' earth science learning outcomes between different preferred-actual learning environment spaces by using a newly developed ESCLEI (Earth Science Classroom Learning Environment Instrument). The instrument emphasizes three simultaneously important classroom components: content, method, and assessment with both student-centered and teacher-centered scales embedded. Findings suggest that preferred-actual space (PASmatch) between posttreatment perceptions and pretreatment preferences accounted for a more substantial and statistically significant amount of learning outcomes in terms of students' attitudes toward the subject matter with greater than large effect size, concerning practical significance in the actual earth science classroom. These findings suggest that earth science instruction in the secondary schools should bridge the gap between students' preferred/perceived learning environment with the aim to enhance their learning outcomes.

  15. Scaled-up dual anode/cathode microbial fuel cell stack for actual ethanolamine wastewater treatment.

    PubMed

    An, Byung-Min; Heo, Yoon; Maitlo, Hubdar-Ali; Park, Joo-Yang

    2016-06-01

    The aim of this work was to develop the scale-up microbial fuel cell technology for actual ethanolamine wastewater treatment, dual anode/cathode MFC stacks connected in series to achieve any desired current, treatment capacity, and volume capacity. However, after feeding actual wastewater into the MFC, maximum power density decreased while the corresponding internal resistance increased. With continuous electricity production, a stack of eight MFCs in series achieved 96.05% of COD removal and 97.30% of ammonia removal at a flow rate of 15.98L/d (HRT 12h). The scaled-up dual anode/cathode MFC stack system in this research was demonstrated to treat actual ETA wastewater with the added benefit of harvesting electricity energy. PMID:26888335

  16. Bezafibrate-mizoribine interaction: Involvement of organic anion transporters OAT1 and OAT3 in rats.

    PubMed

    Feng, Yuan; Wang, Changyuan; Liu, Qi; Meng, Qiang; Huo, Xiaokui; Liu, Zhihao; Sun, Pengyuan; Yang, Xiaobo; Sun, Huijun; Qin, Jianhua; Liu, Kexin

    2016-01-01

    A patient with rheumatoid arthritis developed rhabdomyolysis while undergoing treatment with mizoribine concomitantly with bezafibrate. The symptoms rapidly disappeared and laboratory test results normalized when she discontinued the two drugs. The purpose of the present study was to elucidate the transporter-mediated molecular pharmacokinetic mechanisms of drug-drug interactions between bezafibrate and mizoribine. Comparing bezafibrate-mizoribine group with bezafibrate group, the Tmax and Cmax of bezafibrate were essentially unchanged in rats. The AUC of bezafibrate was significantly increased and t1/2β was prolonged markedly with an obviously reduction in plasma clearance and cumulative urinary excretion. The changes were similar to oral studies following intravenous co-administration. In rat kidney slices, the uptake of bezafibrate was markedly inhibited by p-aminohippurate, benzylpenicillin and probenecid but not by tetraethyl ammonium. Mizoribine not only decreased the uptake of bezafibrate, but also inhibited the uptake of p-aminohippurate and benzylpenicillin. The uptakes of bezafibrate and mizoribine were significantly higher compared to vector-HEK293 cells. The uptakes of bezafibrate and mizoribine in highest concentration were increased 1.63 and 1.46 folds in hOAT1-transfected cells, 1.43 and 1.24 folds in hOAT3-transfected cells, respectively. The Km values of bezafibrate uptake by hOAT1/3hOAT1-/hOAT3-HEK293 K293 cells were increased 1.68 fold in hOAT1-HEK293 cell and 2.12 fold in hOAT3-HEK293 cell in the presence of mizoribine with no change of Vmax. It indicated that mizoribine could inhibit the uptake of bezafibrate by hOAT1/3-HEK293 cells in a competitive way. In conclusion, OAT1 and OAT3 are the target transporters of drug-drug interactions between bezafibrate and mizoribine in pharmacokinetic aspects. PMID:26474691

  17. Prediction of CYP2D6 drug interactions from in vitro data: evidence for substrate-dependent inhibition.

    PubMed

    VandenBrink, Brooke M; Foti, Robert S; Rock, Dan A; Wienkers, Larry C; Wahlstrom, Jan L

