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Sample records for minimizing drug interactions

  1. Turkish Final Year Medical Students' Exposure to and Attitudes Concerning Drug Company Interactions: A Perspective from a Minimally Regulated Environment for Medical Students.

    PubMed

    Beyhun, Nazim Ercument; Kolayli, Cevriye Ceyda; Can, Gamze; Topbas, Murat

    2016-01-01

    Interactions between drug companies and medical students may affect evidence-based medical practice and patient safety. The aim of this study was to assess drug company-medical student interactions in a medical faculty where limited specific national or institutional regulations apply between drug companies and medical students. The objectives of the study were to determine the exposure and attitudes of final year medical students in terms of drug company-medical student and physician interactions, to identify factors affecting those attitudes and to provide data for policymakers working on the regulation of interactions between drug companies and medical students. This anonymous questionnaire-based study of 154 medical final year medical students at the Karadeniz Technical University Medical Faculty, Trabzon, Turkey, in April and May 2015 attracted a response rate of 92.2% (n/N, 154/164). Exposure to interaction with a pharmaceutical representative was reported by 90.3% (139/154) of students, and 68.8% (106/154) reported experiencing such interaction alongside a resident. In addition, 83.7% (128/153) of students reported an interaction during internship. Furthermore, 69.9% (107/153) of students agreed that interactions influence physicians' prescription preferences, while 33.1% (51/154) thought that a medical student should never accept a gift from a drug company and 24.7% (38/154) agreed with the proposition that "drug companies should not hold activities in medical faculties". Students with rational prescription training expressed greater agreement with the statement "I am skeptical concerning the information provided by drug companies during interactions" than those who had not received such training, and this finding was supported by logistic regression [O.R.(C.I), p -3.7(1.2-11.5), p = 0.022]. Acceptance of advertisement brochures was found to significantly reduce the level of agreement with the proposition that "A physician should not accept any gift from a

  2. Food and Drug Interactions.

    PubMed

    Choi, Jong Hwan; Ko, Chang Mann

    2017-01-01

    Natural foods and vegetal supplements have recently become increasingly popular for their roles in medicine and as staple foods. This has, however, led to the increased risk of interaction between prescribed drugs and the bioactive ingredients contained in these foods. These interactions range from pharmacokinetic interactions (absorption, distribution, metabolism, and excretion influencing blood levels of drugs) to pharmacodynamic interactions (drug effects). In a quantitative respect, these interactions occur mainly during metabolism. In addition to the systemic metabolism that occurs mainly in the liver, recent studies have focused on the metabolism in the gastrointestinal tract endothelium before absorption. Inhibition of metabolism causes an increase in the blood levels of drugs and could have adverse reactions. The food-drug interactions causing increased blood levels of drugs may have beneficial or detrimental therapeutic effects depending on the intensity and predictability of these interactions. It is therefore important to understand the potential interactions between foods and drugs should and the specific outcomes of such interactions.

  3. Food-drug interactions.

    PubMed

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

    2011-03-01

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

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

    PubMed

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

    2014-01-01

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

  5. Turkish Final Year Medical Students’ Exposure to and Attitudes Concerning Drug Company Interactions: A Perspective from a Minimally Regulated Environment for Medical Students

    PubMed Central

    Beyhun, Nazim Ercument; Kolayli, Cevriye Ceyda; Can, Gamze; Topbas, Murat

    2016-01-01

    Interactions between drug companies and medical students may affect evidence-based medical practice and patient safety. The aim of this study was to assess drug company–medical student interactions in a medical faculty where limited specific national or institutional regulations apply between drug companies and medical students. The objectives of the study were to determine the exposure and attitudes of final year medical students in terms of drug company–medical student and physician interactions, to identify factors affecting those attitudes and to provide data for policymakers working on the regulation of interactions between drug companies and medical students. This anonymous questionnaire-based study of 154 medical final year medical students at the Karadeniz Technical University Medical Faculty, Trabzon, Turkey, in April and May 2015 attracted a response rate of 92.2% (n/N, 154/164). Exposure to interaction with a pharmaceutical representative was reported by 90.3% (139/154) of students, and 68.8% (106/154) reported experiencing such interaction alongside a resident. In addition, 83.7% (128/153) of students reported an interaction during internship. Furthermore, 69.9% (107/153) of students agreed that interactions influence physicians’ prescription preferences, while 33.1% (51/154) thought that a medical student should never accept a gift from a drug company and 24.7% (38/154) agreed with the proposition that “drug companies should not hold activities in medical faculties”. Students with rational prescription training expressed greater agreement with the statement “I am skeptical concerning the information provided by drug companies during interactions” than those who had not received such training, and this finding was supported by logistic regression [O.R.(C.I), p -3.7(1.2–11.5), p = 0.022]. Acceptance of advertisement brochures was found to significantly reduce the level of agreement with the proposition that “A physician should not

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

    PubMed

    Haen, E

    2014-04-01

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

  7. Food-drug interactions.

    PubMed

    Schmidt, Lars E; Dalhoff, Kim

    2002-01-01

    Interactions between food and drugs may inadvertently reduce or increase the drug effect. The majority of clinically relevant food-drug interactions are caused by food-induced changes in the bioavailability of the drug. Since the bioavailability and clinical effect of most drugs are correlated, the bioavailability is an important pharmacokinetic effect parameter. However, in order to evaluate the clinical relevance of a food-drug interaction, the impact of food intake on the clinical effect of the drug has to be quantified as well. As a result of quality review in healthcare systems, healthcare providers are increasingly required to develop methods for identifying and preventing adverse food-drug interactions. In this review of original literature, we have tried to provide both pharmacokinetic and clinical effect parameters of clinically relevant food-drug interactions. The most important interactions are those associated with a high risk of treatment failure arising from a significantly reduced bioavailability in the fed state. Such interactions are frequently caused by chelation with components in food (as occurs with alendronic acid, clodronic acid, didanosine, etidronic acid, penicillamine and tetracycline) or dairy products (ciprofloxacin and norfloxacin), or by other direct interactions between the drug and certain food components (avitriptan, indinavir, itraconazole solution, levodopa, melphalan, mercaptopurine and perindopril). In addition, the physiological response to food intake, in particular gastric acid secretion, may reduce the bioavailability of certain drugs (ampicillin, azithromycin capsules, didanosine, erythromycin stearate or enteric coated, and isoniazid). For other drugs, concomitant food intake may result in an increase in drug bioavailability either because of a food-induced increase in drug solubility (albendazole, atovaquone, griseofulvin, isotretinoin, lovastatin, mefloquine, saquinavir and tacrolimus) or because of the secretion of

  8. Drug-nutrient interactions.

    PubMed

    Chan, Lingtak-Neander

    2013-07-01

    Drug-nutrient interactions are defined as physical, chemical, physiologic, or pathophysiologic relationships between a drug and a nutrient. The causes of most clinically significant drug-nutrient interactions are usually multifactorial. Failure to identify and properly manage drug-nutrient interactions can lead to very serious consequences and have a negative impact on patient outcomes. Nevertheless, with thorough review and assessment of the patient's history and treatment regimens and a carefully executed management strategy, adverse events associated with drug-nutrient interactions can be prevented. Based on the physiologic sequence of events after a drug or a nutrient has entered the body and the mechanism of interactions, drug-nutrient interactions can be categorized into 4 main types. Each type of interaction can be managed using similar strategies. The existing data that guide the clinical management of most drug-nutrient interactions are mostly anecdotal experience, uncontrolled observations, and opinions, whereas the science in understanding the mechanism of drug-nutrient interactions remains limited. The challenge for researchers and clinicians is to increase both basic and higher level clinical research in this field to bridge the gap between the science and practice. The research should aim to establish a better understanding of the function, regulation, and substrate specificity of the nutrient-related enzymes and transport proteins present in the gastrointestinal tract, as well as assess how the incidence and management of drug-nutrient interactions can be affected by sex, ethnicity, environmental factors, and genetic polymorphisms. This knowledge can help us develop a true personalized medicine approach in the prevention and management of drug-nutrient interactions.

  9. Food and Drug Interactions

    PubMed Central

    Choi, Jong Hwan; Ko, Chang Mann

    2017-01-01

    Natural foods and vegetal supplements have recently become increasingly popular for their roles in medicine and as staple foods. This has, however, led to the increased risk of interaction between prescribed drugs and the bioactive ingredients contained in these foods. These interactions range from pharmacokinetic interactions (absorption, distribution, metabolism, and excretion influencing blood levels of drugs) to pharmacodynamic interactions (drug effects). In a quantitative respect, these interactions occur mainly during metabolism. In addition to the systemic metabolism that occurs mainly in the liver, recent studies have focused on the metabolism in the gastrointestinal tract endothelium before absorption. Inhibition of metabolism causes an increase in the blood levels of drugs and could have adverse reactions. The food-drug interactions causing increased blood levels of drugs may have beneficial or detrimental therapeutic effects depending on the intensity and predictability of these interactions. It is therefore important to understand the potential interactions between foods and drugs should and the specific outcomes of such interactions. PMID:28261555

  10. Grapefruit and drug interactions.

    PubMed

    2012-12-01

    Since the late 1980s, grapefruit juice has been known to affect the metabolism of certain drugs. Several serious adverse effects involving drug interactions with grapefruit juice have been published in detail. The components of grapefruit juice vary considerably depending on the variety, maturity and origin of the fruit, local climatic conditions, and the manufacturing process. No single component accounts for all observed interactions. Other grapefruit products are also occasionally implicated, including preserves, lyophylised grapefruit juice, powdered whole grapefruit, grapefruit seed extract, and zest. Clinical reports of drug interactions with grapefruit juice are supported by pharmacokinetic studies, each usually involving about 10 healthy volunteers, in which the probable clinical consequences were extrapolated from the observed plasma concentrations. Grapefruit juice inhibits CYP3A4, the cytochrome P450 isoenzyme most often involved in drug metabolism. This increases plasma concentrations of the drugs concerned, creating a risk of overdose and dose-dependent adverse effects. Grapefruit juice also inhibits several other cytochrome P450 isoenzymes, but they are less frequently implicated in interactions with clinical consequences. Drugs interacting with grapefruit and inducing serious clinical consequences (confirmed or very probable) include: immunosuppressants, some statins, benzodiazepines, most calcium channel blockers, indinavir and carbamazepine. There are large inter-individual differences in enzyme efficiency. Along with the variable composition of grapefruit juice, this makes it difficult to predict the magnitude and clinical consequences of drug interactions with grapefruit juice in a given patient. There is increasing evidence that transporter proteins such as organic anion transporters and P-glycoprotein are involved in interactions between drugs and grapefruit juice. In practice, numerous drugs interact with grapefruit juice. Although only a few

  11. Transporter-mediated drug-drug interactions.

    PubMed

    Müller, Fabian; Fromm, Martin F

    2011-07-01

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

  12. Herb-drug interactions.

    PubMed

    Fugh-Berman, A

    2000-01-08

    Concurrent use of herbs may mimic, magnify, or oppose the effect of drugs. Plausible cases of herb-drug interactions include: bleeding when warfarin is combined with ginkgo (Ginkgo biloba), garlic (Allium sativum), dong quai (Angelica sinensis), or danshen (Salvia miltiorrhiza); mild serotonin syndrome in patients who mix St John's wort (Hypericum perforatum) with serotonin-reuptake inhibitors; decreased bioavailability of digoxin, theophylline, cyclosporin, and phenprocoumon when these drugs are combined with St John's wort; induction of mania in depressed patients who mix antidepressants and Panax ginseng; exacerbation of extrapyramidal effects with neuroleptic drugs and betel nut (Areca catechu); increased risk of hypertension when tricyclic antidepressants are combined with yohimbine (Pausinystalia yohimbe); potentiation of oral and topical corticosteroids by liquorice (Glycyrrhiza glabra); decreased blood concentrations of prednisolone when taken with the Chinese herbal product xaio chai hu tang (sho-salko-to); and decreased concentrations of phenytoin when combined with the Ayurvedic syrup shankhapushpi. Anthranoid-containing plants (including senna [Cassia senna] and cascara [Rhamnus purshiana]) and soluble fibres (including guar gum and psyllium) can decrease the absorption of drugs. Many reports of herb-drug interactions are sketchy and lack laboratory analysis of suspect preparations. Health-care practitioners should caution patients against mixing herbs and pharmaceutical drugs.

  13. Text mining for drug-drug interaction.

    PubMed

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

    2014-01-01

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

  14. Clinically significant drug interactions with atypical antipsychotics.

    PubMed

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

    2013-12-01

    well as other antiepileptic drugs such as phenobarbital and phenytoin, may decrease plasma SGA concentrations. Some anti-infective agents such as protease inhibitors and fluoroquinolones are of concern as well. Two additional important factors that influence drug interactions with SGAs are dose and time dependence. Smoking is very common among psychiatric patients and can induce CYP1A2 enzymes, thereby lowering expected plasma levels of certain SGAs. It is recommended that ziprasidone and lurasidone are taken with food to promote drug absorption, otherwise their bioavailability can be reduced. Clinicians must be aware of the variety of factors that can increase the likelihood of clinically significant drug interactions with SGAs, and must carefully monitor patients to maximize treatment efficacy while minimizing adverse events.

  15. Drugging Membrane Protein Interactions

    PubMed Central

    Yin, Hang; Flynn, Aaron D.

    2016-01-01

    The majority of therapeutics target membrane proteins, accessible on the surface of cells, to alter cellular signaling. Cells use membrane proteins to transduce signals into cells, transport ions and molecules, bind the cell to a surface or substrate, and catalyze reactions. Newly devised technologies allow us to drug conventionally “undruggable” regions of membrane proteins, enabling modulation of protein–protein, protein–lipid, and protein–nucleic acid interactions. In this review, we survey the state of the art in high-throughput screening and rational design in drug discovery, and we evaluate the advances in biological understanding and technological capacity that will drive pharmacotherapy forward against unorthodox membrane protein targets. PMID:26863923

  16. 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

  17. Drug interactions with oral sulphonylurea hypoglycaemic drugs.

    PubMed

    Hansen, J M; Christensen, L K

    1977-01-01

    The effect of the oral sulphonylurea hypoglycaemic drugs may be influenced by a large number of other drugs. Some of these combinations (e.g. phenylbutazone, sulphaphenazole) may result in cases of severe hypoglycaemic collapse. Tolbutamide and chlorpropamide should never be given to a patient without a prior careful check of which medicaments are already being given. Similarly, no drug should be given to a diabetic treated with tolbutamide and chlorpropamide without consideration of the possibility of interaction phenomena.

  18. Drug interactions and the statins

    PubMed Central

    Herman, R J

    1999-01-01

    Drug interactions commonly occur in patients receiving treatment with multiple medications. Most interactions remain unrecognized because drugs, in general, have a wide margin of safety or because the extent of change in drug levels is small when compared with the variation normally seen in clinical therapy. All drug interactions have a pharmacokinetic or pharmacodynamic basis and are predictable given an understanding of the pharmacology of the drugs involved. Drugs most liable to pose problems are those having concentration-dependent toxicity within, or close to, the therapeutic range; those with steep dose-response curves; those having high first-pass metabolism or those with a single, inhibitable route of elimination. Knowing which drugs possess these intrinsic characteristics, together with a knowledge of hepatic P-450 metabolism and common enzyme-inducing and enzyme-inhibiting drugs, can greatly assist physicians in predicting interactions that may be clinically relevant. This article reviews the pharmacology of drug interactions that can occur with hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) to illustrate the scope of the problem and the ways in which physicians may manage this important therapeutic class of drugs. PMID:10584091

  19. [Drug interactions and the elderly].

    PubMed

    Le Jeunne, C; Hugues, F C

    1995-01-01

    Elderly people are particularly at risk for drug interactions, for several reasons. They are the part of the population who consume the most drugs: over 75 years the mean number of drugs on a prescription is 5.6. As they suffer from various associated diseases, they see several medical specialists, each of them adding a new prescription to the others. Self-prescriptions complicate the problem because they are rarely mentioned. Changes in pharmacokinetics in the elderly tend to increase blood concentrations of drugs. Elderly people suffer from altered homeostatic mechanisms to compensate for adverse drug effects. As a whole, such individuals are more exposed to the side effects of drugs. The drugs most often involved in these interactions are diuretics, non-steroidal anti-inflammatory drugs, benzodiazepines, antiarrhythmics, cardiac glycosides, antihypertensive drugs, oral antidiabetics and antalgics. The clinical accidents most often occurring with these drug interactions are: malaise, orthostatic hypotension, loss of conciousness, amnesia, confusion, renal insufficiency, digestive problems. Since elderly people are less likely to recover easily, this problem of drug interaction should be looked for systematically.

  20. 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.

  1. Studies of food drug interactions.

    PubMed

    Aman, Syed Faisal; Hassan, Fouzia; Naqvi, Baqar S; Hasan, Syed Muhammmad Farid

    2010-07-01

    Medicines can treat and alleviate many diseases provided that they must be taken properly to ensure that they are safe and useful. One issue related with the medicines is that whether to take on empty stomach or with food. The present work gives information regarding food-drug interactions that were studied by collecting seventy five prescriptions from various hospitals. In most of the collected prescriptions, food-drug interactions were detected using the literature available. It was also found that only few studies have been carried out so far on the effect of food on drug disposition in the Asian population. Thus more studies on food-drug interactions particularly in the local population is recommended in order to determine the effect of food and food components on drug disposition and to the kinetics of the drugs which has not yet well highlighted in this part of the world.

  2. Drug-mineral interactions

    SciTech Connect

    Kramer, L.

    1986-03-01

    The effect of drugs such as glucocorticoids and thyroid extract on calcium metabolism is unknown. However, several other medications affect the excretion and intestinal absorption of calcium. A controlled study was carried out to investigate these aspects. Urinary calcium was determined for 3 months during the long-term intake of the antituberculous drug isoniazid (INH) and of the antibiotic tetracycline. The effect of the diuretics furosemide and hydrochlorothiazide, of several aluminum-containing antacids, of thyroid extract and of corticosteroids was also studied. Metabolic balances of calcium, phosphorus, magnesium and zinc were determined, as well as the intestinal absorption of calcium using Ca 47. Plasma levels, urinary and fecal excretions of Ca 47 were determined. All drugs tested increased urinary calcium except for the diuretic hydrochlorothiazide. Regarding the effect of corticosteroids: the intestinal absorption of calcium was unchanged after the short-term use and was very high after long-term use. The studies have shown that several commonly used drugs induce an increase in urinary calcium excretion which may contribute to calcium loss, if this increase persists for prolonged periods of time. Urinary excretions of phosphorus, magnesium and zinc increased in some of the studies.

  3. HIV Treatment: What is a Drug Interaction?

    MedlinePlus

    ... HIV Treatment Services HIV Treatment What is a Drug Interaction? (Last updated 3/13/2017; last reviewed ... taking or plan to take. What is a drug interaction? A drug interaction is a reaction between ...

  4. Adverse food-drug interactions.

    PubMed

    de Boer, Alie; van Hunsel, Florence; Bast, Aalt

    2015-12-01

    Food supplements and herbal products are increasingly popular amongst consumers. This leads to increased risks of interactions between prescribed drugs and these products containing bioactive ingredients. From 1991 up to 2014, 55 cases of suspected adverse drug reactions due to concomitant intake of health-enhancing products and drugs were reported to Lareb, the Netherlands Pharmacovigilance Centre. An overview of these suspected interactions is presented and their potential mechanisms of action are described. Mainly during the metabolism of xenobiotics and due to the pharmacodynamics effects interactions seem to occur, which may result in adverse drug reactions. Where legislation is seen to distinct food and medicine, legislation concerning these different bioactive products is less clear-cut. This can only be resolved by increasing the molecular knowledge on bioactive substances and their potential interactions. Thereby potential interactions can be better understood and prevented on an individual level. By considering the dietary pattern and use of bioactive substances with prescribed medication, both health professionals and consumers will be increasingly aware of interactions and these interactive adverse effects can be prevented.

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

    PubMed

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

    2016-08-01

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

  6. [Antibiotics: drug and food interactions].

    PubMed

    Hodel, M; Genné, D

    2009-10-07

    Antibiotics are widely prescribed in medical practice. Many of them induce or are subject to interactions that may diminish their anti-infectious efficiency or elicit toxic effects. Food intake can influence the effectiveness of an antibiotic. Certain antibiotics can lower the effectiveness of oral contraception. Oral anticoagulation can be influenced to a great extent by antibiotics and controls are necessary. Interactions are also possible via enzymatic induction or inhibition of cytochromes. The use of an interaction list with substrates of cytochromes enables to anticipate. Every new prescription should consider a possible drug or food interaction.

  7. Clinical risk management of herb–drug interactions

    PubMed Central

    De Smet, Peter A G M

    2007-01-01

    The concomitant use of conventional and herbal medicines can lead to clinically relevant herb–drug interactions. Clinical risk management offers a systematic approach to minimize the untoward consequences of these interactions by paying attention to: (i) risk identification and assessment; (ii) development and execution of risk reduction strategies; and (iii) evaluation of risk reduction strategies. This paper reviews which steps should be explored or taken in these domains to improve the clinical risk management of adverse herb–drug interactions. PMID:17116126

  8. Optimizing drug exposure to minimize selection of antibiotic resistance.

    PubMed

    Olofsson, Sara K; Cars, Otto

    2007-09-01

    The worldwide increase in antibiotic resistance is a concern for public health. The fact that the choice of dose and treatment duration can affect the selection of antibiotic-resistant mutants is becoming more evident, and an increased number of studies have used pharmacodynamic models to describe the drug exposure and pharmacodynamic breakpoints needed to minimize and predict the development of resistance. However, there remains a lack of sufficient data, and future work is needed to fully characterize these target drug concentrations. More knowledge is also needed of drug pharmacodynamics versus bacteria with different resistance mutations and susceptibility levels. The dosing regimens should exhibit high efficacy not only against susceptible wild-type bacteria but, preferably, also against mutated bacteria that may exist in low numbers in "susceptible" populations. Thus, to prolong the life span of existing and new antibiotics, it is important that dosing regimens be carefully selected on the basis of pharmacokinetic and pharmacodynamic properties that prevent emergence of preexisting and newly formed mutants.

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

    PubMed Central

    Ganguly, Barna

    2014-01-01

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

  10. Nuclear Receptors in Drug Metabolism, Drug Response and Drug Interactions.

    PubMed

    Prakash, Chandra; Zuniga, Baltazar; Song, Chung Seog; Jiang, Shoulei; Cropper, Jodie; Park, Sulgi; Chatterjee, Bandana

    Orally delivered small-molecule therapeutics are metabolized in the liver and intestine by phase I and phase II drug-metabolizing enzymes (DMEs), and transport proteins coordinate drug influx (phase 0) and drug/drug-metabolite efflux (phase III). Genes involved in drug metabolism and disposition are induced by xenobiotic-activated nuclear receptors (NRs), i.e. PXR (pregnane X receptor) and CAR (constitutive androstane receptor), and by the 1α, 25-dihydroxy vitamin D3-activated vitamin D receptor (VDR), due to transactivation of xenobiotic-response elements (XREs) present in phase 0-III genes. Additional NRs, like HNF4-α, FXR, LXR-α play important roles in drug metabolism in certain settings, such as in relation to cholesterol and bile acid metabolism. The phase I enzymes CYP3A4/A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, CYP1A2, CYP2C8, CYP2A6, CYP2J2, and CYP2E1 metabolize >90% of all prescription drugs, and phase II conjugation of hydrophilic functional groups (with/without phase I modification) facilitates drug clearance. The conjugation step is mediated by broad-specificity transferases like UGTs, SULTs, GSTs. This review delves into our current understanding of PXR/CAR/VDR-mediated regulation of DME and transporter expression, as well as effects of single nucleotide polymorphism (SNP) and epigenome (specified by promoter methylation, histone modification, microRNAs, long non coding RNAs) on the expression of PXR/CAR/VDR and phase 0-III mediators, and their impacts on variable drug response. Therapeutic agents that target epigenetic regulation and the molecular basis and consequences (overdosing, underdosing, or beneficial outcome) of drug-drug/drug-food/drug-herb interactions are also discussed. Precision medicine requires understanding of a drug's impact on DME and transporter activity and their NR-regulated expression in order to achieve optimal drug efficacy without adverse drug reactions. In future drug screening, new tools such as humanized mouse models and

  11. 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

  12. The Clinician's Approach to Drug Interactions

    PubMed Central

    Morrelli, Howard F.; Melmon, Kenneth L.

    1968-01-01

    Drug interactions are important causes of both unexpected toxic and therapeutic effects. Adverse reactions due to drug interaction are proportional to the number of drugs given and the duration of administration. Although drug interactions may be beneficial, they are most often recognized when they increase mortality or morbidity. The frequency of adverse drug interactions in clinical practice makes it mandatory for physicians to know the drugs and mechanisms involved. A drug may potentiate or antagonize the effects of another drug by direct chemical or physical combination, by altering gastrointestinal absorption, by influencing metabolism, transport, or renal clearance, by changing the activity of a drug at its receptor site, or by modifying the patient's response to the drug by a variety of means. This article stresses the importance of avoiding multible drug therapy. When such treatment is unavoidable, patients must be carefully observed for evidence of intensified or diminished drug effect. Only this permits the detection and prevention of untoward drug interactions. PMID:4881984

  13. Food and drug interactions: a general review.

    PubMed

    Ötles, Semih; Senturk, Ahmet

    2014-01-01

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

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

    PubMed

    Mohutsky, Michael; Hall, Stephen D

    2014-01-01

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

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

    PubMed

    Baneyx, Guillaume; Fukushima, Yumi; Parrott, Neil

    2012-04-01

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

  16. Understanding and preventing drug–drug and drug–gene interactions

    PubMed Central

    Tannenbaum, Cara; Sheehan, Nancy L

    2014-01-01

    Concomitant administration of multiple drugs can lead to unanticipated drug interactions and resultant adverse drug events with their associated costs. A more thorough understanding of the different cytochrome P450 isoenzymes and drug transporters has led to new methods to try to predict and prevent clinically relevant drug interactions. There is also an increased recognition of the need to identify the impact of pharmacogenetic polymorphisms on drug interactions. More stringent regulatory requirements have evolved for industry to classify cytochrome inhibitors and inducers, test the effect of drug interactions in the presence of polymorphic enzymes, and evaluate multiple potentially interacting drugs simultaneously. In clinical practice, drug alert software programs have been developed. This review discusses drug interaction mechanisms and strategies for screening and minimizing exposure to drug interactions. We also provide future perspectives for reducing the risk of clinically significant drug interactions. PMID:24745854

  17. [Importance of drug interactions with smoking in modern drug research].

    PubMed

    Laki, Szilvia; Kalapos-Kovács, Bernadett; Antal, István; Klebovich, Imre

    2013-01-01

    Drug interaction is a process during which a drug's fate in the body or its pharmacological properties are altered by an influencing factor. The extent of the drug interaction's effect can vary. The interaction could result from the modulation by another drug, food, alcohol, caffeine, narcotics, a drug influencing absorption or smoking. Moreover, transporter interactions with smoking could also have a major impact on many drug's efficacy. Clinically relevant drug interactions with smoking were classified in terms of their effect: pharmacokinetic, pharmacodynamic and transporter interactions. Policyclic aromatic carbohydrates, found in cigarette smoke, have enzyme inducing properties. The interaction affects mainly the hepatic isoenzyme CYP1A2. Interactions caused by smoking have an effect on all drugs being substrates of and therefore metabolised by CYP1A2. Pharmacokinetic alteration can also occur during the absorption, distribution and elimination process. The pharmacodynamic interactions are mainly caused by the effects of nicotine, a cigarette smoke component. Through interactions, smoking could also modify the activity of transporter proteins, altering this way the ADME properties of many drugs. Since smoking is one of the deadliest artefact in the history of human civilisation, identifying drug interactions with smoking is the physician's and pharmacist's major responsibility and task. Moreover, it is necessary to identify the patient's smoking habits during a medical treatment. This review aims to investigate the main types of drug interactions (PK/PD), identify factors influencing the activity of CYP enzymes and transporters, and also summarize the mechanisms of the most important drug interactions with smoking and their clinically relevant consequences (Table II-VI.). Drugs, with effects somehow altered by smoking-interactions, have been studied.

  18. Live minimal path for interactive segmentation of medical images

    NASA Astrophysics Data System (ADS)

    Chartrand, Gabriel; Tang, An; Chav, Ramnada; Cresson, Thierry; Chantrel, Steeve; De Guise, Jacques A.

    2015-03-01

    Medical image segmentation is nowadays required for medical device development and in a growing number of clinical and research applications. Since dedicated automatic segmentation methods are not always available, generic and efficient interactive tools can alleviate the burden of manual segmentation. In this paper we propose an interactive segmentation tool based on image warping and minimal path segmentation that is efficient for a wide variety of segmentation tasks. While the user roughly delineates the desired organs boundary, a narrow band along the cursors path is straightened, providing an ideal subspace for feature aligned filtering and minimal path algorithm. Once the segmentation is performed on the narrow band, the path is warped back onto the original image, precisely delineating the desired structure. This tool was found to have a highly intuitive dynamic behavior. It is especially efficient against misleading edges and required only coarse interaction from the user to achieve good precision. The proposed segmentation method was tested for 10 difficult liver segmentations on CT and MRI images, and the resulting 2D overlap Dice coefficient was 99% on average..

  19. Psychological Effects of Stimulant Drugs in Children with Minimal Brain Dysfunction

    ERIC Educational Resources Information Center

    Conners, C. Keith

    1972-01-01

    Two technical studies involving the drugs dextroamphetamine, methylphenidate, and magnesium pemoline were reported in regard to the psychological characteristics and effects of stimulant drugs in children with minimal brain injuries. (CB)

  20. Clinically relevant drug interactions with anti-Alzheimer's drugs.

    PubMed

    Caraci, Filippo; Sultana, Janet; Drago, Filippo; Spina, Edoardo

    2017-03-03

    The aging world population had led to an increase in the prevalence of Alzheimer's disease (AD). The drugs used to slow down the onset of AD, galantamine, donepezil, rivastigmine and memantine, are generally well-tolerated. However, drug interactions between these drugs and other drugs are an important aspect of patient safety that should be borne in mind, particularly given the high burden of polypharmacy in the elderly. The aim of this review is to provide an updated review of clinically significant drug-drug interactions concerning drugs approved for AD. PubMed was searched for relevant keywords. No time limit was imposed but only articles in English published in peer-reviewed journals were selected. Relevant literature was also identified from the references of identified articles. Further information was obtained from drug summary of product characteristics. The major pharmacokinetic interactions identified concerned fluoxetine, paroxetine and ketoconazole when used with galantamine or donepezil. On the other hand, the major potential pharmacodynamic interactions concerned anti-dementia drugs and general anesthesia agents, anti-cholinergic drugs, conventional antipsychotics and bradycardia-inducing drugs. In clinical practice memantine shows a lower potential for pharmacodynamic drug-drug interactions (DDIs) compared to other drug classes. In conclusion, the concomitant use of anti-dementia drugs with other drugs can have variable clinical effects, making appropriate prescribing of these drugs very challenging. A simple and coherent way of presenting evidence on complex drug interaction information from heterogenous sources to clinicians is needed in order for the voluminous data available to have an impact on clinical practice.

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

    PubMed

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

    2006-04-01

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

  2. Weakly interacting dark matter from the minimal walking technicolor

    SciTech Connect

    Kainulainen, Kimmo; Virkajärvi, Jussi; Tuominen, Kimmo E-mail: jussi.virkajarvi@jyu.fi

    2010-02-01

    We study a weakly interacting dark matter particle motivated by minimal walking technicolor theories. Our WIMP is a mixture of a sterile state and a state with the charges of a standard model fourth family neutrino. We show that the model can give the right amount of dark matter over a range of the WIMP mass and mixing angle. We compute bounds on the model parameters from the current accelerator data including the oblique corrections to the precision electroweak parameters, as well as from cryogenic experiments, Super-Kamiokande and from the IceCube experiment. We show that consistent dark matter solutions exist which satisfy all current constraints. However, almost the entire parameter range of the model lies within the the combined reach of the next generation experiments.

  3. Text Mining for Drug–Drug Interaction

    PubMed Central

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

    2015-01-01

    In order to understand the mechanisms of drug–drug interaction (DDI), the study of pharmacokinetics (PK), pharmacodynamics (PD), and pharmacogenetics (PG) data are significant. In recent years, drug PK parameters, drug interaction parameters, and PG data have been unevenly collected in different databases and published extensively in literature. Also the lack of an appropriate PK ontology and a well-annotated PK corpus, which provide the background knowledge and the criteria of determining DDI, respectively, lead to the difficulty of developing DDI text mining tools for PK data collection from the literature and data integration from multiple databases. To conquer the issues, we constructed a comprehensive pharmacokinetics ontology. It includes all aspects of in vitro pharmacokinetics experiments, in vivo pharmacokinetics studies, as well as drug metabolism and transportation enzymes. Using our pharmacokinetics ontology, a PK corpus was constructed to present four classes of pharmacokinetics abstracts: in vivo pharmacokinetics studies, in vivo pharmacogenetic studies, in vivo drug interaction studies, and in vitro drug interaction studies. A novel hierarchical three-level annotation scheme was proposed and implemented to tag key terms, drug interaction sentences, and drug interaction pairs. The utility of the pharmacokinetics ontology was demonstrated by annotating three pharmacokinetics studies; and the utility of the PK corpus was demonstrated by a drug interaction extraction text mining analysis. The pharmacokinetics ontology annotates both in vitro pharmacokinetics experiments and in vivo pharmacokinetics studies. The PK corpus is a highly valuable resource for the text mining of pharmacokinetics parameters and drug interactions. PMID:24788261

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

    PubMed

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

    2014-01-01

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

  5. Cytochrome P450 enzyme mediated herbal drug interactions (Part 1)

    PubMed Central

    Wanwimolruk, Sompon; Prachayasittikul, Virapong

    2014-01-01

    knowledge of the mechanisms of herbal drug interactions is necessary for assessing and minimizing clinical risks. These processes help prediction of interactions between herbal supplements and prescription drugs. Healthcare professionals should remain vigilant for potential interactions between herbal supplements/medicines and prescription drugs, especially for drugs with a narrow therapeutic index are used. PMID:26417265

  6. [Interactions of cytostatic agents with other drugs].

    PubMed

    Sauter, C

    1991-08-31

    With the degree of polypharmacy currently practiced in the field of oncology, there are undoubtedly many drug interactions. In the present study the influence of "non-cytotoxic" drugs on anticancer drugs is discussed, but not the reverse. Not only is the augmentation (reversal of multidrug resistance) or the reduction of antitumor properties of cytotoxic drugs observed, but also cytostatic activities of "non-cytotoxic" drugs themselves. Examples are calmodulin inhibitors such as phenothiazines and tricyclic antidepressants. Interactions may also increase side effects of cytostatic drugs or even neutralize the antitumoral activity. To ensure that interactions are not overlooked, all medicaments being administered should be listed. It is, however, not feasible yet to determine serum concentrations of all the drugs given to the patient. The antitumor activity of supportive care could be evaluated in randomized studies (e.g. cytostatic drugs +/- antidepressants).

  7. Profile of drug interactions in hospitalized children

    PubMed Central

    Martinbiancho, Jacqueline; Zuckermann, Joice; Dos Santos, Luciana; Silva, Mariane M.

    Introduction The expected therapeutic response may be affected by the presence of drug interactions. With the high number of reports on new drug interactions, it has been difficult for health professionals to keep constantly updated. For this reason, computer systems have helped identify such interactions. Objectives To verify the rate and profile of drug interactions in medical prescriptions to hospitalized pediatric patients. Methods A descriptive study investigated prescriptions to hospitalized pediatric patients. The study included patients between 0 and 12 years old, containing 4 or more drugs in their prescriptions. The analysis of interaction and incompatibility possibilities in prescribed drugs used Micromedex / Drug-Reax® program. Results From 2005 to 2006, 3,170 patients were investigated, and 11,181 prescriptions were analyzed, a mean value of 3.5 prescriptions/patient. In total, 6,857 drug interactions were found, which corresponds to 1.9 interaction/prescription. Among them, relevance to ampicillin and gentamicin, found in 220 (3.2%) prescriptions. In total, 2,411 drug incompatibilities in via y were found, a mean value of 0.5/prescription, with emphasis on vancomycin and cefepime, found in 243 (10.0%) prescriptions. Conclusion The presence of drug interactions is a permanent risk in hospitals. This way, the utilization of computer programs, pharmacotherapy monitoring of patients and the pharmacist presence in the multidisciplinary team are some manners of contributing to hospitalized patients’ treatment. PMID:25170352

  8. Prescribing in prison: minimizing psychotropic drug diversion in correctional practice.

    PubMed

    Pilkinton, Patricia D; Pilkinton, James C

    2014-04-01

    Correctional facilities are a major provider of mental health care throughout the United States. In spite of the numerous benefits of providing care in this setting, clinicians are sometimes concerned about entering into correctional care because of uncertainty in prescribing practices. This article provides an introduction to prescription drug use, abuse, and diversion in the correctional setting, including systems issues in prescribing, commonly abused prescription medications, motivation for and detection of prescription drug abuse, and the use of laboratory monitoring. By understanding the personal and systemic factors that affect prescribing habits, the clinician can develop a more rewarding correctional practice and improve care for inmates with mental illness.

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

    PubMed

    Strobach, Dorothea

    2012-07-01

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

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

    PubMed

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

    2015-06-01

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

  11. 78 FR 36194 - Draft Guidance for Industry and FDA Staff: Investigational New Drug Applications for Minimally...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-17

    ... guidance document provides advice to potential sponsors, such as cord blood banks, registries, transplant... New Drug Applications for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood..., Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic and...

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2003-01-01

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

  14. An Oral Contraceptive Drug Interaction Study

    ERIC Educational Resources Information Center

    Bradstreet, Thomas E.; Panebianco, Deborah L.

    2004-01-01

    This article focuses on a two treatment, two period, two treatment sequence crossover drug interaction study of a new drug and a standard oral contraceptive therapy. Both normal theory and distribution-free statistical analyses are provided along with a notable amount of graphical insight into the dataset. For one of the variables, the decision on…

  15. Minimizing the risk of chemically reactive metabolite formation of new drug candidates: implications for preclinical drug design.

    PubMed

    Brink, Andreas; Pähler, Axel; Funk, Christoph; Schuler, Franz; Schadt, Simone

    2016-11-27

    Many pharmaceutical companies aim to reduce reactive metabolite formation by chemical modification at early stages of drug discovery. A practice often applied is the detection of stable trapping products of electrophilic intermediates with nucleophilic trapping reagents to guide rational structure-based drug design. This contribution delineates this strategy to minimize the potential for reactive metabolite formation of clinical candidates during preclinical drug optimization, exemplified by the experience at Roche over the past decade. For the majority of research programs it was possible to proceed with compounds optimized for reduced covalent binding potential. Such optimized candidates are expected to have a higher likelihood of succeeding throughout the development processes, resulting in safer drugs.

  16. 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

  17. 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.

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

    PubMed

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

    2017-03-01

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

  19. Can vaccines interact with drug metabolism?

    PubMed

    Pellegrino, Paolo; Clementi, Emilio; Capuano, Annalisa; Radice, Sonia

    2015-02-01

    Vaccines are safe and efficacious in reducing the burden of several serious infections affecting children and adults. Due to their efficacy, vaccines are often administered in patients with chronic diseases, likely to be under poly-therapy. Because of several case reports indicating changes in drug metabolism after vaccination, the hypothesis of an interaction between vaccines and specific drugs has been put forward. These interactions are conceivably of great concern, especially in patients treated with molecules characterised by a narrow therapeutic index. Herein, we review and systematise the available evidence on vaccine-drug interactions. The picture that emerges indicates that reduction in the activity of specific CYPs following vaccination may occur, most likely via interferon γ overproduction, and for specific drugs such as anticonvulsivant and theophylline may have significant clinical relevance. Clinical interaction between vaccines and drugs that are metabolised by cytochromes uninfluenced by INFγ levels, such as warfarin, are instead unlikely to happen. Further studies are however needed to gain a complete picture of vaccine-drug interactions and define their relevance in terms of possible negative clinical impact.