    2012-01-01

    Predicting the magnitude of potential drug-drug interactions is important for underwriting patient safety in the clinical setting. Substrate-dependent inhibition of cytochrome P450 enzymes may confound extrapolation of in vitro results to the in vivo situation. However, the potential for substrate-dependent inhibition with CYP2D6 has not been well characterized. The inhibition profiles of 20 known inhibitors of CYP2D6 were characterized in vitro against four clinically relevant CYP2D6 substrates (desipramine, dextromethorphan, metoprolol, and thioridazine) and bufuralol. Dextromethorphan exhibited the highest sensitivity to in vitro inhibition, whereas metoprolol was the least sensitive. In addition, when metoprolol was the substrate, inhibitors with structurally constrained amino moieties (clozapine, debrisoquine, harmine, quinidine, and yohimbine) exhibited at least a 5-fold decrease in inhibition potency when results were compared with those for dextromethorphan. Atypical inhibition kinetics were observed for these and other inhibitor-substrate pairings. In silico docking studies suggested that interactions with Glu216 and an adjacent hydrophobic binding pocket may influence substrate sensitivity and inhibition potency for CYP2D6. The in vivo sensitivities of the clinically relevant CYP2D6 substrates desipramine, dextromethorphan, and metoprolol were determined on the basis of literature drug-drug interaction (DDI) outcomes. Similar to the in vitro results, dextromethorphan exhibited the highest sensitivity to CYP2D6 inhibition in vivo. Finally, the magnitude of in vivo CYP2D6 DDIs caused by quinidine was predicted using desipramine, dextromethorphan, and metoprolol. Comparisons of the predictions with literature results indicated that the marked decrease in inhibition potency observed for the metoprolol-quinidine interaction in vitro translated to the in vivo situation. PMID:21976621

  18. Are Noachian-age ridged plains (Nplr) actually Early Hesperian in age?. [Mars volcanology

    NASA Technical Reports Server (NTRS)

    Frey, H. V.; Doudnikoff, C. E.; Mongeon, A. M.

    1991-01-01

    The Nplr ridged plains studied are quite thin (less than 150 m, with some less than 90 m) based on the smallest surviving craters from the different preserved crater retention surfaces. The thinness of the Nplr ridged plains permits craters from older surfaces to show through, leading to a greater total crater count than actually applies to the ridged-plains component of those surfaces. It is found that the ridged-plains mapped as Noachian-age Nplr actually resurfaced older Noachian cratered terrain in the Early Hesperian, creating crater retention surfaces of N(1) equals (25,000 +/- 3000) in the Memnonia and Argyre regions.

  19. Strontium and Actinides Removal from Savannah River Site Actual Waste Samples by Freshly Precipitated Manganese Oxide

    SciTech Connect

    Barnes, M.J.

    2003-10-30

    The authors investigated the performance of freshly precipitated manganese oxide and monosodium titanate (MST) for the removal of strontium (Sr) and actinides from actual high-level waste. Manganese oxide precipitation occurs upon addition of a reductant such as formate (HCO2-) or peroxide (H2O2) to a waste solution containing permanganate (MnO4-). Tests described in this document address the capability of manganese oxide treatment to remove Rs, Pu, and Np from actual high-level waste containing elevated concentrations of Pu. Additionally, tests investigate MST (using two unique batches) performance with the same waste for direct comparison to the manganese oxide performance.

  20. 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.

  1. Actual defect observation results of an extreme-ultraviolet blank mask by coherent diffraction imaging

    NASA Astrophysics Data System (ADS)

    Harada, Tetsuo; Hashimoto, Hiraku; Amano, Tsuyoshi; Kinoshita, Hiroo; Watanabe, Takeo

    2016-03-01

    Extreme-ultraviolet (EUV) lithography poses a number of challenges, one of which is the production of a defect-free mask. To observe the defects on an EUV mask in a quantitative phase image, we have developed a microcoherent EUV scatterometry microscope. The intensity and phase images of the defects are reconstructed using ptychography. We observe four actual defects on an EUV blank mask using the microscope. The reconstructed shapes of the actual defects correspond well to those measured by atomic force microscopy (AFM). Our microscope should therefore function as an essential review tool in characterizing defects.

  2. 41 CFR 302-6.103 - What is the latest period for which actual TQSE reimbursement may begin?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 41 Public Contracts and Property Management 4 2010-07-01 2010-07-01 false What is the latest period for which actual TQSE reimbursement may begin? 302-6.103 Section 302-6.103 Public Contracts and... EXPENSES Actual TQSE Method of Reimbursement § 302-6.103 What is the latest period for which actual...