  20. Food-drug interactions: grapefruit juice.

    PubMed

    Diaconu, Camelia Harapu; Cuciureanu, Magdalena; Vlase, L; Cuciureanu, Rodica

    2011-01-01

    Food-drug interactions are increasingly recognized as important clinical events which may change significantly the bioavailability of oral administrated drugs. Grapefruit juice (GFJ) demonstrated multiple interactions with drugs leading to loss of the therapeutic effects or increased side-effects. GFJ decreases pre-systemic metabolism through a) competitive or mechanism-based inhibition of gut wall CYP3A4 isoenzymes and b) P-glycoprotein (P-gp), c) multidrug resistance protein-2 (MRP2) or d) organic anion-transporting polypeptide (OATP) inhibition. Although, GFJ presents high amounts of flavonoids (e.g. naringin, naringenin), furanocoumarins (e.g. 6',7'-dihydroxybergamottin, bergamottin) are the main chemicals involved in the pharmacokinetic interactions. As compounds of GFJ show additive or synergistic effects, all the major furanocoumarins are necessary for the maximal inhibitory effect. Also, related citrus fruits (sweeties, pummelo and sour orange) or various plants containing furanocoumarins may present pharmacological interactions, yet to be discovered.

  1. Important drug interactions in patients with rheumatic disorders: interactions of glucocorticoids, immunosuppressants and antimalarial drugs.

    PubMed

    Hromadkova, L; Soukup, T; Vlcek, J

    2012-08-01

    Despite the fact that biological treatments are very promising, classical immunosuppressants, antimalarial drugs and glucocorticosteroids are still very important and widely used in practice. Although drug interactions can have fatal consequences, few studies have reviewed drug interactions of these classical drugs used in rheumatology, and very few guidelines are available on this subject. Therefore, this report summarizes important interactions of immunosuppressants, antimalarial drugs and glucocorticosteroids with drugs commonly used in internal medicine. In the present study, more than 300 interactions were retrieved from the Micromedex ® database. The selection was reduced to the interactions rated as moderate, major or contraindicated. The selected interactions were further checked against PubMed ®, MEDLINE ®, InfoPharm Compendium of Drug Interactions and Summaries of Product Characteristics. For each interaction, its nature, mechanism, onset and clinical severity were indicated, documentation quality was rated and recommendations for clinical practice were formulated. Twenty significant interactions that we rated as moderate, severe and very severe were identified. Interacting drugs were warfarin, fluoroquinolones, azole antifungals, co-trimoxazole, proton pump inhibitors, amiodarone, cholestyramine, activated carbon, allopurinol, angiotensin-converting enzyme inhibitors, statins, digoxin, iron, aluminium and magnesium salts, and hepatotoxic and nephrotoxic agents.

  2. Clinically significant drug interactions with newer antidepressants.

    PubMed

    Spina, Edoardo; Trifirò, Gianluca; Caraci, Filippo

    2012-01-01

    After the introduction of selective serotonin reuptake inhibitors (SSRIs), other newer antidepressants with different mechanisms of action have been introduced in clinical practice. Because antidepressants are commonly prescribed in combination with other medications used to treat co-morbid psychiatric or somatic disorders, they are likely to be involved in clinically significant drug interactions. This review examines the drug interaction profiles of the following newer antidepressants: escitalopram, venlafaxine, desvenlafaxine, duloxetine, milnacipran, mirtazapine, reboxetine, bupropion, agomelatine and vilazodone. In general, by virtue of a more selective mechanism of action and receptor profile, newer antidepressants carry a relatively low risk for pharmacodynamic drug interactions, at least as compared with first-generation antidepressants, i.e. monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). On the other hand, they are susceptible to pharmacokinetic drug interactions. All new antidepressants are extensively metabolized in the liver by cytochrome P450 (CYP) isoenzymes, and therefore may be the target of metabolically based drug interactions. Concomitant administration of inhibitors or inducers of the CYP isoenzymes involved in the biotransformation of specific antidepressants may cause changes in their plasma concentrations. However, due to their relatively wide margin of safety, the consequences of such kinetic modifications are usually not clinically relevant. Conversely, some newer antidepressants may cause pharmacokinetic interactions through their ability to inhibit specific CYPs. With regard to this, duloxetine and bupropion are moderate inhibitors of CYP2D6. Therefore, potentially harmful drug interactions may occur when they are coadministered with substrates of these isoforms, especially compounds with a narrow therapeutic index. The other new antidepressants are only weak inhibitors or are not inhibitors of CYP isoforms at

  3. 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

  4. Evaluation of resources for analyzing drug interactions*†

    PubMed Central

    Patel, Risha I.; Beckett, Robert D.

    2016-01-01

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

  5. Drug–drug interactions with imatinib

    PubMed Central

    Récoché, Isabelle; Rousseau, Vanessa; Bourrel, Robert; Lapeyre-Mestre, Maryse; Chebane, Leila; Despas, Fabien; Montastruc, Jean-Louis; Bondon-Guitton, Emmanuelle

    2016-01-01

    Abstract Many patients treated with imatinib, used in cancer treatment, are using several other drugs that could interact with imatinib. Our aim was to study all the drug–drug interactions (DDIs) observed in patients treated with imatinib. We performed 2 observational studies, between the 1st January 2012 and the 31st August 2015 in the Midi-Pyrénées area (South Western France), using the French health insurance reimbursement database and then the French Pharmacovigilance Database (FPVD). A total of 544 patients received at least 1 reimbursement for imatinib. Among them, 486 (89.3%) had at least 1 drug that could potentially interact with imatinib. Paracetamol was the most frequent drug involved (77.4%). Proton pump inhibitors, dexamethasone and levothyroxine, were found in >10% of patients. In the FPVD, among a total of 25 reports of ADRs with imatinib recorded in the Midi-Pyrénées area, 10 (40%) had potential DDIs with imatinib. Imatinib was most frequently prescribed by hospital physicians and drugs interacting with imatinib, by general practitioners. Our study showed that at least 40% of the patients treated with imatinib were at risk of DDIs and that all prescribers must be cautious with DDIs in patients treated with imatinib. During imatinib treatment, we particularly recommend to limit the dose of paracetamol at 1300 mg per day, to avoid the use of dexamethasone, and to double the dose of levothyroxine. PMID:27749579

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

    PubMed

    Huang, Shiew-Mei; Lesko, Lawrence J

    2004-06-01

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

  7. Mechanisms and Consequences of Drug-Drug Interactions.

    PubMed

    Greenblatt, David J

    2017-03-01

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

  8. Collagen interactions: Drug design and delivery.

    PubMed

    An, Bo; Lin, Yu-Shan; Brodsky, Barbara

    2016-02-01

    Collagen is a major component in a wide range of drug delivery systems and biomaterial applications. Its basic physical and structural properties, together with its low immunogenicity and natural turnover, are keys to its biocompatibility and effectiveness. In addition to its material properties, the collagen triple-helix interacts with a large number of molecules that trigger biological events. Collagen interactions with cell surface receptors regulate many cellular processes, while interactions with other ECM components are critical for matrix structure and remodeling. Collagen also interacts with enzymes involved in its biosynthesis and degradation, including matrix metalloproteinases. Over the past decade, much information has been gained about the nature and specificity of collagen interactions with its partners. These studies have defined collagen sequences responsible for binding and the high-resolution structures of triple-helical peptides bound to its natural binding partners. Strategies to target collagen interactions are already being developed, including the use of monoclonal antibodies to interfere with collagen fibril formation and the use of triple-helical peptides to direct liposomes to melanoma cells. The molecular information about collagen interactions will further serve as a foundation for computational studies to design small molecules that can interfere with specific interactions or target tumor cells. Intelligent control of collagen biological interactions within a material context will expand the effectiveness of collagen-based drug delivery.

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

    PubMed

    Pal, Dhananjay; Mitra, Ashim K

    2006-09-01

    , and sparfloxacin are potent inhibitors of P-gp-mediated efflux of 14C erythromycin and (3)H cyclosporin. Simultaneous administration of fluoroquinolones and macrolides could minimize the efflux and metabolism of both of the drugs. Effects of erythromycin and ketoconazole on carbamazepine metabolism were examined. Formation of 10,11-epoxy carbamazepine, a major CBZ metabolite, was significantly inhibited by these agents. Therefore, drug efflux proteins (P-gp, MRPs) and metabolizing enzyme (CYP450) are major factors in drug interactions. Overlapping substrate specificities of these proteins result in complex and sometimes perplexing pharmacokinetic profiles of multidrug regimens. Drug-drug interactions with PIs and other coadministered agents for human immunodeficiency virus (HIV) positive population have been discussed in light of efflux transporters and metabolizing enzymes. This article provides an insight into low and variable oral bioavailability and related complications leading to loss of therapeutic activity of MDR and CYP 450 substrates.

  10. [Terbinafine : Relevant drug interactions and their management].

    PubMed

    Dürrbeck, A; Nenoff, P

    2016-09-01

    The allylamine terbinafine is the probably most frequently prescribed systemic antifungal agent in Germany for the treatment of dermatomycoses and onychomycoses. According to the German drug law, terbinafine is approved for patients who are 18 years and older; however, this antifungal agent is increasingly used off-label for treatment of onychomycoses and tinea capitis in children. Terbinafine is associated with only a few interactions with other drugs, which is why terbinafine can generally be used without problems in older and multimorbid patients. Nevertheless, some potential interactions of terbinafine with certain drug substances are known, including substances of the group of antidepressants/antipsychotics and some cardiovascular drugs. Decisive for the relevance of interactions is-along with the therapeutic index of the substrate and the possible alternative degradation pathways-the genetically determined type of metabolism. When combining terbinafine with tricyclic antidepressants or selective serotonin reuptake inhibitors and serotonin/noradrenalin reuptake inhibitors, the clinical response and potential side effects must be monitored. Problematic is the use of terbinafine with simultaneous treatment with tamoxifen. The administration of potent CYP2D6 inhibitors leads to a diminished efficacy of tamoxifen because one of its most important active metabolites-endoxifen-is not sufficiently available. Therefore, combination of tamoxifen and terbinafine should be avoided. In conclusion, the number of substances which are able to cause clinically relevant interactions in case of simultaneously administration with terbinafine is clear and should be manageable in the dermatological office with adequate monitoring.

  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.

  12. Clinical drug interactions: a holistic view.

    PubMed

    Rahal, Anu; Ahmad, A H; Kumar, Amit; Mahima; Verma, Amit Kumar; Chakraborty, Sandip; Dhama, Kuldeep

    2013-08-15

    Every time a drug is administered to the animal to treat an ailment, no matter whether it is acute or chronic manifestation, it usually goes together with some other prescription medicine, OTC (Over the counter) formulation, herbs or even food. All the xenobiotics such as drugs, toxins and food components as well as the endogenous compound that are formed in the animal body as a routine phenomenon exert a stimulatory or inhibitory effect on the different physiological and biochemical processes going in the body. These effects may alter the normal metabolism and/or drug transport or its efficacy drastically and thus expose the man and animals to the risk of a potentially dangerous interaction. The present review discusses these potential reactions and their mechanisms that help in navigating the hazardous combinations of drugs with other medicines, food, herbs, vitamins and minerals with confidence.

  13. Synergistic interactions between ampakines and antipsychotic drugs.

    PubMed

    Johnson, S A; Luu, N T; Herbst, T A; Knapp, R; Lutz, D; Arai, A; Rogers, G A; Lynch, G

    1999-04-01

    Tests were made for interactions between antipsychotic drugs and compounds that enhance synaptic currents mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate receptors ("ampakines"). Typical and atypical antipsychotic drugs decreased methamphetamine-induced hyperactivity in rats; the effects of near or even subthreshold doses of the antipsychotics were greatly enhanced by the ampakines. Interactions between the ampakine CX516 and low doses of different antipsychotics were generally additive and often synergistic. The ampakine did not exacerbate neuroleptic-induced catalepsy, indicating that the interaction between the different pharmacological classes was selective. These results suggest that positive modulators of cortical glutamatergic systems may be useful adjuncts in treating schizophrenia.

  14. Anticoagulant Medicine: Potential for Drug-Food Interactions

    MedlinePlus

    ... Medications Anticoagulants and Drug-Food Interactions Anticoagulants and Drug-Food Interactions Make an Appointment Ask a Question ... care provider before making the change. Anticoagulants and Medicine There are many medicines that can interact with ...

  15. Pharmacokinetic drug interactions involving Ginkgo biloba.

    PubMed

    Unger, Matthias

    2013-08-01

    Ginkgo biloba leaf extracts (GLEs) are popular herbal remedies for the treatment of Alzheimer's dementia, tinnitus, vertigo and peripheral arterial disease. As GLEs are taken regularly by older people who are likely to also use multiple other drugs for the treatment of, e.g. hypertension, diabetes, rheumatism or heart failure, potential herb-drug interactions are of interest. Preclinical studies of high doses/concentrations of GLEs of varying quality and standardization hinted at both an inhibition and induction of metabolic enzymes and transporters. However, in humans, positive in vitro-findings could not be replicated in vivo. At maximum recommended doses of 240 mg/day, a clinically relevant interaction potential of the standardized GLE EGb 761 could not be shown. GLE doses higher than the recommended ones led to a weak induction of the CYP2C19-mediated omeprazole 5-hydroxylation, and a weak inhibition of the CYP3A4-mediated midazolam 1'-hydroxylation, respectively. Also, the regular intake of a poorly characterized GLE at a dose of 360 mg/day slightly increased the bioavailability of talinolol, a substrate of P-glycoprotein and various organic anion-transporting polypeptides. Thus, regarding pharmacokinetic herb-drug interactions, the intake of the standardized GLE, EGb 761, together with synthetic drugs appears to be safe as long as daily doses up to 240 mg are consumed. If this applies to other extracts prepared according to the European Pharmacopoeia remains uncertain. Also, a relevant potential for drug interactions cannot be excluded for poorly standardized GLEs used in many food supplements.

  16. On global minimizers of repulsive–attractive power-law interaction energies

    PubMed Central

    Carrillo, José Antonio; Chipot, Michel; Huang, Yanghong

    2014-01-01

    We consider the minimization of the repulsive–attractive power-law interaction energies that occur in many biological and physical situations. We show the existence of global minimizers in the discrete setting and obtain bounds for their supports independently of the number of Dirac deltas in a certain range of exponents. These global discrete minimizers correspond to the stable spatial profiles of flock patterns in swarming models. Global minimizers of the continuum problem are obtained by compactness. We also illustrate our results through numerical simulations. PMID:25288810

  17. Selective serotonin reuptake inhibitor drug interactions in patients receiving statins.

    PubMed

    Andrade, Chittaranjan

    2014-02-01

    Elderly patients commonly receive statin drugs for the primary or secondary prevention of cardiovascular and cerebrovascular events. Elderly patients also commonly receive antidepressant drugs, usually selective serotonin reuptake inhibitors (SSRIs), for the treatment of depression, anxiety, or other conditions. SSRIs are associated with many pharmacokinetic drug interactions related to the inhibition of the cytochrome P450 (CYP) metabolic pathways. There is concern that drugs that inhibit statin metabolism can trigger statin adverse effects, especially myopathy (which can be potentially serious, if rhabdomyolysis occurs). However, a detailed literature review of statin metabolism and of SSRI effects on CYP enzymes suggests that escitalopram, citalopram, and paroxetine are almost certain to be safe with all statins, and rosuvastatin, pitavastatin, and pravastatin are almost certain to be safe with all SSRIs. Even though other SSRI-statin combinations may theoretically be associated with risks, the magnitude of the pharmacokinetic interaction is likely to be below the threshold for clinical significance. Risk, if at all, lies in combining fluvoxamine with atorvastatin, simvastatin, or lovastatin, and even this risk can be minimized by using lower statin doses and monitoring the patient.

  18. Antiplatelet drug interactions with proton pump inhibitors

    PubMed Central

    Scott, Stuart A; Obeng, Aniwaa Owusu; Hulot, Jean-Sébastien

    2014-01-01

    Introduction Non-aspirin antiplatelet agents (e.g., clopidogrel, prasugrel, ticagrelor) are commonly prescribed for the prevention of recurrent cardiovascular events among patients with acute coronary syndromes (ACS) and/or those undergoing percutaneous coronary intervention (PCI). In addition, combination therapy with proton pump inhibitors (PPIs) is often recommended to attenuate gastrointestinal bleeding risk, particularly during dual antiplatelet therapy (DAPT) with clopidogrel and aspirin. Importantly, a pharmacological interaction between clopidogrel and some PPIs has been proposed based on mutual CYP450-dependent metabolism, but available evidence is inconsistent. Areas covered This article provides an overview of the currently approved antiplatelet agents and PPIs, including their metabolic pathways. Additionally, the CYP450 isoenzyme at the center of the drug interaction, CYP2C19, is described in detail, and the available evidence on both the potential pharmacological interaction and influence on clinical outcomes are summarized and evaluated. Expert opinion Although concomitant DAPT and PPI use reduces clopidogrel active metabolite levels and ex vivo-measured platelet inhibition, the influence of the drug interaction on clinical outcomes has been conflicting and largely reported from non-randomized observational studies. Despite this inconsistency, a clinically important interaction cannot be definitively excluded, particularly among patient subgroups with higher overall cardiovascular risk and potentially among CYP2C19 loss-of-function allele carriers. PMID:24205916

  19. 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

  20. 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.

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

    PubMed

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

    2013-01-01

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

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

    PubMed

    Yin, Jia; Wang, Joanne

    2016-09-01

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

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

    PubMed

    Poirier, T I; Giudici, R A

    1989-12-01

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

  4. 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.

  5. Drug interactions at the blood-brain barrier: fact or fantasy?

    PubMed Central

    Eyal, Sara; Hsiao, Peng; Unadkat, Jashvant D.

    2009-01-01

    There is considerable interest in the therapeutic and adverse outcomes of drug interactions at the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). These include altered efficacy of drugs used in the treatment of CNS disorders, such as AIDS dementia and malignant tumors, and enhanced neurotoxicity of drugs that normally penetrate poorly into the brain. BBB- and BCSFB-mediated interactions are possible because these interfaces are not only passive anatomical barriers, but are also dynamic in that they express a variety of influx and efflux transporters and drug metabolizing enzymes. Based on studies in rodents, it has been widely postulated that efflux transporters play an important role at the human BBB in terms of drug delivery. Furthermore, it is assumed that chemical inhibition of transporters or their genetic ablation in rodents is predictive of the magnitude of interaction to be expected at the human BBB. However, studies in humans challenge this well-established paradigm and claim that such drug interactions will be lesser in magnitude but yet may be clinically significant. This review focuses on current known mechanisms of drug interactions at the blood-brain and blood-CSF barriers and the potential impact of such interactions in humans. We also explore whether such drug interactions can be predicted from preclinical studies. Defining the mechanisms and the impact of drug-drug interactions at the BBB is important for improving efficacy of drugs used in the treatment of CNS disorders while minimizing their toxicity as well as minimizing neurotoxicity of non-CNS drugs. PMID:19393264

  6. 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

  7. Interactions between drugs and occupied receptors.

    PubMed

    Tallarida, Ronald J

    2007-01-01

    This review has 2 parts. Part I deals with isobolographic procedures that are traditionally applied to the joint action of agonists that individually produce overtly similar effects. Special attention is directed to newer computational procedures that apply to agonists with dissimilar concentration-effect curves. These newer procedures are consistent with the isobolographic methods introduced and used by Loewe, however, the present communications provides the needed graphical and mathematical detail. A major aim is distinguishing super and sub-addictive interactions from those that are simply additive. The detection and measurement of an interaction is an important step in exploring drug mechanism and is also important clinically. Part II discusses a new use of isoboles that is applicable to a single drug or chemical whose effect is mediated by 2 or more receptor subtypes. This application produces a metric that characterizes the interaction between the receptor subtypes. The expansion of traditional isobolographic theory to this multi-receptor situation follows from the newer approaches for 2-drug combination analysis in Part I. This topic leads naturally to a re-examination of competitive antagonism and the classic Schild plot. In particular, it is shown here that the Schild plot in the multi-receptor case is not necessarily linear with unit slope. Both parts of this review emphasize the quantitative aspects rather than the many drugs that have been analyzed with isobolographic methods. The mathematical exposition is rather elementary and is further aided by several graphs. An appendix is included for the reader interested in the mathematical details.