  3. 41 CFR 302-6.103 - What is the latest period for which actual TQSE reimbursement may begin?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 41 Public Contracts and Property Management 4 2013-07-01 2012-07-01 true What is the latest period for which actual TQSE reimbursement may begin? 302-6.103 Section 302-6.103 Public Contracts and... EXPENSES Actual TQSE Method of Reimbursement § 302-6.103 What is the latest period for which actual...

  4. 41 CFR 302-6.103 - What is the latest period for which actual TQSE reimbursement may begin?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 41 Public Contracts and Property Management 4 2012-07-01 2012-07-01 false What is the latest period for which actual TQSE reimbursement may begin? 302-6.103 Section 302-6.103 Public Contracts and... EXPENSES Actual TQSE Method of Reimbursement § 302-6.103 What is the latest period for which actual...

  5. 41 CFR 302-6.103 - What is the latest period for which actual TQSE reimbursement may begin?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 41 Public Contracts and Property Management 4 2011-07-01 2011-07-01 false What is the latest period for which actual TQSE reimbursement may begin? 302-6.103 Section 302-6.103 Public Contracts and... EXPENSES Actual TQSE Method of Reimbursement § 302-6.103 What is the latest period for which actual...

  6. 41 CFR 302-6.103 - What is the latest period for which actual TQSE reimbursement may begin?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 41 Public Contracts and Property Management 4 2014-07-01 2014-07-01 false What is the latest period for which actual TQSE reimbursement may begin? 302-6.103 Section 302-6.103 Public Contracts and... EXPENSES Actual TQSE Method of Reimbursement § 302-6.103 What is the latest period for which actual...

  7. 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

  8. How Are Mate Preferences Linked with Actual Mate Selection? Tests of Mate Preference Integration Algorithms Using Computer Simulations and Actual Mating Couples.

    PubMed

    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. Management of drug interactions with beta-blockers: continuing education has a short-term impact

    PubMed Central

    Driesen, Annelies; Simoens, Steven; Laekeman, Gert

    There is a lack of clear guidelines regarding the management of drug-drug interactions. Objective To assess the impact of an educational intervention on the management of drug interactions with beta-blockers. Methods The study had a controlled before-and-after design. The intervention group (n=10 pharmacies) received a continuing education course and guidelines on the management of drug interactions with beta-blockers. The control group (n=10 pharmacies) received no intervention. Pharmacy students and staff of internship pharmacies participated in this study. Before and after the intervention, students registered interactions with beta-blockers during two weeks. Information was obtained on drug information of the beta-blocker and the interacting drug, patient’s demographics, and the mode of transaction. Results A total number of 288 interactions were detected during both study periods. Most beta-blockers causing an interaction were prescribed for hypertension, and interacted with hypoglycemic agents, NSAIDs, or beta2-agonists. Pharmacists’ intervention rate was low (14% in the pre-test compared to 39% in the post-test), but increased significantly in the post-test in the intervention group. Reasons for overriding the interaction included limited clinical relevance, refill prescriptions, not being aware of the interaction, and communication problems with the prescriber. Conclusion An interactive continuing education course, during which practice-oriented guidelines were offered, affected pharmacists’ short-term behavior at the counter in dealing with interactions of beta-blockers. Continuing education plays a role in raising pharmacists’ awareness and responsibility towards the detection and management of drug interactions in the pharmacy. PMID:25214902

  11. 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…

  12. 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…

  13. 30 CFR 206.180 - How do I determine an actual processing allowance?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...) When MMS conducts reviews and audits, we will examine whether the contract reflects more than the...-contract situation are subject to monitoring, review, audit, and adjustment. You must submit the actual... processing plant. (i) Allowable operating expenses include operations supervision and engineering,...

  14. 41 CFR 302-6.100 - What am I paid under the actual TQSE reimbursement method?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... your immediate family who is under age 12 may receive is For: The first 30 days of temporary quarters... 41 Public Contracts and Property Management 4 2013-07-01 2012-07-01 true What am I paid under the... Method of Reimbursement § 302-6.100 What am I paid under the actual TQSE reimbursement method?...

  15. 41 CFR 302-6.100 - What am I paid under the actual TQSE reimbursement method?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... your immediate family who is under age 12 may receive is For: The first 30 days of temporary quarters... 41 Public Contracts and Property Management 4 2012-07-01 2012-07-01 false What am I paid under the... Method of Reimbursement § 302-6.100 What am I paid under the actual TQSE reimbursement method?...