  8. 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

  9. Measurement of nuclear effects in neutrino interactions with minimal dependence on neutrino energy

    NASA Astrophysics Data System (ADS)

    Lu, X.-G.; Pickering, L.; Dolan, S.; Barr, G.; Coplowe, D.; Uchida, Y.; Wark, D.; Wascko, M. O.; Weber, A.; Yuan, T.

    2016-07-01

    We present a phenomenological study of nuclear effects in neutrino charged-current interactions, using transverse kinematic imbalances in exclusive measurements. Novel observables with minimal dependence on neutrino energy are proposed to study quasielastic scattering and especially resonance production. They should be able to provide direct constraints on nuclear effects in neutrino- and antineutrino-nucleus interactions.

  10. Drug interactions with cisapride: clinical implications.

    PubMed

    Michalets, E L; Williams, C R

    2000-07-01

    Cisapride, a prokinetic agent, has been used for the treatment of a number of gastrointestinal disorders, particularly gastro-oesophageal reflux disease in adults and children. Since 1993, 341 cases of ventricular arrhythmias, including 80 deaths, have been reported to the US Food and Drug Administration. Marketing of the drug has now been discontinued in the US; however, it is still available under a limited-access protocol. Knowledge of the risk factors for cisapride-associated arrhythmias will be essential for its continued use in those patients who meet the eligibility criteria. This review summarises the published literature on the pharmacokinetic and pharmacodynamic interactions of cisapride with concomitantly administered drugs, providing clinicians with practical recommendations for avoiding these potentially fatal events. Pharmacokinetic interactions with cisapride involve inhibition of cytochrome P450 (CYP) 3A4, the primary mode of elimination of cisapride, thereby increasing plasma concentrations of the drug. The macrolide antibacterials clarithromycin, erythromycin and troleandomycin are inhibitors of CYP3A4 and should not be used in conjunction with cisapride. Azithromycin is an alternative. Similarly, azole antifungal agents such as fluconazole, itraconazole and ketoconazole are CYP3A4 inhibitors and their concomitant use with cisapride should be avoided. Of the antidepressants nefazodone and fluvoxamine should be avoided with cisapride. Data with fluoxetine is controversial, we favour the avoidance of its use. Citalopram, paroxetine and sertraline are alternatives. The HIV protease inhibitors amprenavir, indinavir, nelfinavir, ritonavir and saquinavir inhibit CYP3A4. Clinical experience with cisapride is lacking but avoidance with all protease inhibitors is recommended, although saquinavir is thought to have clinically insignificant effects on CYP3A4. Delavirdine is also a CYP3A4 inhibitor and should be avoided with cisapride. We also recommend

  11. Interactions between magnesium and psychotropic drugs.

    PubMed

    Nechifor, Mihai

    2008-06-01

    Psychotropic drugs (antidepressants, antimanic drugs, antipsychotics, analgesic opioids, and others) are among the most frequently used medicines. Between these drugs and magnesium there are pharmacokinetic and pharmacodynamic interactions. Erythrocyte magnesium is decreased in patients with severe major depression (MD) vs normal subjects (44 +/- 2.7 mg/L in MD group vs 59.1 +/- 3.2 mg/L in control group, p < 0.01). Therapy with sertraline, 150 mg/day p.o. -21 days or with amitryptiline 3 x 25 mg/day p.o. 28 days increases significantly erythrocyte concentration of magnesium (56.9 +/- 5.22 mg/L after sertraline vs 44 +/- 2.7 mg/L before sertraline, p < 0.01). In patients with acute paranoid schizophrenia, erythrocyte magnesium concentration is decreased vs healthy subjects. Haloperidol, 8 mg/day, p.o. for 21 days or risperidone, 6 mg/day p.o. for 21 days have increased significantly erythrocyte magnesium concentration (46.21 +/- 3.1 mg/L before haloperidol and 54.6 +/- 2.7 mg/L after haloperidol, p < 0.05). Antimanic drugs (mood stabilizers) as carbamazepine, 600 mg/day, p.o., 4 weeks and sodium valproate, 900 mg/day p.o., 4 weeks, increased significantly magnesium in patients with bipolar disorder type I. Increased magnesium status positively correlated with enhancement of the clinical state. The existent data sustain the idea that an increase of erythrocyte magnesium is involved in the mechanism of action of some psychotropic drugs. Magnesium supply decreased the intensity of morphine-induced physical drug dependence. In heroin addicts, the plasma magnesium concentration is decreased.

  12. Alterations of chemotherapeutic pharmacokinetic profiles by drug–drug interactions

    PubMed Central

    Ghalib, Mohammed; Chaudhary, Imran; Goel, Sanjay

    2012-01-01

    Background Drug interactions in oncology are common place and largely ignored as we tolerate high thresholds of ‘toxic’ drug responses in these patients. However, in the era of ‘targeted’ or seemingly ‘less toxic’ therapy, these interactions are more commonly flagged and contribute significantly towards poor ‘quality of life’ and medical fatalities. Objective This review and opinion article focuses on alteration of chemotherapeutic pharmacokinetic profiles by drug interactions in the setting of polypharmacy. The assumption is that the drugs, with changes in their pharmacokinetics, will contribute towards changes in their pharmacodynamics. Methods The examples cited for such drug–drug interactions are culled from published literature with an emphasis on those interactions that have been well characterized at the molecular level. Results Although very few drug interaction studies have been performed on approved oncology based drugs, it is clear that drugs whose pharmacokinetics profiles are closely related to their pharmacodynamics will indeed result in clinically important drug interactions. Some newer mechanisms are described that involve interactions at the level of gene transcription, whereby, drug metabolism is significantly altered. However, for any given drug interaction, there does not seem to be a comprehensive model describing interactions. Conclusions Mechanisms based drug interactions are plentiful in oncology; however, there is an absolute lack of a comprehensive model that would predict drug–drug interactions. PMID:19239394

  13. [Drug interactions and clinical relevance: it all began with cheese].

    PubMed

    Carrillo Norte, Juan Antonio

    2012-04-01

    In a drug interaction, the effects of one drug can be increased or decreased or a quite new effect produced by the previous, concurrent or subsequent administration of another substance, including prescription and nonprescription drugs, food, tobacco or alcohol. The effect of the interaction can be desirable, inconsequential, or adverse. The increasing number of drugs available and the increasing use of multidrug therapeutic regimens enhance the potential for drug interactions. However, in clinical practice, most interactions are not significant or rarely of significance. It is when the interaction leads to adverse consequences that it comes to the attention of the patient and physician. Interactions may occur by pharmacokinetic or pharmacodynamics mechanisms. Pharmacokinetic interactions represent the modification of one substance (the interacting substance) on the ADME processes of absorption, distribution, metabolism or excretion of a drug (the index drug). Subsequently, it may lead to changes in the concentration of the index drug at the receptor sites. Drug interactions with a pharmacodynamic basis involve actions on the same receptor or physiological systems through either synergism or antagonism. Many drug interactions can be predicted if the pharmacodynamics effects, pharmacokinetic properties and mechanisms of action of the interacting agents are known. The most obvious interactions are those producing altered pharmacokinetic of drugs with a low therapeutic index (oral anticoagulants, antidiabetic drugs, digoxin, benzodiazepines and immunosuppressant and cytotoxic drugs).

  14. Drug and dietary interactions of warfarin and novel oral anticoagulants: an update.

    PubMed

    Nutescu, Edith; Chuatrisorn, Ittiporn; Hellenbart, Erika

    2011-04-01

    Clinicians and patients around the world have been intrigued by the concept of developing an oral anticoagulant with a broad therapeutic window and few drug and dietary interactions that can be administered at fixed doses with no or minimal monitoring. The recently approved oral direct thrombin inhibitor dabigatran, along with the emerging oral anti-factor Xa inhibitors, rivaroxaban, apixaban, and edoxaban, have been developed to address many of the shortcomings of warfarin therapy. As warfarin is associated with extensive food and drug interactions, there is also a need to consider such interactions with the new oral anticoagulants. While to date few drug and dietary interactions have been reported with the new oral anticoagulants, it is still early in their development and clinical use cycle. Pharmacokinetic and pharmacodynamic profiles will have to be closely accounted for when determining the likelihood of a potential drug interaction prior to therapy initiation. As the list of drugs and supplements that interact with warfarin is continuously expanding, and the knowledge on drug interactions with the novel oral anticoagulants is still in its infancy, clinicians need to be vigilant when initiating any of these agents or when any changes in the patient's medication profile occur and perform a close screening for potential drug and dietary interactions. The objective of this paper is to give an update on drug and dietary interactions with warfarin and the novel oral anticoagulants, dabigatran, rivaroxaban, apixaban, and edoxaban.

  15. Drug interactions between hormonal contraceptives and antiretrovirals

    PubMed Central

    Nanda, Kavita; Stuart, Gretchen S.; Robinson, Jennifer; Gray, Andrew L.; Tepper, Naomi K.; Gaffield, Mary E.

    2017-01-01

    Objective: To summarize published evidence on drug interactions between hormonal contraceptives and antiretrovirals. Design: Systematic review of the published literature. Methods: We searched PubMed, POPLINE, and EMBASE for peer-reviewed publications of studies (in any language) from inception to 21 September 2015. We included studies of women using hormonal contraceptives and antiretrovirals concurrently. Outcomes of interest were effectiveness of either therapy, toxicity, or pharmacokinetics. We used standard abstraction forms to summarize and assess strengths and weaknesses. Results: Fifty reports from 46 studies were included. Most antiretrovirals whether used for therapy or prevention, have limited interactions with hormonal contraceptive methods, with the exception of efavirenz. Although depot medroxyprogesterone acetate is not affected, limited data on implants and combined oral contraceptive pills suggest that efavirenz-containing combination antiretroviral therapy may compromise contraceptive effectiveness of these methods. However, implants remain very effective despite such drug interactions. Antiretroviral plasma concentrations and effectiveness are generally not affected by hormonal contraceptives. Conclusion: Women taking antiretrovirals, for treatment or prevention, should not be denied access to the full range of hormonal contraceptive options, but should be counseled on the expected rates of unplanned pregnancy associated with all contraceptive methods, in order to make their own informed choices. PMID:28060009

  16. [Food-drug interactions: an underestimated risk].

    PubMed

    Sönnichsen, A C; Donner-Banzhoff, N; Baum, E

    2005-11-03

    With only few exceptions, administration of medicaments should, in principle, be independent of food intake (at least half an hour before or two hours after eating). This ensures uniform and assessable bioavailability. However, it also entails the risk that the patient is more likely to forget to take medication postponed to 2 hours after a meal, than when it is directly coupled to a meal. Certain foodstuffs or food constituents, such as, for example, grapefruit, Seville orange juice, red wine, alcoholic drinks in general, or large quantities of caffeine and garlic should be avoided during drug treatment. In addition, specific interactions with certain drugs must also be taken into account (e.g. MAO inhibitors and tyramine, curamine and vitamin K).

  17. Impact insertion of transfer-molded microneedle for localized and minimally invasive ocular drug delivery.

    PubMed

    Song, Hyun Beom; Lee, Kang Ju; Seo, Il Ho; Lee, Ji Yong; Lee, Sang-Mok; Kim, Jin Hyoung; Kim, Jeong Hun; Ryu, WonHyoung

    2015-07-10

    It has been challenging for microneedles to deliver drugs effectively to thin tissues with little background support such as the cornea. Herein, we designed a microneedle pen system, a single microneedle with a spring-loaded microneedle applicator to provide impact insertion. To firmly attach solid microneedles with 140 μm in height at the end of macro-scale applicators, a transfer molding process was employed. The fabricated microneedle pens were then applied to mouse corneas. The microneedle pens successfully delivered rhodamine dye deep enough to reach the stromal layer of the cornea with small entry only about 1000 μm(2). When compared with syringes or 30 G needle tips, microneedle pens could achieve more localized and minimally invasive delivery without any chances of perforation. To investigate the efficacy of microneedle pens as a way of drug delivery, sunitinib malate proven to inhibit in vitro angiogenesis, was delivered to suture-induced angiogenesis model. When compared with delivery by a 30 G needle tip dipped with sunitinib malate, only delivery by microneedle pens could effectively inhibit corneal neovascularization in vivo. Microneedle pens could effectively deliver drugs to thin tissues without impairing merits of using microneedles: localized and minimally invasive delivery.

  18. Inferring cuisine--drug interactions using the linked data approach.

    PubMed

    Jovanovik, Milos; Bogojeska, Aleksandra; Trajanov, Dimitar; Kocarev, Ljupco

    2015-03-20

    Food - drug interactions are well studied, however much less is known about cuisine - drug interactions. Non-native cuisines are becoming increasingly more popular as they are available in (almost) all regions in the world. Here we address the problem of how known negative food - drug interactions are spread in different cuisines. We show that different drug categories have different distribution of the negative effects in different parts of the world. The effects certain ingredients have on different drug categories and in different cuisines are also analyzed. This analysis is aimed towards stressing out the importance of cuisine - drug interactions for patients which are being administered drugs with known negative food interactions. A patient being under a treatment with one such drug should be advised not only about the possible negative food - drug interactions, but also about the cuisines that could be avoided from the patient's diet.

  19. Scattering States of HULTHÉN Interaction in Minimal Length Quantum Mechanics

    NASA Astrophysics Data System (ADS)

    Hassanabadi, H.; Zarrinkamar, S.; Maghsoodi, E.

    2013-05-01

    We first revisit the nonrelativistic minimal length quantum mechanics and reveal an interesting symmetry of the problem. In fact, we will show that the cumbersome problem can be cast into the ordinary Schrödinger equation with a new effective potential. Next, as a typical example, we show the minimal length Schrödinger equation in the presence of a nonminimal Hulthén vector interaction. The transmission and reflection coefficients are reported as well.

  20. [Interactions between herbal medicines and drugs].

    PubMed

    Tůmová, L

    2000-07-01

    At present the use of medicaments of plant origin is on the increase. It is therefore necessary to take into consideration that there exist known as well as potential interactions between the medicament of the medicinal plant. The problematic plants include Echinacea, Allium cepa, Gingko biloba, Panax ginseng, as well as Hypericum perforatum, Valeriana officinalis, or Glycyrrhiza glabra. Its use should be limited, or completely excluded in the cases of simultaneous therapy with, e.g., warfarin, hepatotoxically acting medicaments, MAOI inhibitors, phenelzin sulphate, or phenytoin, as they may decrease of completely eliminate the therapeutic effect of the administered drugs, or they may cause a toxic damage to the organism.

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

    PubMed Central

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

    2016-01-01

    OBJECTIVE: To identify the main severe potential drug-drug interactions in older adults with dementia and to examine the factors associated with these interactions. METHOD: This was a cross-sectional study. The enrolled patients were selected from six geriatrics clinics of tertiary care hospitals across Mexico City. The patients had received a clinical diagnosis of dementia based on the current standards and were further divided into the following two groups: those with severe drug-drug interactions (contraindicated/severe) (n=64) and those with non-severe drug-drug interactions (moderate/minor/absent) (n=117). Additional socio-demographic, clinical and caregiver data were included. Potential drug-drug interactions were identified using Micromedex Drug Reax 2.0® database. RESULTS: A total of 181 patients were enrolled, including 57 men (31.5%) and 124 women (68.5%) with a mean age of 80.11±8.28 years. One hundred and seven (59.1%) patients in our population had potential drug-drug interactions, of which 64 (59.81%) were severe/contraindicated. The main severe potential drug-drug interactions were caused by the combinations citalopram/anti-platelet (11.6%), clopidogrel/omeprazole (6.1%), and clopidogrel/aspirin (5.5%). Depression, the use of a higher number of medications, dementia severity and caregiver burden were the most significant factors associated with severe potential drug-drug interactions. CONCLUSIONS: Older people with dementia experience many severe potential drug-drug interactions. Anti-depressants, antiplatelets, anti-psychotics and omeprazole were the drugs most commonly involved in these interactions. Despite their frequent use, anti-dementia drugs were not involved in severe potential drug-drug interactions. The number and type of medications taken, dementia severity and depression in patients in addition to caregiver burden should be considered to avoid possible drug interactions in this population. PMID:26872079

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

    PubMed

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

    2015-01-01

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

  3. Five dimensional spherically symmetric minimally interacting holographic dark energy model in Brans-Dicke theory

    NASA Astrophysics Data System (ADS)

    Reddy, D. R. K.; Raju, P.; Sobhanbabu, K.

    2016-04-01

    Five dimensional spherically symmetric space-time filled with two minimally interacting fields; matter and holographic dark energy components is investigated in a scalar tensor theory of gravitation proposed by Brans and Dicke (Phys. Rev. 124:925, 1961). To obtain a determinate solution of the highly non-linear field equations we have used (i) a relation between metric potentials and (ii) an equation of state which represents disordered radiation in five dimensional universe. The solution obtained represents a minimally interacting and radiating holographic dark energy model in five dimensional universe. Some physical and Kinematical properties of the model are, also, studied.

  4. Minimizing repolarization-related proarrhythmic risk in drug development and clinical practice.

    PubMed

    Farkas, Attila S; Nattel, Stanley

    2010-03-26

    electrocardiographic intervals (particularly QT) and cardiac rhythm are often needed, both prior to drug approval and after successful introduction on the market (postmarketing surveillance). The successful avoidance of proarrhythmic complications is a shared responsibility of the innovative pharmaceutical industry, regulatory authorities, partners in the clinical drug development phase and practicing physicians. This paper reviews the principal forms of proarrhythmia and the methods that can be used to minimize the risk of proarrhythmia in drug development and clinical practice, with particular emphasis on the most common and problematic form, acquired LQTS.

  5. Interactive mixture as a rapid drug delivery system.

    PubMed

    Lee, Chin Chiat; Ong, Charlene Li Ching; Heng, Paul Wan Sia; Chan, Lai Wah; Wong, Tin Wui

    2008-02-01

    The effectiveness of an interactive mixture as a rapid drug delivery system is compared with that of a solid dispersion. The influences of drug load, particle size, and crystallinity of these test systems are investigated. The interactive mixtures and solid dispersions were prepared from polyethylene glycol (PEG) 3350 and hydrophobic nifedipine drug by means of physical mixing and melting methods, respectively. The formed products were subjected to drug particle size and crystallinity analyses, and dissolution tests. In comparison with the interactive mixtures, the solid dispersions with low drug load were more effective as a rapid drug delivery system, as the size of a given batch of drug particles was markedly reduced by the molten PEG 3350. The rate and extent of drug dissolution were mainly promoted by decreasing effective drug particle size. However, these were lower in the solid dispersions than in the interactive mixtures when a high load of fine drug particles was used as the starting material. This was attributed to drug coarsening during the preparation of the solid dispersion. Unlike solid dispersions, the interactive mixtures could accommodate a high load of fine drug particles without compromising its capacity to enhance the rate and extent of drug dissolution. The interactive mixture is appropriate for use to deliver a fine hydrophobic drug in a formulation requiring a high drug load.

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

    PubMed

    Scheen, André J

    2007-01-01

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

  7. 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

  8. Potential food-drug interactions in long-term care.

    PubMed

    Anderson, Judy K; Fox, Jodie R

    2012-04-01

    Medication administration at mealtimes may result in food-drug interactions. Older adults are especially at risk of food-drug interactions leading to adverse drug effects and subtherapeutic responses. Research on potential food-drug interactions is limited and dated. This study examined the frequency of potential food-drug interactions in long-term care. Forty-nine percent of drugs administered at mealtimes had potential for interaction, with cardiovascular medications given most frequently. The frequency of potential interactions makes this phenomenon critically important to review. Collaboration between nurses and pharmacists may identify optimal medication scheduling. Nurses can enhance care by identifying strategies to limit interactions through knowledge and creative, collaborative administration schedules.

  9. A physiologically based pharmacokinetic model linking plasma protein binding interactions with drug disposition.

    PubMed

    Buur, J L; Baynes, R E; Smith, G W; Riviere, J E

    2009-04-01

    Combination drug therapy increases the chance for an adverse drug reactions due to drug-drug interactions. Altered disposition for sulfamethazine (SMZ) when concurrently administered with flunixin meglumine (FLU) in swine could lead to increased tissue residues. There is a need for a pharmacokinetic modeling technique that can predict the consequences of possible drug interactions. A physiologically based pharmacokinetic model was developed that links plasma protein binding interactions to drug disposition for SMZ and FLU in swine. The model predicted a sustained decrease in total drug and a temporary increase in free drug concentration. An in vivo study confirmed the presence of a drug interaction. Neither the model nor the in vivo study revealed clinically significant changes that alter tissue disposition. This novel linkage approach has use in the prediction of the clinical impact of plasma protein binding interactions. Ultimately it could be used in the design of dosing regimens and in the protection of the food supply through prediction and minimization of tissue residues.

  10. Drug interactions associated with HAART: focus on treatments for addiction and recreational drugs.

    PubMed

    Faragon, John J; Piliero, Peter J

    2003-09-01

    The advent of HAART has improved survival in patients infected with HIV; however, treatment is complicated by potential drug interactions. The risk of drug interactions is compounded by the use of additional therapies for comorbid conditions, such as substance abuse, and by the use of recreational drugs. HIV health care providers should be aware of the potential interaction of recreational drugs and addiction treatments with HAART because of the potential for significant adverse effects for their HIV-infected patients. This article provides a review of the literature on drug interactions among addiction therapies, recreational drugs, and HAART.

  11. Interaction Patterns among Drug Dealers. Drug Abuse Information Research Project.

    ERIC Educational Resources Information Center

    Atkyns, Robert L.; Hanneman, Gerhard J.

    Drug dealers are often popularly stereotyped as "pushers" who actively engage in enticing young people into the drug habit, but there have been no scientific studies of their behavior or their attitudes on drug abuse or public health. In an attempt to gain information about behavior characteristics and communication patterns of middle…

  12. Alcohol Prevention and School Students: Findings from an Australian 2-Year Trial of Integrated Harm Minimization School Drug Education

    ERIC Educational Resources Information Center

    Midford, Richard; Ramsden, Robyn; Lester, Leanne; Cahill, Helen; Mitchell, Johanna; Foxcroft, David R.; Venning, Lynne

    2014-01-01

    The Drug Education in Victorian Schools program provided integrated education about licit and illicit drugs, employed a harm minimization approach that incorporated participatory, critical thinking and skill-based teaching methods, and engaged parental influence through home activities. A cluster-randomized, controlled trial of the program was…

  13. Drug interaction studies on new drug applications: current situations and regulatory views in Japan.

    PubMed

    Nagai, Naomi

    2010-01-01

    Drug interaction studies on new drug applications (NDAs) for new molecular entities (NMEs) approved in Japan between 1997 and 2008 are examined in the Pharmaceuticals and Medical Devices Agency (PMDA). The situations of drug interaction studies in NDAs have changed over the past 12 years, especially in metabolizing enzyme and transporter-based drug interactions. Materials and approaches to study drug-metabolizing enzyme-based drug interactions have improved, and become more rational based on mechanistic theory and new technologies. On the basis of incremental evidence of transporter roles in human pharmacokinetics, transporter-based drug interactions have been increasingly studied during drug development and submitted in recent NDAs. Some recently approved NMEs include transporter-based drug interaction information in their package inserts (PIs). The regulatory document "Methods of Drug Interaction Studies," in addition to recent advances in science and technology, has also contributed to plan and evaluation of drug interaction studies in recent new drug development. This review summarizes current situations and further discussion points on drug interaction studies in NDAs in Japan.

  14. Potential drug interactions in patients given antiretroviral therapy

    PubMed Central

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

    2016-01-01

    ABSTRACT Objective: to investigate potential drug-drug interactions (PDDI) in patients with HIV infection on antiretroviral therapy. Methods: a cross-sectional study was conducted on 161 adults with HIV infection. Clinical, socio demographic, and antiretroviral treatment data were collected. To analyze the potential drug interactions, we used the software Micromedex(r). Statistical analysis was performed by binary logistic regression, with a p-value of ≤0.05 considered statistically significant. Results: of the participants, 52.2% were exposed to potential drug-drug interactions. In total, there were 218 potential drug-drug interactions, of which 79.8% occurred between drugs used for antiretroviral therapy. There was an association between the use of five or more medications and potential drug-drug interactions (p = 0.000) and between the time period of antiretroviral therapy being over six years and potential drug-drug interactions (p < 0.00). The clinical impact was prevalent sedation and cardiotoxicity. Conclusions: the PDDI identified in this study of moderate and higher severity are events that not only affect the therapeutic response leading to toxicity in the central nervous and cardiovascular systems, but also can interfere in tests used for detection of HIV resistance to antiretroviral drugs. PMID:27878224

  15. 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

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

    PubMed

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

    2008-01-01

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

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

    PubMed

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

    2014-12-01

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

  18. Quantifying long-range correlations and 1/f patterns in a minimal experiment of social interaction.

    PubMed

    Bedia, Manuel G; Aguilera, Miguel; Gómez, Tomás; Larrode, David G; Seron, Francisco

    2014-01-01

    In recent years, researchers in social cognition have found the "perceptual crossing paradigm" to be both a theoretical and practical advance toward meeting particular challenges. This paradigm has been used to analyze the type of interactive processes that emerge in minimal interactions and it has allowed progress toward understanding of the principles of social cognition processes. In this paper, we analyze whether some critical aspects of these interactions could not have been observed by previous studies. We consider alternative indicators that could complete, or even lead us to rethink, the current interpretation of the results obtained from both experimental and simulated modeling in the fields of social interactions and minimal perceptual crossing. In particular, we discuss the possibility that previous experiments have been analytically constrained to a short-term dynamic type of player response. Additionally, we propose the possibility of considering these experiments from a more suitable framework based on the use and analysis of long-range correlations and fractal dynamics. We will also reveal evidence supporting the idea that social interactions are deployed along many scales of activity. Specifically, we propose that the fractal structure of the interactions could be a more adequate framework to understand the type of social interaction patterns generated in a social engagement.

  19. Quantifying long-range correlations and 1/f patterns in a minimal experiment of social interaction

    PubMed Central

    Bedia, Manuel G.; Aguilera, Miguel; Gómez, Tomás; Larrode, David G.; Seron, Francisco

    2014-01-01

    In recent years, researchers in social cognition have found the “perceptual crossing paradigm” to be both a theoretical and practical advance toward meeting particular challenges. This paradigm has been used to analyze the type of interactive processes that emerge in minimal interactions and it has allowed progress toward understanding of the principles of social cognition processes. In this paper, we analyze whether some critical aspects of these interactions could not have been observed by previous studies. We consider alternative indicators that could complete, or even lead us to rethink, the current interpretation of the results obtained from both experimental and simulated modeling in the fields of social interactions and minimal perceptual crossing. In particular, we discuss the possibility that previous experiments have been analytically constrained to a short-term dynamic type of player response. Additionally, we propose the possibility of considering these experiments from a more suitable framework based on the use and analysis of long-range correlations and fractal dynamics. We will also reveal evidence supporting the idea that social interactions are deployed along many scales of activity. Specifically, we propose that the fractal structure of the interactions could be a more adequate framework to understand the type of social interaction patterns generated in a social engagement. PMID:25429277

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

    PubMed Central

    Weinstein, Zohar B.; Zaman, Muhammad H.

    2017-01-01

    Drug interaction analysis, which reports the extent to which the presence of one drug affects the efficacy of another, is a powerful tool to select potent combinatorial therapies and predict connectivity between cellular components. Combinatorial effects of drug pairs often vary even for drugs with similar mechanism of actions. Therefore, drug interaction fingerprinting may be harnessed to differentiate drug identities. We developed a method to analyze drug interactions for the application of identifying active pharmaceutical ingredients, an essential step to assess drug quality. We developed a novel approach towards the identification of active pharmaceutical ingredients by comparing drug interaction fingerprint similarity metrics such as correlation and Euclidean distance. To expedite this method, we used bioluminescent E. coli in a simplified checkerboard assay to generate unique drug interaction fingerprints of antimicrobial drugs. Of 30 antibiotics studied, 29 could be identified based on their drug interaction fingerprints. We present drug interaction fingerprint analysis as a cheap, sensitive and quantitative method towards substandard and counterfeit drug detection. PMID:28205640

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

    PubMed

    Weinstein, Zohar B; Zaman, Muhammad H

    2017-02-16

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

  2. Updates on cytochrome P450-mediated cardiovascular drug interactions.

    PubMed

    Cheng, Judy W M; Frishman, William H; Aronow, Wilbert S

    2009-01-01

    Cytochrome P (CYP) 450 is a superfamily of hemoproteins that play an important role in the metabolism of steroid hormones, fatty acids, and many medications. Many agents used for management of cardiovascular diseases are substrates, inhibitors, or inducers of CYP450 enzymes.When two agents that are substrates, inhibitors, or inducers of CYP450 are administered together, drug interactions with significant clinical consequences may occur. This review discusses CYP450-mediated cardiovascular drug interactions as well as noncardiovascular drug interactions that produced significant cardiovascular side effects. The principles in predicting drug interactions are also discussed.

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

    PubMed

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

    2016-01-01

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

  4. Seasonal species interactions minimize the impact of species turnover on the likelihood of community persistence.

    PubMed

    Saavedra, Serguei; Rohr, Rudolf P; Fortuna, Miguel A; Selva, Nuria; Bascompte, Jordi

    2016-04-01

    Many of the observed species interactions embedded in ecological communities are not permanent, but are characterized by temporal changes that are observed along with abiotic and biotic variations. While work has been done describing and quantifying these changes, little is known about their consequences for species coexistence. Here, we investigate the extent to which changes of species composition impact the likelihood of persistence of the predator-prey community in the highly seasonal Białowieza Primeval Forest (northeast Poland), and the extent to which seasonal changes of species interactions (predator diet) modulate the expected impact. This likelihood is estimated extending recent developments on the study of structural stability in ecological communities. We find that the observed species turnover strongly varies the likelihood of community persistence between summer and winter. Importantly, we demonstrate that the observed seasonal interaction changes minimize the variation in the likelihood of persistence associated with species turnover across the year. We find that these community dynamics can be explained as the coupling of individual species to their environment by minimizing both the variation in persistence conditions and the interaction changes between seasons. Our results provide a homeostatic explanation for seasonal species interactions and suggest that monitoring the association of interactions changes with the level of variation in community dynamics can provide a good indicator of the response of species to environmental pressures.

  5. 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.

  6. Biophysical interactions with model lipid membranes: applications in drug discovery and drug delivery

    PubMed Central

    Peetla, Chiranjeevi; Stine, Andrew; Labhasetwar, Vinod

    2009-01-01

    The transport of drugs or drug delivery systems across the cell membrane is a complex biological process, often difficult to understand because of its dynamic nature. In this regard, model lipid membranes, which mimic many aspects of cell-membrane lipids, have been very useful in helping investigators to discern the roles of lipids in cellular interactions. One can use drug-lipid interactions to predict pharmacokinetic properties of drugs, such as their transport, biodistribution, accumulation, and hence efficacy. These interactions can also be used to study the mechanisms of transport, based on the structure and hydrophilicity/hydrophobicity of drug molecules. In recent years, model lipid membranes have also been explored to understand their mechanisms of interactions with peptides, polymers, and nanocarriers. These interaction studies can be used to design and develop efficient drug delivery systems. Changes in the lipid composition of cells and tissue in certain disease conditions may alter biophysical interactions, which could be explored to develop target-specific drugs and drug delivery systems. In this review, we discuss different model membranes, drug-lipid interactions and their significance, studies of model membrane interactions with nanocarriers, and how biophysical interaction studies with lipid model membranes could play an important role in drug discovery and drug delivery. PMID:19432455

  7. 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

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

    PubMed Central

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

    2016-01-01

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

  9. Sculpting proteins interactively: continual energy minimization embedded in a graphical modeling system.

    PubMed Central

    Surles, M. C.; Richardson, J. S.; Richardson, D. C.; Brooks, F. P.

    1994-01-01

    We describe a new paradigm for modeling proteins in interactive computer graphics systems--continual maintenance of a physically valid representation, combined with direct user control and visualization. This is achieved by a fast algorithm for energy minimization, capable of real-time performance on all atoms of a small protein, plus graphically specified user tugs. The modeling system, called Sculpt, rigidly constrains bond lengths, bond angles, and planar groups (similar to existing interactive modeling programs), while it applies elastic restraints to minimize the potential energy due to torsions, hydrogen bonds, and van der Waals and electrostatic interactions (similar to existing batch minimization programs), and user-specified springs. The graphical interface can show bad and/or favorable contacts, and individual energy terms can be turned on or off to determine their effects and interactions. Sculpt finds a local minimum of the total energy that satisfies all the constraints using an augmented Lagrange-multiplier method; calculation time increases only linearly with the number of atoms because the matrix of constraint gradients is sparse and banded. On a 100-MHz MIPS R4000 processor (Silicon Graphics Indigo), Sculpt achieves 11 updates per second on a 20-residue fragment and 2 updates per second on an 80-residue protein, using all atoms except non-H-bonding hydrogens, and without electrostatic interactions. Applications of Sculpt are described: to reverse the direction of bundle packing in a designed 4-helix bundle protein, to fold up a 2-stranded beta-ribbon into an approximate beta-barrel, and to design the sequence and conformation of a 30-residue peptide that mimics one partner of a protein subunit interaction. Computer models that are both interactive and physically realistic (within the limitations of a given force field) have 2 significant advantages: (1) they make feasible the modeling of very large changes (such as needed for de novo design), and

  10. Sculpting proteins interactively: continual energy minimization embedded in a graphical modeling system.

    PubMed

    Surles, M C; Richardson, J S; Richardson, D C; Brooks, F P

    1994-02-01

    We describe a new paradigm for modeling proteins in interactive computer graphics systems--continual maintenance of a physically valid representation, combined with direct user control and visualization. This is achieved by a fast algorithm for energy minimization, capable of real-time performance on all atoms of a small protein, plus graphically specified user tugs. The modeling system, called Sculpt, rigidly constrains bond lengths, bond angles, and planar groups (similar to existing interactive modeling programs), while it applies elastic restraints to minimize the potential energy due to torsions, hydrogen bonds, and van der Waals and electrostatic interactions (similar to existing batch minimization programs), and user-specified springs. The graphical interface can show bad and/or favorable contacts, and individual energy terms can be turned on or off to determine their effects and interactions. Sculpt finds a local minimum of the total energy that satisfies all the constraints using an augmented Lagrange-multiplier method; calculation time increases only linearly with the number of atoms because the matrix of constraint gradients is sparse and banded. On a 100-MHz MIPS R4000 processor (Silicon Graphics Indigo), Sculpt achieves 11 updates per second on a 20-residue fragment and 2 updates per second on an 80-residue protein, using all atoms except non-H-bonding hydrogens, and without electrostatic interactions. Applications of Sculpt are described: to reverse the direction of bundle packing in a designed 4-helix bundle protein, to fold up a 2-stranded beta-ribbon into an approximate beta-barrel, and to design the sequence and conformation of a 30-residue peptide that mimics one partner of a protein subunit interaction. Computer models that are both interactive and physically realistic (within the limitations of a given force field) have 2 significant advantages: (1) they make feasible the modeling of very large changes (such as needed for de novo design), and

  11. Structure and thermodynamics of Drug-RNA aptamer interactions.

    PubMed

    Da Costa, J B; Dieckmann, T

    2013-04-01

    This mini-review will provide an overview on the recent studies of structure and thermodynamics of RNA aptamers that target drug molecules. These aptamers are studied to provide insight into RNA drug interactions. This interaction is important due to the many roles RNA plays in cell biology.

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

    PubMed

    Freeman, Camille; Spelman, Kevin

    2008-07-01

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

  13. An adverse drug interaction of haloperidol with levodopa.

    PubMed

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

    2015-01-01

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

  14. Drug interactions involving antiepileptic drugs: assessment of the consistency among three drug compendia and FDA-approved labels.

    PubMed

    Ekstein, Dana; Tirosh, Matanya; Eyal, Yonatan; Eyal, Sara

    2015-03-01

    Interactions of antiepileptic drugs (AEDs) with other substances may lead to adverse effects and treatment failure. To avoid such interactions, clinicians often rely on drug interaction compendia. Our objective was to compare the concordance for twenty-two AEDs among three drug interaction compendia (Micromedex, Lexi-Interact, and Clinical Pharmacology) and the US Food and Drug Administration-approved product labels. For each AED, the overall concordance among data sources regarding existence of interactions and their classification was poor, with less than twenty percent of interactions listed in all four sources. Concordance among the three drug compendia decreased with the fraction of the drug excreted unchanged and was greater for established inducers of hepatic drug-metabolizing enzymes than for the drugs that are not inducers (R-square=0.83, P<0.01). For interactions classified as contraindications, major, and severe, concordance among the four data sources was, in most cases, less than 30%. Prescribers should be aware of the differences between drug interaction sources of information for both older AEDs and newer AEDs, in particular for those AEDs which are not involved in hepatic enzyme-mediated interactions.

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

    PubMed

    Petersen, Karl-Uwe

    2011-08-01

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

  16. Membrane–drug interactions studied using model membrane systems

    PubMed Central

    Knobloch, Jacqueline; Suhendro, Daniel K.; Zieleniecki, Julius L.; Shapter, Joseph G.; Köper, Ingo

    2015-01-01

    The direct interaction of drugs with the cell membrane is often neglected when drug effects are studied. Systematic investigations are hindered by the complexity of the natural membrane and model membrane systems can offer a useful alternative. Here some examples are reviewed of how model membrane architectures including vesicles, Langmuir monolayers and solid supported membranes can be used to investigate the effects of drug molecules on the membrane structure, and how these interactions can translate into effects on embedded membrane proteins. PMID:26586998

  17. Our knowledge of drug interactions with oral contraceptives.

    PubMed

    Seregély, G

    1989-01-01

    In the introduction the author points out the importance, mechanism and consequence of interactions between oral contraceptives and other drugs. The interactions between certain drugs with different pharmacological action and the contraceptive tablets which decrease or increase the contraceptive effect as well as the drugs whose effect may be influenced by the contraceptive tablets have been discussed. Cases in which only a few data refer to, or no clinical proof supports interaction, are also mentioned. According to interactions observed until present in women taking Anteovin, the recommended measures to be taken in these cases have been described. Finally it has been emphasized that the knowledge of interactions between drugs is just as important in family planning counselling as is when prescribing other drug treatments.

  18. 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

  19. Pharmacokinetic Drug Interactions of Antimicrobial Drugs: A Systematic Review on Oxazolidinones, Rifamycines, Macrolides, Fluoroquinolones, and Beta-Lactams.

    PubMed

    Bolhuis, Mathieu S; Panday, Prashant N; Pranger, Arianna D; Kosterink, Jos G W; Alffenaar, Jan-Willem C

    2011-11-18

    Like any other drug, antimicrobial drugs are prone to pharmacokinetic drug interactions. These drug interactions are a major concern in clinical practice as they may have an effect on efficacy and toxicity. This article provides an overview of all published pharmacokinetic studies on drug interactions of the commonly prescribed antimicrobial drugs oxazolidinones, rifamycines, macrolides, fluoroquinolones, and beta-lactams, focusing on systematic research. We describe drug-food and drug-drug interaction studies in humans, affecting antimicrobial drugs as well as concomitantly administered drugs. Since knowledge about mechanisms is of paramount importance for adequate management of drug interactions, the most plausible underlying mechanism of the drug interaction is provided when available. This overview can be used in daily practice to support the management of pharmacokinetic drug interactions of antimicrobial drugs.

  20. Deep-Learning-Based Drug-Target Interaction Prediction.

    PubMed

    Wen, Ming; Zhang, Zhimin; Niu, Shaoyu; Sha, Haozhi; Yang, Ruihan; Yun, Yonghuan; Lu, Hongmei

    2017-04-07

    Identifying interactions between known drugs and targets is a major challenge in drug repositioning. In silico prediction of drug-target interaction (DTI) can speed up the expensive and time-consuming experimental work by providing the most potent DTIs. In silico prediction of DTI can also provide insights about the potential drug-drug interaction and promote the exploration of drug side effects. Traditionally, the performance of DTI prediction depends heavily on the descriptors used to represent the drugs and the target proteins. In this paper, to accurately predict new DTIs between approved drugs and targets without separating the targets into different classes, we developed a deep-learning-based algorithmic framework named DeepDTIs. It first abstracts representations from raw input descriptors using unsupervised pretraining and then applies known label pairs of interaction to build a classification model. Compared with other methods, it is found that DeepDTIs reaches or outperforms other state-of-the-art methods. The DeepDTIs can be further used to predict whether a new drug targets to some existing targets or whether a new target interacts with some existing drugs.