  16. 41 CFR 302-6.100 - What am I paid under the actual TQSE reimbursement method?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... your immediate family who is under age 12 may receive is For: The first 30 days of temporary quarters... 41 Public Contracts and Property Management 4 2014-07-01 2014-07-01 false What am I paid under the... Method of Reimbursement § 302-6.100 What am I paid under the actual TQSE reimbursement method?...

  17. 41 CFR 302-6.100 - What am I paid under the actual TQSE reimbursement method?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... immediate family who is age 12 or older may receive is A member of your immediate family who is under age 12... 41 Public Contracts and Property Management 4 2010-07-01 2010-07-01 false What am I paid under the... Method of Reimbursement § 302-6.100 What am I paid under the actual TQSE reimbursement method?...

  18. 41 CFR 302-6.100 - What am I paid under the actual TQSE reimbursement method?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... your immediate family who is under age 12 may receive is For: The first 30 days of temporary quarters... 41 Public Contracts and Property Management 4 2011-07-01 2011-07-01 false What am I paid under the... Method of Reimbursement § 302-6.100 What am I paid under the actual TQSE reimbursement method?...

  19. 29 CFR 776.10 - Employees participating in the actual movement of commerce.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 3 2013-07-01 2013-07-01 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...

  20. 29 CFR 776.10 - Employees participating in the actual movement of commerce.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 3 2012-07-01 2012-07-01 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...

  1. Estimating riparian and agricultural actual evapotranspiration by reference evapotranspiration and MODIS Enhanced Vegetation Index

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dryland river basins frequently support both irrigated agriculture and riparian vegetation and remote sensing methods are needed to monitor water use by both crops and natural vegetation in these districts. We developed a general algorithm for estimating actual evapotranspiration (ETa) based on the ...

  2. 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…

  3. 7 CFR 400.55 - Qualification for actual production history coverage program.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... whenever crop rotation requirements and land leasing practices limit the yield history available. FCIC will...) FEDERAL CROP INSURANCE CORPORATION, DEPARTMENT OF AGRICULTURE GENERAL ADMINISTRATIVE REGULATIONS Actual... subsequent crop year. The database may contain a maximum of the 10 most recent crop years and may...

  4. 7 CFR 400.55 - Qualification for actual production history coverage program.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... whenever crop rotation requirements and land leasing practices limit the yield history available. FCIC will...) FEDERAL CROP INSURANCE CORPORATION, DEPARTMENT OF AGRICULTURE GENERAL ADMINISTRATIVE REGULATIONS Actual... subsequent crop year. The database may contain a maximum of the 10 most recent crop years and may...

  5. 33 CFR 142.4 - Duties of lessees, permittees, and persons responsible for actual operations.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Duties of lessees, permittees, and persons responsible for actual operations. 142.4 Section 142.4 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OUTER CONTINENTAL SHELF ACTIVITIES...

  6. 26 CFR 1.544-6 - Constructive ownership as actual ownership.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 7 2011-04-01 2009-04-01 true Constructive ownership as actual ownership. 1.544-6 Section 1.544-6 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED..., owns all the stock of the M Corporation, which in turn owns all the stock of the O Corporation. The...

  7. Using Student Perceptions to Compare Actual and Preferred Classroom Environment in Queensland Schools

    ERIC Educational Resources Information Center

    Dorman, Jeffrey P.

    2008-01-01

    Students' perceptions of actual and preferred classroom environment were investigated using the "What is happening in this class? questionnaire" (WIHIC). The WIHIC assesses seven classroom environment dimensions: student cohesiveness, teacher support, involvement, task orientation, investigation, cooperation and equity. A sample of 978 secondary…

  8. Identity That Makes a Difference: Substantial Learning as Closing the Gap between Actual and Designated Identities

    ERIC Educational Resources Information Center

    Sfard, Anna; Prusak, Anna

    2005-01-01

    In the attempt to account for striking differences between learning activities of immigrant mathematics students from the former Soviet Union and of their native Israeli classmates, the authors introduce the notions of "actual" and "designated identities." These identities are subsequently presented as important factors that mold learning and…

  9. 36 CFR 805.4 - Ensuring environmental documents are actually considered in Council decisionmaking.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... POLICY ACT § 805.4 Ensuring environmental documents are actually considered in Council decisionmaking. (a) Section 1505.1 of the NEPA regulations (40 CFR 1505.1) contains requirements to ensure adequate... the NEPA process begins, the point at which it ends, and the key officials required to...

  10. Convergence and the Cauchy Property of Sequences in the Setting of Actual Infinity

    ERIC Educational Resources Information Center

    Shipman, Barbara A.

    2013-01-01

    Traditional definitions, language, and visualizations of convergence and the Cauchy property of sequences convey a sense of the sequence as a potentially infinite process rather than an actually infinite object. This has a deep-rooted influence on how we think about and teach concepts on sequences, particularly in undergraduate calculus and…

  11. Professionalism of Associate Degree Nurses: The Role of Self-Actualization.

    ERIC Educational Resources Information Center

    Fetzer, Susan Jane

    2003-01-01

    Usable data from 304 of 1,495 associate degree nursing graduates showed that self-actualization was positively and significantly related to professional attitudes, values, and behaviors. Length and intensity of work experience were only slightly related. The need to reevaluate the induction model of professional socialization was suggested.…

  12. 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…

  13. An equation to calculate the actual methylene middle parameter as a function of temperature.

    PubMed

    Mohammad, Mohammad Amin

    2015-08-21

    Methylene middle parameter [Formula: see text] , the product of the methylene group's cross-sectional area ( [Formula: see text] ) and the root square of its dispersive free energy ( [Formula: see text] ), is the key parameter to calculate the dispersive surface components of solids (γs(d)) using inverse gas chromatography (IGC) at different temperatures. The only method reported to calculate [Formula: see text] as a function of temperature is the Dorris-Gray method. However, the conventional values of [Formula: see text] calculated by the Dorris-Gray method depend heavily on theoretical aspects. This paper establishes a novel equation calculating the actual [Formula: see text] as a function of temperature using the latest and most accurate surface parameters of seven successive n-alkanes. The obtained actual [Formula: see text] values are slightly higher those of the conventional [Formula: see text] . At 20°C, the actual [Formula: see text] generates γs(d) values less than those generated using the conventional [Formula: see text] by ∼3%, and this reduction in calculated γs(d) values increases linearly to become ∼5% at 100°C. Therefore, using the new actual [Formula: see text] seems to mitigate the discrepancy between the γs(d) values measured by IGC and those measured by the contact angle method. PMID:26187766

  14. 45 CFR 149.335 - Documentation of costs of actual claims involved.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 45 Public Welfare 1 2012-10-01 2012-10-01 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...

  15. 45 CFR 149.335 - Documentation of costs of actual claims involved.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 45 Public Welfare 1 2013-10-01 2013-10-01 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...

  16. 40 CFR 63.5335 - How do I determine the actual HAP loss?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... process operation type. (2) Chemical Inventory Mass Balance. Determine the actual monthly HAP loss from... month, and business purchasing records to indicate additions to the inventory of chemical supplies. The... chemical inventory from the beginning of the month chemical inventory and adding the quantities of...

  17. 40 CFR 63.5335 - How do I determine the actual HAP loss?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... operation type. (2) Chemical Inventory Mass Balance. Determine the actual monthly HAP loss from your..., and business purchasing records to indicate additions to the inventory of chemical supplies. The net... chemical inventory from the beginning of the month chemical inventory and adding the quantities of...

  18. The Survey and Analysis of Excellent Senior High School Physics Teachers' Professional Growth Actuality

    ERIC Educational Resources Information Center

    Sun, Haibin; Liu, Tingting

    2010-01-01

    Excellent senior high school physics teachers are the backbone power in the new course reform of physics in China. The excellent senior high school physics teachers' professional growth actuality in Shandong is surveyed in this article by the self-made "Questionnaire of Excellent Senior High School Physics Teachers' Professional Growth",…

  19. Relation of Racial Identity Attitudes to Self-Actualization and Affective States of Black Students.

    ERIC Educational Resources Information Center

    Parham, Thomas A.; Helms, Janet E.

    1985-01-01

    The relation between identity attitudes, or Black self-ac4ualization, and various affective states were investigated in 166 Black university students. Both pro-White/anti-Black and pro-Black/anti-White attitudes were associated with greater personal distress. Awakening Black identity was positively related to self-actualization tendencies and…

  20. 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…