  1. An eigenvalue transformation technique for predicting drug-target interaction.

    PubMed

    Kuang, Qifan; Xu, Xin; Li, Rong; Dong, Yongcheng; Li, Yan; Huang, Ziyan; Li, Yizhou; Li, Menglong

    2015-09-09

    The prediction of drug-target interactions is a key step in the drug discovery process, which serves to identify new drugs or novel targets for existing drugs. However, experimental methods for predicting drug-target interactions are expensive and time-consuming. Therefore, the in silico prediction of drug-target interactions has recently attracted increasing attention. In this study, we propose an eigenvalue transformation technique and apply this technique to two representative algorithms, the Regularized Least Squares classifier (RLS) and the semi-supervised link prediction classifier (SLP), that have been used to predict drug-target interaction. The results of computational experiments with these techniques show that algorithms including eigenvalue transformation achieved better performance on drug-target interaction prediction than did the original algorithms. These findings show that eigenvalue transformation is an efficient technique for improving the performance of methods for predicting drug-target interactions. We further show that, in theory, eigenvalue transformation can be viewed as a feature transformation on the kernel matrix. Accordingly, although we only apply this technique to two algorithms in the current study, eigenvalue transformation also has the potential to be applied to other algorithms based on kernels.

  2. iDrug-Target: predicting the interactions between drug compounds and target proteins in cellular networking via benchmark dataset optimization approach.

    PubMed

    Xiao, Xuan; Min, Jian-Liang; Lin, Wei-Zhong; Liu, Zi; Cheng, Xiang; Chou, Kuo-Chen

    2015-01-01

    Information about the interactions of drug compounds with proteins in cellular networking is very important for drug development. Unfortunately, all the existing predictors for identifying drug-protein interactions were trained by a skewed benchmark data-set where the number of non-interactive drug-protein pairs is overwhelmingly larger than that of the interactive ones. Using this kind of highly unbalanced benchmark data-set to train predictors would lead to the outcome that many interactive drug-protein pairs might be mispredicted as non-interactive. Since the minority interactive pairs often contain the most important information for drug design, it is necessary to minimize this kind of misprediction. In this study, we adopted the neighborhood cleaning rule and synthetic minority over-sampling technique to treat the skewed benchmark datasets and balance the positive and negative subsets. The new benchmark datasets thus obtained are called the optimized benchmark datasets, based on which a new predictor called iDrug-Target was developed that contains four sub-predictors: iDrug-GPCR, iDrug-Chl, iDrug-Ezy, and iDrug-NR, specialized for identifying the interactions of drug compounds with GPCRs (G-protein-coupled receptors), ion channels, enzymes, and NR (nuclear receptors), respectively. Rigorous cross-validations on a set of experiment-confirmed datasets have indicated that these new predictors remarkably outperformed the existing ones for the same purpose. To maximize users' convenience, a public accessible Web server for iDrug-Target has been established at http://www.jci-bioinfo.cn/iDrug-Target/ , by which users can easily get their desired results. It has not escaped our notice that the aforementioned strategy can be widely used in many other areas as well.

  3. Definition of a minimal munc18c domain that interacts with syntaxin 4.

    PubMed

    Grusovin, J; Stoichevska, V; Gough, K H; Nunan, K; Ward, C W; Macaulay, S L

    2000-09-15

    munc18c is a critical protein involved in trafficking events associated with syntaxin 4 and which also mediates inhibitory effects on vesicle docking and/or fusion. To investigate the domains of munc18c responsible for its interaction with syntaxin 4, fragments of munc18c were generated and their interaction with syntaxin 4 examined in vivo by the yeast two-hybrid assay. In vitro protein-protein interaction studies were then used to confirm that the interaction between the proteins was direct. Full-length munc18c(1-592), munc18c(1-139) and munc18c(1-225), but not munc18c(226-592), munc18c(1-100), munc18c(43-139) or munc18c(66-139), interacted with the cytoplasmic portion of syntaxin 4, Stx4(2-273), as assessed by yeast two-hybrid assay of growth on nutritionally deficient media and by beta-galactosidase reporter induction. The N-terminal predicted helix-a-helix-b-helix-c region of syntaxin 4, Stx4(29-157), failed to interact with full-length munc18c(1-592), indicating that a larger portion of syntaxin 4 is necessary for the interaction. The yeast two-hybrid results were confirmed by protein-protein interaction studies between Stx4(2-273) and glutathione S-transferase fusion proteins of munc18c. Full-length munc18c(1-592), munc18c(1-139) and munc18c(1-225) interacted with Stx4(2-273) whereas munc18c(1-100) did not, consistent with the yeast two-hybrid data. These data thus identify a region of munc18c between residues 1 and 139 as a minimal domain for its interaction with syntaxin 4.

  4. Cartilage-targeting drug delivery: can electrostatic interactions help?

    PubMed

    Bajpayee, Ambika G; Grodzinsky, Alan J

    2017-03-01

    Current intra-articular drug delivery methods do not guarantee sufficient drug penetration into cartilage tissue to reach cell and matrix targets at the concentrations necessary to elicit the desired biological response. Here, we provide our perspective on the utilization of charge-charge (electrostatic) interactions to enhance drug penetration and transport into cartilage, and to enable sustained binding of drugs within the tissue's highly negatively charged extracellular matrix. By coupling drugs to positively charged nanocarriers that have optimal size and charge, cartilage can be converted from a drug barrier into a drug reservoir for sustained intra-tissue delivery. Alternatively, a wide variety of drugs themselves can be made cartilage-penetrating by functionalizing them with specialized positively charged protein domains. Finally, we emphasize that appropriate animal models, with cartilage thickness similar to that of humans, must be used for the study of drug transport and retention in cartilage.

  5. Interaction of amphiphilic drugs with human and bovine serum albumins

    NASA Astrophysics Data System (ADS)

    Khan, Abbul Bashar; Khan, Javed Masood; Ali, Mohd. Sajid; Khan, Rizwan Hasan; Kabir-ud-Din

    2012-11-01

    To know the interaction of amphiphilic drugs nortriptyline hydrochloride (NOT) and promazine hydrochloride (PMZ) with serum albumins (i.e., human serum albumin (HSA) and bovine serum albumin (BSA)), techniques of UV-visible, fluorescence, and circular dichroism (CD) spectroscopies are used. The binding affinity is more in case of PMZ with both the serum albumins. The quenching rate constant (kq) values suggest a static quenching process for all the drug-serum albumin interactions. The UV-visible results show that the change in protein conformation of PMZ-serum albumin interactions are more prominent as compared to NOT-serum albumin interactions. The CD results also explain the conformational changes in the serum albumins on binding with the drugs. The increment in %α-helical structure is slightly more for drug-BSA complexes as compared to drug-HSA complexes.

  6. Interaction of amphiphilic drugs with human and bovine serum albumins.

    PubMed

    Khan, Abbul Bashar; Khan, Javed Masood; Ali, Mohd Sajid; Khan, Rizwan Hasan; Kabir-Ud-Din

    2012-11-01

    To know the interaction of amphiphilic drugs nortriptyline hydrochloride (NOT) and promazine hydrochloride (PMZ) with serum albumins (i.e., human serum albumin (HSA) and bovine serum albumin (BSA)), techniques of UV-visible, fluorescence, and circular dichroism (CD) spectroscopies are used. The binding affinity is more in case of PMZ with both the serum albumins. The quenching rate constant (k(q)) values suggest a static quenching process for all the drug-serum albumin interactions. The UV-visible results show that the change in protein conformation of PMZ-serum albumin interactions are more prominent as compared to NOT-serum albumin interactions. The CD results also explain the conformational changes in the serum albumins on binding with the drugs. The increment in %α-helical structure is slightly more for drug-BSA complexes as compared to drug-HSA complexes.

  7. 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

  8. Pediatric Minimal Knowledge and Skills: The First Step in Developing a Curriculum in Alcohol and Other Drugs for Pediatricians.

    ERIC Educational Resources Information Center

    Adger, Hoover; And Others

    Based on an initial group of consensus statements developed at the Annenburg Center for Health Science Conference in November 1985, this resource manual for alcohol and other drug abuse education specifies minimum knowledge and skills levels for pediatric physicians. A first section details minimal knowledge and skills in alcohol and other drug…

  9. Clinically and pharmacologically relevant interactions of antidiabetic drugs

    PubMed Central

    May, Marcus; Schindler, Christoph

    2016-01-01

    Patients with type 2 diabetes mellitus often require multifactorial pharmacological treatment due to different comorbidities. An increasing number of concomitantly taken medications elevate the risk of the patient experiencing adverse drug effects or drug interactions. Drug interactions can be divided into pharmacokinetic and pharmacodynamic interactions affecting cytochrome (CYP) enzymes, absorption properties, transporter activities and receptor affinities. Furthermore, nutrition, herbal supplements, patient’s age and gender are of clinical importance. Relevant drug interactions are predominantly related to sulfonylureas, thiazolidinediones and glinides. Although metformin has a very low interaction potential, caution is advised when drugs that impair renal function are used concomitantly. With the exception of saxagliptin, dipeptidyl peptidase-4 (DPP-4) inhibitors also show a low interaction potential, but all drugs affecting the drug transporter P-glycoprotein should be used with caution. Incretin mimetics and sodium–glucose cotransporter-2 (SGLT-2) inhibitors comprise a very low interaction potential and are therefore recommended as an ideal combination partner from the clinical–pharmacologic point of view. PMID:27092232

  10. Herb–Drug Interactions: Challenges and Opportunities for Improved Predictions

    PubMed Central

    Brantley, Scott J.; Argikar, Aneesh A.; Lin, Yvonne S.; Nagar, Swati

    2014-01-01

    Supported by a usage history that predates written records and the perception that “natural” ensures safety, herbal products have increasingly been incorporated into Western health care. Consumers often self-administer these products concomitantly with conventional medications without informing their health care provider(s). Such herb–drug combinations can produce untoward effects when the herbal product perturbs the activity of drug metabolizing enzymes and/or transporters. Despite increasing recognition of these types of herb–drug interactions, a standard system for interaction prediction and evaluation is nonexistent. Consequently, the mechanisms underlying herb–drug interactions remain an understudied area of pharmacotherapy. Evaluation of herbal product interaction liability is challenging due to variability in herbal product composition, uncertainty of the causative constituents, and often scant knowledge of causative constituent pharmacokinetics. These limitations are confounded further by the varying perspectives concerning herbal product regulation. Systematic evaluation of herbal product drug interaction liability, as is routine for new drugs under development, necessitates identifying individual constituents from herbal products and characterizing the interaction potential of such constituents. Integration of this information into in silico models that estimate the pharmacokinetics of individual constituents should facilitate prospective identification of herb–drug interactions. These concepts are highlighted with the exemplar herbal products milk thistle and resveratrol. Implementation of this methodology should help provide definitive information to both consumers and clinicians about the risk of adding herbal products to conventional pharmacotherapeutic regimens. PMID:24335390

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

    PubMed

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

    2014-07-01

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

  12. Minimizing the injury potential of deploying airbag interactions with car occupants.

    PubMed

    Mertz, Harold J; Prasad, Priya; Dalmotas, Dainius

    2013-11-01

    Minimizing the injury potential of the interactions between deploying airbags and car occupants is the major issue with the design of airbag systems. This concern was identified in 1964 by Carl Clark when he presented the results of human volunteer and dummy testing of the "Airstop" system that was being developed for aircraft. The following is a chronological summary of the actions taken by the car manufacturers, airbag suppliers, SAE and ISO task groups, research institutes and universities, and consumer and government groups to address this issue.

  13. 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.

  14. 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

  15. Herbal product–drug interactions mediated by induction

    PubMed Central

    Tirona, Rommel G; Bailey, David G

    2006-01-01

    Despite their common use, it is not widely recognized that herbal medicines can alter the efficacy of coadministered prescription drugs. Constituents in herbs interact with nuclear receptors to enhance metabolizing enzyme and/or transporter activity leading to reduced drug concentrations. Although St John’s wort was the first and most frequently reported source of induction-style herb–drug interactions, this knowledge has not yet changed its current availability. This type of interaction is likely to be relevant to other herbal products. Caregivers need to be aware of the issues and options for therapeutic management. PMID:16722828

  16. Exploiting large-scale drug-protein interaction information for computational drug repurposing

    PubMed Central

    2014-01-01

    Background Despite increased investment in pharmaceutical research and development, fewer and fewer new drugs are entering the marketplace. This has prompted studies in repurposing existing drugs for use against diseases with unmet medical needs. A popular approach is to develop a classification model based on drugs with and without a desired therapeutic effect. For this approach to be statistically sound, it requires a large number of drugs in both classes. However, given few or no approved drugs for the diseases of highest medical urgency and interest, different strategies need to be investigated. Results We developed a computational method termed “drug-protein interaction-based repurposing” (DPIR) that is potentially applicable to diseases with very few approved drugs. The method, based on genome-wide drug-protein interaction information and Bayesian statistics, first identifies drug-protein interactions associated with a desired therapeutic effect. Then, it uses key drug-protein interactions to score other drugs for their potential to have the same therapeutic effect. Conclusions Detailed cross-validation studies using United States Food and Drug Administration-approved drugs for hypertension, human immunodeficiency virus, and malaria indicated that DPIR provides robust predictions. It achieves high levels of enrichment of drugs approved for a disease even with models developed based on a single drug known to treat the disease. Analysis of our model predictions also indicated that the method is potentially useful for understanding molecular mechanisms of drug action and for identifying protein targets that may potentiate the desired therapeutic effects of other drugs (combination therapies). PMID:24950817

  17. Predicting drug-target interactions using restricted Boltzmann machines

    PubMed Central

    Wang, Yuhao; Zeng, Jianyang

    2013-01-01

    Motivation: In silico prediction of drug-target interactions plays an important role toward identifying and developing new uses of existing or abandoned drugs. Network-based approaches have recently become a popular tool for discovering new drug-target interactions (DTIs). Unfortunately, most of these network-based approaches can only predict binary interactions between drugs and targets, and information about different types of interactions has not been well exploited for DTI prediction in previous studies. On the other hand, incorporating additional information about drug-target relationships or drug modes of action can improve prediction of DTIs. Furthermore, the predicted types of DTIs can broaden our understanding about the molecular basis of drug action. Results: We propose a first machine learning approach to integrate multiple types of DTIs and predict unknown drug-target relationships or drug modes of action. We cast the new DTI prediction problem into a two-layer graphical model, called restricted Boltzmann machine, and apply a practical learning algorithm to train our model and make predictions. Tests on two public databases show that our restricted Boltzmann machine model can effectively capture the latent features of a DTI network and achieve excellent performance on predicting different types of DTIs, with the area under precision-recall curve up to 89.6. In addition, we demonstrate that integrating multiple types of DTIs can significantly outperform other predictions either by simply mixing multiple types of interactions without distinction or using only a single interaction type. Further tests show that our approach can infer a high fraction of novel DTIs that has been validated by known experiments in the literature or other databases. These results indicate that our approach can have highly practical relevance to DTI prediction and drug repositioning, and hence advance the drug discovery process. Availability: Software and datasets are available

  18. Data-driven prediction of drug effects and interactions.

    PubMed

    Tatonetti, Nicholas P; Ye, Patrick P; Daneshjou, Roxana; Altman, Russ B

    2012-03-14

    Adverse drug events remain a leading cause of morbidity and mortality around the world. Many adverse events are not detected during clinical trials before a drug receives approval for use in the clinic. Fortunately, as part of postmarketing surveillance, regulatory agencies and other institutions maintain large collections of adverse event reports, and these databases present an opportunity to study drug effects from patient population data. However, confounding factors such as concomitant medications, patient demographics, patient medical histories, and reasons for prescribing a drug often are uncharacterized in spontaneous reporting systems, and these omissions can limit the use of quantitative signal detection methods used in the analysis of such data. Here, we present an adaptive data-driven approach for correcting these factors in cases for which the covariates are unknown or unmeasured and combine this approach with existing methods to improve analyses of drug effects using three test data sets. We also present a comprehensive database of drug effects (Offsides) and a database of drug-drug interaction side effects (Twosides). To demonstrate the biological use of these new resources, we used them to identify drug targets, predict drug indications, and discover drug class interactions. We then corroborated 47 (P < 0.0001) of the drug class interactions using an independent analysis of electronic medical records. Our analysis suggests that combined treatment with selective serotonin reuptake inhibitors and thiazides is associated with significantly increased incidence of prolonged QT intervals. We conclude that confounding effects from covariates in observational clinical data can be controlled in data analyses and thus improve the detection and prediction of adverse drug effects and interactions.

  19. Herb–drug interactions: Review and assessment of report reliability

    PubMed Central

    Fugh-Berman, Adriane; Ernst, E

    2001-01-01

    Aims The aim of this systematic review was to assess the published clinical evidence on interactions between herbal and conventional drugs. Methods Four electronic databases were searched for case reports, case series or clinical trials of such interactions. The data were extracted and validated using a scoring system for interaction probability. Results One hundred and eight cases of suspected interactions were found. 68.5% were classified as ‘unable to be evaluated’, 13% as ‘well-documented’ and 18.5% as ‘possible’ interactions. Warfarin was the most common drug (18 cases) and St John's wort the most common herb (54 cases) involved. Conclusion Herb–drug interactions undoubtedly do occur and may put individuals at risk. However our present knowledge is incomplete and more research is urgently needed. PMID:11736868

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

    PubMed

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

    2005-08-01

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

  1. Cytochrome P450 enzyme mediated herbal drug interactions (Part 2)

    PubMed Central

    Wanwimolruk, Sompon; Phopin, Kamonrat; Prachayasittikul, Virapong

    2014-01-01

    To date, a number of significant herbal drug interactions have their origins in the alteration of cytochrome P450 (CYP) activity by various phytochemicals. Among the most noteworthy are those involving St. John's wort and drugs metabolized by human CYP3A4 enzyme. This review article is the continued work from our previous article (Part 1) published in this journal (Wanwimolruk and Prachayasittikul, 2014[ref:133]). This article extends the scope of the review to six more herbs and updates information on herbal drug interactions. These include black cohosh, ginseng, grape seed extract, green tea, kava, saw palmetto and some important Chinese medicines are also presented. Even though there have been many studies to determine the effects of herbs and herbal medicines on the activity of CYP, most of them were in vitro and in animal studies. Therefore, the studies are limited in predicting the clinical relevance of herbal drug interactions. It appeared that the majority of the herbal medicines have no clear effects on most of the CYPs examined. For example, the existing clinical trial data imply that black cohosh, ginseng and saw palmetto are unlikely to affect the pharmacokinetics of conventional drugs metabolized by human CYPs. For grape seed extract and green tea, adverse herbal drug interactions are unlikely when they are concomitantly taken with prescription drugs that are CYP substrates. Although there were few clinical studies on potential CYP-mediated interactions produced by kava, present data suggest that kava supplements have the ability to inhibit CYP1A2 and CYP2E1 significantly. Therefore, caution should be taken when patients take kava with CYP1A2 or CYP2E1 substrate drugs as it may enhance their therapeutic and adverse effects. Despite the long use of traditional Chinese herbal medicines, little is known about the potential drug interactions with these herbs. Many popularly used Chinese medicines have been shown in vitro to significantly change the

  2. Integrating risk minimization planning throughout the clinical development and commercialization lifecycle: an opinion on how drug development could be improved

    PubMed Central

    Morrato, Elaine H; Smith, Meredith Y

    2015-01-01

    Pharmaceutical risk minimization programs are now an established requirement in the regulatory landscape. However, pharmaceutical companies have been slow to recognize and embrace the significant potential these programs offer in terms of enhancing trust with health care professionals and patients, and for providing a mechanism for bringing products to the market that might not otherwise have been approved. Pitfalls of the current drug development process include risk minimization programs that are not data driven; missed opportunities to incorporate pragmatic methods and market-based insights, outmoded tools and data sources, lack of rapid evaluative learning to support timely adaption, lack of systematic approaches for patient engagement, and questions on staffing and organizational infrastructure. We propose better integration of risk minimization with clinical drug development and commercialization work streams throughout the product lifecycle. We articulate a vision and propose broad adoption of organizational models for incorporating risk minimization expertise into the drug development process. Three organizational models are discussed and compared: outsource/external vendor, embedded risk management specialist model, and Center of Excellence. PMID:25750537

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

    PubMed

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

    2014-09-01

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

  4. Clinically relevant drug–drug interactions in oncology

    PubMed Central

    McLeod, Howard L

    1998-01-01

    Although anticancer agents are one of the most toxic classes of medication prescribed today, there is relatively little information available about clinically relevant drug–drug interactions. Pharmacokinetic drug interactions have been described, including alterations in absorption, catabolism, and excretion. For example, an increased bioavailability of 6-mercaptopurine has been observed when combined with either allopurinol or methotrexate, leading to increased toxicity in some patients. Induction of etoposide or teniposide clearance by anticonvulsants has also been described, resulting in a lower systemic exposure and risk for lower anticancer activity. Alterations in elimination of methotrexate has been observed with probenecid, presumably through competition for renal secretion. There are also several examples of pharmacodynamic interactions. The combination of 5-fluorouracil plus folinic acid results in more efficient inhibition of thymidylate synthase, a finding which is now utilized routinely in the treatment of colorectal cancer. Improvements in the in vitro and early clinical testing now allow a relatively high degree of prediction of potential clinical drug interactions, prior to observations of untoward drug effects. In conclusion, drug interactions among commonly used anticancer agents have been identified. Their clinical significance can have more impact than many other classes of medications due to the narrow therapeutic index of antineoplastic agents and the potential for lethal side-effects. It is only through prospective, preclinical and early clinical evaluation that the presence of clinically significant drug interactions can be identified and the information used to provide better therapy for this significant health problem. PMID:9663808

  5. Predicting drug-target interactions using probabilistic matrix factorization.

    PubMed

    Cobanoglu, Murat Can; Liu, Chang; Hu, Feizhuo; Oltvai, Zoltán N; Bahar, Ivet

    2013-12-23

    Quantitative analysis of known drug-target interactions emerged in recent years as a useful approach for drug repurposing and assessing side effects. In the present study, we present a method that uses probabilistic matrix factorization (PMF) for this purpose, which is particularly useful for analyzing large interaction networks. DrugBank drugs clustered based on PMF latent variables show phenotypic similarity even in the absence of 3D shape similarity. Benchmarking computations show that the method outperforms those recently introduced provided that the input data set of known interactions is sufficiently large--which is the case for enzymes and ion channels, but not for G-protein coupled receptors (GPCRs) and nuclear receptors. Runs performed on DrugBank after hiding 70% of known interactions show that, on average, 88 of the top 100 predictions hit the hidden interactions. De novo predictions permit us to identify new potential interactions. Drug-target pairs implicated in neurobiological disorders are overrepresented among de novo predictions.

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed

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

    2012-03-12

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

  8. Transdermal patch drug delivery interactions with exercise.

    PubMed

    Lenz, Thomas L; Gillespie, Nicole

    2011-03-01

    Transdermal drug delivery systems, such as the transdermal patch, continue to be a popular and convenient way to administer medications. There are currently several medications that use a transdermal patch drug delivery system. This article describes the potential untoward side effects of increased drug absorption through the use of a transdermal patch in individuals who exercise or participate in sporting events. Four studies have been reported that demonstrate a significant increase in the plasma concentration of nitroglycerin when individuals exercise compared with rest. Likewise, several case reports and two studies have been conducted that demonstrate nicotine toxicity and increased plasma nicotine while wearing a nicotine patch in individuals who exercise or participate in sporting events compared with rest. Healthcare providers, trainers and coaches should be aware of proper transdermal patch use, especially while exercising, in order to provide needed information to their respective patients and athletes to avoid potential untoward side effects. Particular caution should be given to individuals who participate in an extreme sporting event of long duration. Further research that includes more medications is needed in this area.

  9. Interactive association of drugs binding to human serum albumin.

    PubMed

    Yang, Feng; Zhang, Yao; Liang, Hong

    2014-02-27

    Human serum albumin (HSA) is an abundant plasma protein, which attracts great interest in the pharmaceutical industry since it can bind a remarkable variety of drugs impacting their delivery and efficacy and ultimately altering the drug's pharmacokinetic and pharmacodynamic properties. Additionally, HSA is widely used in clinical settings as a drug delivery system due to its potential for improving targeting while decreasing the side effects of drugs. It is thus of great importance from the viewpoint of pharmaceutical sciences to clarify the structure, function, and properties of HSA-drug complexes. This review will succinctly outline the properties of binding site of drugs in IIA subdomain within the structure of HSA. We will also give an overview on the binding characterization of interactive association of drugs to human serum albumin that may potentially lead to significant clinical applications.

  10. Developing a molecular roadmap of drug-food interactions.

    PubMed

    Jensen, Kasper; Ni, Yueqiong; Panagiotou, Gianni; Kouskoumvekaki, Irene

    2015-02-01

    Recent research has demonstrated that consumption of food -especially fruits and vegetables- can alter the effects of drugs by interfering either with their pharmacokinetic or pharmacodynamic processes. Despite the recognition of such drug-food associations as an important element for successful therapeutic interventions, a systematic approach for identifying, predicting and preventing potential interactions between food and marketed or novel drugs is not yet available. The overall objective of this work was to sketch a comprehensive picture of the interference of ∼ 4,000 dietary components present in ∼1800 plant-based foods with the pharmacokinetics and pharmacodynamics processes of medicine, with the purpose of elucidating the molecular mechanisms involved. By employing a systems chemical biology approach that integrates data from the scientific literature and online databases, we gained a global view of the associations between diet and dietary molecules with drug targets, metabolic enzymes, drug transporters and carriers currently deposited in DrugBank. Moreover, we identified disease areas and drug targets that are most prone to the negative effects of drug-food interactions, showcasing a platform for making recommendations in relation to foods that should be avoided under certain medications. Lastly, by investigating the correlation of gene expression signatures of foods and drugs we were able to generate a completely novel drug-diet interactome map.

  11. Developing a Molecular Roadmap of Drug-Food Interactions

    PubMed Central

    Jensen, Kasper; Ni, Yueqiong; Panagiotou, Gianni; Kouskoumvekaki, Irene

    2015-01-01

    Recent research has demonstrated that consumption of food -especially fruits and vegetables- can alter the effects of drugs by interfering either with their pharmacokinetic or pharmacodynamic processes. Despite the recognition of such drug-food associations as an important element for successful therapeutic interventions, a systematic approach for identifying, predicting and preventing potential interactions between food and marketed or novel drugs is not yet available. The overall objective of this work was to sketch a comprehensive picture of the interference of ∼ 4,000 dietary components present in ∼1800 plant-based foods with the pharmacokinetics and pharmacodynamics processes of medicine, with the purpose of elucidating the molecular mechanisms involved. By employing a systems chemical biology approach that integrates data from the scientific literature and online databases, we gained a global view of the associations between diet and dietary molecules with drug targets, metabolic enzymes, drug transporters and carriers currently deposited in DrugBank. Moreover, we identified disease areas and drug targets that are most prone to the negative effects of drug-food interactions, showcasing a platform for making recommendations in relation to foods that should be avoided under certain medications. Lastly, by investigating the correlation of gene expression signatures of foods and drugs we were able to generate a completely novel drug-diet interactome map. PMID:25668218

  12. Herb–drug interactions: an overview of systematic reviews

    PubMed Central

    Posadzki, Paul; Watson, Leala; Ernst, Edzard

    2013-01-01

    OBJECTIVES The aim of this overview of systematic reviews (SRs) is to evaluate critically the evidence regarding interactions between herbal medicinal products (HMPs) and synthetic drugs. METHODS Four electronic databases were searched to identify relevant SRs. RESULTS Forty‐six SRs of 46 different HMPs met our inclusion criteria. The vast majority of SRs were of poor methodological quality. The majority of these HMPs were not associated with severe herb–drug interactions. Serious herb–drug interactions were noted for Hypericum perforatum and Viscum album. The most severe interactions resulted in transplant rejection, delayed emergence from anaesthesia, cardiovascular collapse, renal and liver toxicity, cardiotoxicity, bradycardia, hypovolaemic shock, inflammatory reactions with organ fibrosis and death. Moderately severe interactions were noted for Ginkgo biloba, Panax ginseng, Piper methysticum, Serenoa repens and Camellia sinensis. The most commonly interacting drugs were antiplatelet agents and anticoagulants. CONCLUSION The majority of the HMPs evaluated in SRs were not associated with drug interactions with serious consequences. However, the poor quality and the scarcity of the primary data prevent firm conclusions. PMID:22670731

  13. Drug-target interaction prediction from PSSM based evolutionary information.

    PubMed

    Mousavian, Zaynab; Khakabimamaghani, Sahand; Kavousi, Kaveh; Masoudi-Nejad, Ali

    2016-01-01

    The labor-intensive and expensive experimental process of drug-target interaction prediction has motivated many researchers to focus on in silico prediction, which leads to the helpful information in supporting the experimental interaction data. Therefore, they have proposed several computational approaches for discovering new drug-target interactions. Several learning-based methods have been increasingly developed which can be categorized into two main groups: similarity-based and feature-based. In this paper, we firstly use the bi-gram features extracted from the Position Specific Scoring Matrix (PSSM) of proteins in predicting drug-target interactions. Our results demonstrate the high-confidence prediction ability of the Bigram-PSSM model in terms of several performance indicators specifically for enzymes and ion channels. Moreover, we investigate the impact of negative selection strategy on the performance of the prediction, which is not widely taken into account in the other relevant studies. This is important, as the number of non-interacting drug-target pairs are usually extremely large in comparison with the number of interacting ones in existing drug-target interaction data. An interesting observation is that different levels of performance reduction have been attained for four datasets when we change the sampling method from the random sampling to the balanced sampling.

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

    PubMed

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

    2016-01-28

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

  15. Potential risks resulting from fruit/vegetable-drug interactions: effects on drug-metabolizing enzymes and drug transporters.

    PubMed

    Rodríguez-Fragoso, Lourdes; Martínez-Arismendi, José Luis; Orozco-Bustos, Danae; Reyes-Esparza, Jorge; Torres, Eliseo; Burchiel, Scott W

    2011-05-01

    It has been well established that complex mixtures of phytochemicals in fruits and vegetables can be beneficial for human health. Moreover, it is becoming increasingly apparent that phytochemicals can influence the pharmacological activity of drugs by modifying their absorption characteristics through interactions with drug transporters as well as drug-metabolizing enzyme systems. Such effects are more likely to occur in the intestine and liver, where high concentrations of phytochemicals may occur. Alterations in cytochrome P450 and other enzyme activities may influence the fate of drugs subject to extensive first-pass metabolism. Although numerous studies of nutrient-drug interactions have been published and systematic reviews and meta-analyses of these studies are available, no generalizations on the effect of nutrient-drug interactions on drug bioavailability are currently available. Several publications have highlighted the unintended consequences of the combined use of nutrients and drugs. Many phytochemicals have been shown to have pharmacokinetic interactions with drugs. The present review is limited to commonly consumed fruits and vegetables with significant beneficial effects as nutrients and components in folk medicine. Here, we discuss the phytochemistry and pharmacokinetic interactions of the following fruit and vegetables: grapefruit, orange, tangerine, grapes, cranberry, pomegranate, mango, guava, black raspberry, black mulberry, apple, broccoli, cauliflower, watercress, spinach, tomato, carrot, and avocado. We conclude that our knowledge of the potential risk of nutrient-drug interactions is still limited. Therefore, efforts to elucidate potential risks resulting from food-drug interactions should be intensified in order to prevent undesired and harmful clinical consequences.

  16. Drug interactions between prescribed and over-the-counter medication.

    PubMed

    Honig, P K; Gillespie, B K

    1995-11-01

    The use and availability of over-the-counter (OTC) medication is increasing. Although regulatory agencies take care to assure than nonprescription medications are safe and effective, these drugs still have the potential to have clinically significant interactions with prescription medicines. The major classes of OTC medication to be considered in this light include antacids, histamine H2 receptor antagonists, NSAIDs, cough and cold preparations and the antiasthma products. Healthcare providers and patients/consumers should be educated regarding possible drug interactions, patient drug regimens should be simplified where possible, and all therapeutic failures and adverse reactions should be investigated with regard to the potential contribution of OTC drug products. Regulatory agencies and pharmaceutical manufacturers should ensure that nonprescription drug labelling is complete and intelligible to meet these objectives. Consideration should be given to improving the postmarketing surveillance of OTC medications.

  17. Vitamin E-drug interactions: molecular basis and clinical relevance.

    PubMed

    Podszun, Maren; Frank, Jan

    2014-12-01

    Vitamin E (α-, β-, γ- and δ-tocopherol and -tocotrienol) is an essential factor in the human diet and regularly taken as a dietary supplement by many people, who act under the assumption that it may be good for their health and can do no harm. With the publication of meta-analyses reporting increased mortality in persons taking vitamin E supplements, the safety of the micronutrient was questioned and interactions with prescription drugs were suggested as one potentially underlying mechanism. Here, we review the evidence in the scientific literature for adverse vitamin E-drug interactions and discuss the potential of each of the eight vitamin E congeners to alter the activity of drugs. In summary, there is no evidence from animal models or randomised controlled human trials to suggest that the intake of tocopherols and tocotrienols at nutritionally relevant doses may cause adverse nutrient-drug interactions. Consumption of high-dose vitamin E supplements ( ≥  300 mg/d), however, may lead to interactions with the drugs aspirin, warfarin, tamoxifen and cyclosporine A that may alter their activities. For the majority of drugs, however, interactions with vitamin E, even at high doses, have not been observed and are thus unlikely.

  18. Food-drug interactions: Putting evidence into practice.

    PubMed

    Nicoteri, Jo Ann L

    2016-02-18

    Food-drug interactions occur more often than thought. This manuscript describes the most common interactions the NP may encounter in primary care practice. A thorough and detailed health history and dietary recall are essential for identifying potential problems when prescribing or evaluating medication efficacy. Prevention and education are vital.

  19. Clinically relevant pharmacokinetic herb-drug interactions in antiretroviral therapy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    For healthcare professionals, the volume of literature available on herb-drug interactions often makes it difficult to separate experimental/potential interactions from those deemed clinically relevant. There is a need for concise and conclusive information to guide pharmacotherapy in HIV/AIDS. In t...

  20. Design considerations to minimize the impact of drug absorption in polymer-based organ-on-a-chip platforms.

    PubMed

    Shirure, V S; George, S C

    2017-02-14

    Biocompatible polymers, such as polydimethylsiloxane (PDMS), are the materials of choice for creating organ-on-a-chip microfluidic platforms. Desirable qualities include ease of fabrication, optical clarity, and hydrophobicity, the latter of which facilitates oxygen transport to encased cells. An emerging and important application of organ-on-a-chip technology is drug discovery; however, a potential issue for polymer-based microfluidic devices has been highlighted by recent studies with PDMS, which have demonstrated absorption (and thus loss) of hydrophobic drugs into PDMS under certain experimental conditions. Absorption of drug in the polymer can also lead to undesirable transfer of drug between adjacent microfluidic lines. Given the benefits of polymers, it is essential to develop a comprehensive understanding of drug absorption. In this study, we considered convection, dissolution, and diffusion of a drug within a polymer-based microfluidic device to characterize the dynamics of drug loss in a quantitative manner. We solved Fick's 2nd law of diffusion (unsteady diffusion-convection) by finite element analysis in COMSOL®, and experimentally validated the numerical model for loss of three hydrophobic molecules (rhodamine B, cyanine NHS ester, and paclitaxel) in PDMS. Drug loss, as well as the unintended mixing of drugs by adjacent microfluidic channels, depends strongly on platform design parameters, experimental conditions, and the physico-chemical properties of the drug, and can be captured in a simple quantitate relationship that employs four scalable dimensionless numbers. This simple quantitative framework can be used in the design of a wide range of polymer-based microfluidic devices to minimize the impact of drug absorption.

  1. Potential drug interactions with dietary and herbal supplements during hospitalization.

    PubMed

    Levy, Ilana; Attias, Samuel; Ben-Arye, Eran; Goldstein, Lee; Schiff, Elad

    2017-04-01

    Dietary and herbal supplements (DHS) are widely used in the general population, including during hospitalization. Yet, their potential interactions with prescription drugs have seldom been delineated among inpatients. We aimed to evaluate potentially dangerous interactions of DHS with prescribed medications among inpatients. This was a cross-sectional prospective study involving a cohort of patients hospitalized in 12 departments of a public academic medical center (Bnai Zion Medical Center, Haifa, Israel) from 2009 to 2014. DHS users were determined via a questionnaire. The Natural Medicine database was used to search for potential DHS-drug interactions for identified DHS, and the clinical significance was evaluated using Lexi-interact online interaction analysis. Medical files were assessed for documentation of DHS use. Univariate and multivariate logistic regression analyses were used to characterize potential risk factors for DHS-drug interactions. Of 927 patients consenting to answer the questionnaire, 458 (49 %) reported DHS use. Of these, 215 (47 %) had at least one potential interaction during hospitalization (759 interactions). Of these interactions, 116 (15 %) were potentially clinically significant. Older age [OR = 1.02 (1.01-1.04), p = 0.002], males [OR = 2.11 (1.35-3.29), p = 0.001] and increased number of used DHS [OR = 4.28 (2.28-8.03), p < 0.001] or drugs [OR = 1.95 (1.17-3.26), p = 0.011] were associated with potential interactions in DHS users. Physicians documented only 16.5 % of DHS involved in these interactions in patients' medical files. In conclusion, a substantial number of inpatients use DHS with potential interactions with concomitant medications. Medical staff should be aware of this, question patients on DHS usage and check for such interactions.

  2. Drug–drug interactions between anti-retroviral therapies and drugs of abuse in HIV systems

    PubMed Central

    Rao, PSS; Earla, Ravindra; Kumar, Anil

    2015-01-01

    Introduction Substance abuse is a common problem among HIV-infected individuals. Importantly, addictions as well as moderate use of alcohol, smoking, or other illicit drugs have been identified as major reasons for non-adherence to antiretroviral therapy (ART) among HIV patients. The literature also suggests a decrease in the response to ART among HIV patients who use these substances, leading to failure to achieve optimal virological response and increased disease progression. Areas covered This review discusses the challenges with adherence to ART as well as observed drug interactions and known toxicities with major drugs of abuse, such as alcohol, smoking, methamphetamine, cocaine, marijuana, and opioids. The lack of adherence and drug interactions potentially lead to decreased efficacy of ART drugs and increased ART, and drugs of abuse-mediated toxicity. As CYP is the common pathway in metabolizing both ART and drugs of abuse, we discuss the possible involvement of CYP pathways in such drug interactions. Expert opinion We acknowledge that further studies focusing on common metabolic pathways involving CYP and advance research in this area would help to potentially develop novel/alternate interventions and drug dose/regimen adjustments to improve medication outcomes in HIV patients who consume drugs of abuse. PMID:25539046

  3. 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

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

    PubMed

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

    2013-10-01

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

  5. Drug Hypersensitivity: How Drugs Stimulate T Cells via Pharmacological Interaction with Immune Receptors.

    PubMed

    Pichler, Werner J; Adam, Jacqueline; Watkins, Stephen; Wuillemin, Natascha; Yun, James; Yerly, Daniel

    2015-01-01

    Small chemicals like drugs tend to bind to proteins via noncovalent bonds, e.g. hydrogen bonds, salt bridges or electrostatic interactions. Some chemicals interact with other molecules than the actual target ligand, representing so-called 'off-target' activities of drugs. Such interactions are a main cause of adverse side effects to drugs and are normally classified as predictable type A reactions. Detailed analysis of drug-induced immune reactions revealed that off-target activities also affect immune receptors, such as highly polymorphic human leukocyte antigens (HLA) or T cell receptors (TCR). Such drug interactions with immune receptors may lead to T cell stimulation, resulting in clinical symptoms of delayed-type hypersensitivity. They are assigned the 'pharmacological interaction with immune receptors' (p-i) concept. Analysis of p-i has revealed that drugs bind preferentially or exclusively to distinct HLA molecules (p-i HLA) or to distinct TCR (p-i TCR). P-i reactions differ from 'conventional' off-target drug reactions as the outcome is not due to the effect on the drug-modified cells themselves, but is the consequence of reactive T cells. Hence, the complex and diverse clinical manifestations of delayed-type hypersensitivity are caused by the functional heterogeneity of T cells. In the abacavir model of p-i HLA, the drug binding to HLA may result in alteration of the presenting peptides. More importantly, the drug binding to HLA generates a drug-modified HLA, which stimulates T cells directly, like an allo-HLA. In the sulfamethoxazole model of p-i TCR, responsive T cells likely require costimulation for full T cell activation. These findings may explain the similarity of delayed-type hypersensitivity reactions to graft-versus-host disease, and how systemic viral infections increase the risk of delayed-type hypersensitivity reactions.

  6. Drug interactions with HMG-CoA reductase inhibitors (statins): the importance of CYP enzymes, transporters and pharmacogenetics.

    PubMed

    Neuvonen, Pertti J

    2010-03-01

    HMG-CoA reductase inhibitors (statins) can cause skeletal muscle toxicity; the risk of toxicity is elevated by drug interactions and pharmacogenetic factors that increase the concentration of statins in the plasma. Statins are substrates for several membrane transporters that may mediate drug interactions. Inhibitors of the organic anion transporting polypeptide 1B1 can decrease the hepatic uptake of many statins, as well as the therapeutic index of these agents. Potent inhibitors of cytochrome P450 (CYP)3A4 can significantly increase the plasma concentrations of the active forms of simvastatin, lovastatin and atorvastatin. Fluvastatin, which is metabolized by CYP2C9, is less prone to pharmacokinetic interactions, while pravastatin, rosuvastatin and pitavastatin are not susceptible to any CYP inhibition. An understanding of the mechanisms of statin interactions will help to minimize drug interactions and to develop statins that are less prone to adverse interactions.

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

    PubMed Central

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

    2016-01-01

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

  8. Soft Interaction in Liposome Nanocarriers for Therapeutic Drug Delivery

    PubMed Central

    Lombardo, Domenico; Calandra, Pietro; Barreca, Davide; Magazù, Salvatore; Kiselev, Mikhail A.

    2016-01-01

    The development of smart nanocarriers for the delivery of therapeutic drugs has experienced considerable expansion in recent decades, with the development of new medicines devoted to cancer treatment. In this respect a wide range of strategies can be developed by employing liposome nanocarriers with desired physico-chemical properties that, by exploiting a combination of a number of suitable soft interactions, can facilitate the transit through the biological barriers from the point of administration up to the site of drug action. As a result, the materials engineer has generated through the bottom up approach a variety of supramolecular nanocarriers for the encapsulation and controlled delivery of therapeutics which have revealed beneficial developments for stabilizing drug compounds, overcoming impediments to cellular and tissue uptake, and improving biodistribution of therapeutic compounds to target sites. Herein we present recent advances in liposome drug delivery by analyzing the main structural features of liposome nanocarriers which strongly influence their interaction in solution. More specifically, we will focus on the analysis of the relevant soft interactions involved in drug delivery processes which are responsible of main behaviour of soft nanocarriers in complex physiological fluids. Investigation of the interaction between liposomes at the molecular level can be considered an important platform for the modeling of the molecular recognition processes occurring between cells. Some relevant strategies to overcome the biological barriers during the drug delivery of the nanocarriers are presented which outline the main structure-properties relationships as well as their advantages (and drawbacks) in therapeutic and biomedical applications. PMID:28335253

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

    PubMed Central

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

    2015-01-01

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

  10. Pharmacokinetic and pharmacodynamic drug interactions with ethanol (alcohol).

    PubMed

    Chan, Lingtak-Neander; Anderson, Gail D

    2014-12-01

    Ethanol (alcohol) is one of the most widely used legal drugs in the world. Ethanol is metabolized by alcohol dehydrogenase (ADH) and the cytochrome P450 (CYP) 2E1 drug-metabolizing enzyme that is also responsible for the biotransformation of xenobiotics and fatty acids. Drugs that inhibit ADH or CYP2E1 are the most likely theoretical compounds that would lead to a clinically significant pharmacokinetic interaction with ethanol, which include only a limited number of drugs. Acute ethanol primarily alters the pharmacokinetics of other drugs by changing the rate and extent of absorption, with more limited effects on clearance. Both acute and chronic ethanol use can cause transient changes to many physiologic responses in different organ systems such as hypotension and impairment of motor and cognitive functions, resulting in both pharmacokinetic and pharmacodynamic interactions. Evaluating drug interactions with long-term use of ethanol is uniquely challenging. Specifically, it is difficult to distinguish between the effects of long-term ethanol use on liver pathology and chronic malnutrition. Ethanol-induced liver disease results in decreased activity of hepatic metabolic enzymes and changes in protein binding. Clinical studies that include patients with chronic alcohol use may be evaluating the effects of mild cirrhosis on liver metabolism, and not just ethanol itself. The definition of chronic alcohol use is very inconsistent, which greatly affects the quality of the data and clinical application of the results. Our study of the literature has shown that a significantly higher volume of clinical studies have focused on the pharmacokinetic interactions of ethanol and other drugs. The data on pharmacodynamic interactions are more limited and future research addressing pharmacodynamic interactions with ethanol, especially regarding the non-central nervous system effects, is much needed.

  11. Potential drug interactions with statins: Estonian register-based study

    PubMed Central

    Volmer, Daisy; Hartikainen, Sirpa; Zharkovsky, Alexander

    2015-01-01

    In Estonia, HMG-CoA reductase inhibitors are widely used to modify lipid levels but there are no current data on additional medicines prescribed alongside the statins. The aim of this study was to identify the frequency of potential clinically relevant interactions at a national level among an outpatient population treated with statins between January and June 2008, based on the prescription database of the Estonian Health Insurance Fund. This retrospective prevalence study included 203,646 outpatients aged 50 years or older, of whom 29,367 received statin therapy. The study analysed individuals who had used at least one prescription medicine for a minimum of 7 days concomitantly with statins. Potential drug interactions were analysed using Epocrates online, Stockley’s Drug Interactions, and the drug interaction database developed in Estonia. Statins metabolised by the CYP3A4 isoenzyme were prescribed to 64% of all statin users. Medicines known to have potentially clinically significant interactions with statins were prescribed to 4.6% of patients. The drugs prescribed concomitantly most often with simvastatin were warfarin (5.7%) and amiodarone (3.9%), whereas digoxin (1.2%) and ethinylestradiol (2%) were prescribed with atorvastatin. Potential interactions were not detected in the treatment regimens of rosuvastatin, pravastatin, and fluvastatin users. PMID:28352703

  12. Social interaction and drug attitude effectiveness in patients with schizophrenia.

    PubMed

    Tsai, Jui-Kang; Lin, Wen-Kuo; Lung, For-Wey

    2011-12-01

    This study aimed to explore the relationship between dosage of paliperidone and drug attitude, and also clarify the factors associated with drug attitude, using Intention-to-Treat (ITT) analysis. Three hundred thirty-one patients diagnosed with schizophrenia, who prescribed paliperidone between April 2008 and April 2009, from 10 hospitals in Taiwan were enrolled. By structural equation modeling, inpatient/outpatient status associated with occupation status, sex, and score on the Clinical Global Impression-Severity (CGIS) Scale. The score on the Personal and Social Performance (PSP) Scale associated with occupation status, inpatient/outpatient status, and the score on the CGIS Scale. The scores on the DAI-10 associated with the score on the PSP Scale and age. Good drug attitude and medication adherence significantly related to good social interaction. We should enhance the drug attitude and medication adherence of patients with schizophrenia who have poor social interaction to improve the outcome of schizophrenia.

  13. Communication growth in minimally verbal children with ASD: The importance of interaction.

    PubMed

    DiStefano, Charlotte; Shih, Wendy; Kaiser, Ann; Landa, Rebecca; Kasari, Connie

    2016-10-01

    Little is known about language development in children with Autism Spectrum Disorders (ASD) who remain minimally verbal past age 5. While there is evidence that children can develop language after age 5, we lack detailed information. Studies of this population generally focus on discrete language skills without addressing broader social-communication abilities. As communication and social deficits are both inherent to ASD, an examination of not only what language skills are acquired, but how those skills are used in interactions is relevant. Research in typical development has examined how communication interchanges (unbroken back-and-forth exchanges around a unified purpose) develop, which can be used as a framework for studying minimally verbal children. This study examined the interchange use by 55 children with ASD over the course of a 6-month play and engagement-based communication intervention. Half of the children received intervention sessions that also incorporated a speech-generating device (SGD). Interchanges were coded by: frequency, length, function, and initiator (child or adult). Results indicated that children initiated a large proportion of interchanges and this proportion increased over time. The average length and number of interchanges increased over time, with children in the SGD group showing even greater growth. Finally, children's total number of interchanges at baseline was positively associated with their spoken language gains over the course of intervention. This study supports the crucial relationship between social engagement and expressive language development, and highlights the need to include sustained communication interchanges as a target for intervention with this population. Autism Res 2016, 9: 1093-1102. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

  14. Update on clinically significant drug interactions in dermatology.

    PubMed

    Barranco, Vincent P

    2006-04-01

    Although there are thousands of drug interactions (DIs) listed in computers and manuals, only about 10% are clinically significant. Equally disturbing is these systems fail to detect up to one third of all dangerous DIs. This update on clinically significant DIs is current through September 2005 and discusses systemic drugs important to dermatologists. In addition, 4 aspects of DIs are discussed that are helpful in replacing rote memory with a step-by-step, logical approach based on scientific evidence.

  15. Interaction of injectable neurotropic drugs with the red cell membrane.

    PubMed

    Reinhart, Walter H; Lubszky, Szabina; Thöny, Sandra; Schulzki, Thomas

    2014-10-01

    The normal red blood cell (RBC) shape is a biconcave discocyte. An intercalation of a drug in the outer half of the membrane lipid bilayer leads to echinocytosis, an intercalation in the inner half to stomatocytosis. We have used the shape transforming capacity of RBCs as a model to analyse the membrane interaction potential of various neurotropic drugs. Chlorpromazine, clomipramine, citalopram, clonazepam, and diazepam induced a reversible stomatocytosis, phenytoin induced echinocytosis, while the anticonvulsants levetiracetam, valproic acid and phenobarbital had no effect. This diversity of RBC shape transformations suggests that the pharmacological action is not linked to the membrane interaction. We conclude that this simple RBC shape transformation assay could be a useful tool to screen for potential drug interactions with cell membranes.

  16. Computational Drug Target Screening through Protein Interaction Profiles

    PubMed Central

    Vilar, Santiago; Quezada, Elías; Uriarte, Eugenio; Costanzi, Stefano; Borges, Fernanda; Viña, Dolores; Hripcsak, George

    2016-01-01

    The development of computational methods to discover novel drug-target interactions on a large scale is of great interest. We propose a new method for virtual screening based on protein interaction profile similarity to discover new targets for molecules, including existing drugs. We calculated Target Interaction Profile Fingerprints (TIPFs) based on ChEMBL database to evaluate drug similarity and generated new putative compound-target candidates from the non-intersecting targets in each pair of compounds. A set of drugs was further studied in monoamine oxidase B (MAO-B) and cyclooxygenase-1 (COX-1) enzyme through molecular docking and experimental assays. The drug ethoxzolamide and the natural compound piperlongumine, present in Piper longum L, showed hMAO-B activity with IC50 values of 25 and 65 μM respectively. Five candidates, including lapatinib, SB-202190, RO-316233, GW786460X and indirubin-3′-monoxime were tested against human COX-1. Compounds SB-202190 and RO-316233 showed a IC50 in hCOX-1 of 24 and 25 μM respectively (similar range as potent inhibitors such as diclofenac and indomethacin in the same experimental conditions). Lapatinib and indirubin-3′-monoxime showed moderate hCOX-1 activity (19.5% and 28% of enzyme inhibition at 25 μM respectively). Our modeling constitutes a multi-target predictor for large scale virtual screening with potential in lead discovery, repositioning and drug safety. PMID:27845365

  17. Herbal medication: potential for adverse interactions with analgesic drugs.

    PubMed

    Abebe, W

    2002-12-01

    The use of herbal supplements in the US has increased dramatically in recent years. These products are not regulated by the Food and Drug Administration (FDA) with the same scrutiny as conventional drugs. Patients who use herbal supplements often do so in conjunction with conventional drugs. This article is a review of potential adverse interactions between some of the commonly used herbal supplements and analgesic drugs. Non-steroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, have the potential to interact with herbal supplements that are known to possess antiplatelet activity (ginkgo, garlic, ginger, bilberry, dong quai, feverfew, ginseng, turmeric, meadowsweet and willow), with those containing coumarin (chamomile, motherworth, horse chestnut, fenugreek and red clover) and with tamarind, enhancing the risk of bleeding. Acetaminophen may also interact with ginkgo and possibly with at least some of the above herbs to increase the risk of bleeding. Further, the incidences of hepatotoxicity and nephrotoxicity may be augmented by acetaminophen when concomitantly used with the potentially hepatotoxic herbs Echinacea and kava, and with herbs containing salicylate (willow, meadowsweet), respectively. The concomitant use of opioid analgesics with the sedative herbal supplements, valerian, kava and chamomile, may lead to increased central nervous system (CNS) depression. The analgesic effect of opioids may also be inhibited by ginseng. It is suggested that health-care professionals should be more aware of the potential adverse interactions between herbal supplements and analgesic drugs, and take appropriate precautionary measures to avoid their possible occurrences. However, as most of the interaction information available is based on individual case reports, animal studies and in vitro data, further research is needed to confirm and assess the clinical significance of these potential interactions.

  18. Prevalence of the Prescription of Potentially Interacting Drugs

    PubMed Central

    Tragni, Elena; Casula, Manuela; Pieri, Vasco; Favato, Giampiero; Marcobelli, Alberico; Trotta, Maria Giovanna; Catapano, Alberico Luigi

    2013-01-01

    The use of multiple medications is becoming more common, with a correspondingly increased risk of untoward effects and drug-related morbidity and mortality. We aimed at estimating the prevalence of prescription of relevant potentially interacting drugs and at evaluating possible predictors of potentially interacting drug exposure. We retrospectively analyzed data on prescriptions dispensed from January 2004 to August 2005 to individuals of two Italian regions with a population of almost 2.1 million individuals. We identified 27 pairs of potentially interacting drugs by examining clinical relevance, documentation, and volume of use in Italy. Subjects who received at least one prescription of both drugs were selected. Co-prescribing denotes “two prescriptions in the same day”, and concomitant medication “the prescription of two drugs with overlapping coverage”. A logistic regression analysis was conducted to examine the predictors of potential Drug-Drug Interaction (pDDIs). 957,553 subjects (45.3% of study population) were exposed to at least one of the drugs/classes of the 27 pairs. Overall, pDDIs occurred 2,465,819 times. The highest rates of concomitant prescription and of co-prescription were for ACE inhibitors+NSAIDs (6,253 and 4,621/100,000 plan participants). Considering concomitance, the male/female ratio was <1 in 17/27 pairs (from 0.31 for NSAIDs-ASA+SSRI to 0.74 for omeprazole+clopidogrel). The mean age was lowest for methotrexate pairs (+omeprazole, 59.9 years; +NSAIDs-ASA, 59.1 years) and highest for digoxin+verapamil (75.4 years). In 13/27 pairs, the mean ages were ≥70 years. On average, subjects involved in pDDIs received ≥10 drugs. The odds of exposure were more frequently higher for age ≥65 years, males, and those taking a large number of drugs. A substantial number of clinically important pDDIs were observed, particularly among warfarin users. Awareness of the most prevalent pDDIs could help practitioners in preventing concomitant use

  19. Potential food-drug interactions in patients with rheumatoid arthritis.

    PubMed

    Masuko, Kayo; Tohma, Shigeto; Matsui, Toshihiro

    2013-04-01

    Various medications are used for the treatment of rheumatoid arthritis (RA). Food-drug interactions may occur with concomitant ingestion of particular food. For example, methotrexate (MTX), the anchor drug in the therapeutic strategy against RA, is an antifolate agent. Excessive presence or absence of dietary folic acid may regulate MTX metabolism, possibly leading to unexpected adverse reactions. In this review, we focus on MTX, isoniazide and calcineurin inhibitors, and the implications of potential food-drug reactions in rheumatology, suggesting the important role of nutritional evaluations in RA patients.

  20. Drug interaction networks: an introduction to translational and clinical applications.

    PubMed

    Azuaje, Francisco

    2013-03-15

    This article introduces fundamental concepts to guide the analysis and interpretation of drug-target interaction networks. An overview of the generation and integration of interaction networks is followed by key strategies for extracting biologically meaningful information. The article highlights how this information can enable novel translational and clinically motivated applications. Important advances for the discovery of new treatments and for the detection of adverse drug effects are discussed. Examples of applications and findings originating from cardiovascular research are presented. The review ends with a discussion of crucial challenges and opportunities.

  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.

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

    PubMed

    Eyal, Sara; Rasaby, Sivan; Ekstein, Dana

    2014-02-01

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

  3. 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

  4. Acaricide, Fungicide and Drug Interactions in Honey Bees (Apis mellifera)

    PubMed Central

    Johnson, Reed M.; Dahlgren, Lizette; Siegfried, Blair D.; Ellis, Marion D.

    2013-01-01

    Background Chemical analysis shows that honey bees (Apis mellifera) and hive products contain many pesticides derived from various sources. The most abundant pesticides are acaricides applied by beekeepers to control Varroa destructor. Beekeepers also apply antimicrobial drugs to control bacterial and microsporidial diseases. Fungicides may enter the hive when applied to nearby flowering crops. Acaricides, antimicrobial drugs and fungicides are not highly toxic to bees alone, but in combination there is potential for heightened toxicity due to interactive effects. Methodology/Principal Findings Laboratory bioassays based on mortality rates in adult worker bees demonstrated interactive effects among acaricides, as well as between acaricides and antimicrobial drugs and between acaricides and fungicides. Toxicity of the acaricide tau-fluvalinate increased in combination with other acaricides and most other compounds tested (15 of 17) while amitraz toxicity was mostly unchanged (1 of 15). The sterol biosynthesis inhibiting (SBI) fungicide prochloraz elevated the toxicity of the acaricides tau-fluvalinate, coumaphos and fenpyroximate, likely through inhibition of detoxicative cytochrome P450 monooxygenase activity. Four other SBI fungicides increased the toxicity of tau-fluvalinate in a dose-dependent manner, although possible evidence of P450 induction was observed at the lowest fungicide doses. Non-transitive interactions between some acaricides were observed. Sublethal amitraz pre-treatment increased the toxicity of the three P450-detoxified acaricides, but amitraz toxicity was not changed by sublethal treatment with the same three acaricides. A two-fold change in the toxicity of tau-fluvalinate was observed between years, suggesting a possible change in the genetic composition of the bees tested. Conclusions/Significance Interactions with acaricides in honey bees are similar to drug interactions in other animals in that P450-mediated detoxication appears to play an

  5. Drug release from hydroethanolic gels. Effect of drug's lipophilicity (logP), polymer-drug interactions and solvent lipophilicity.

    PubMed

    Sawant, Prashant D; Luu, Dewitt; Ye, Rose; Buchta, Richard

    2010-08-30

    We demonstrate drug release properties from hydroethanolic formulations as a function of the drug's lipophilicity (logP), solvent lipophilicity and drug-polymer interactions, for the first time. A hydrophilic polymer, hydroxypropyl cellulose (HPC), provides the non-Fickian slower release of the lipophilic drug, lidocaine (logP=2.6) and the burst (Fickian) release of hydrophilic drug, lidocaine hydrochloride (logPdrugs helps predict the drug release properties. Hydrophobic Eudragit polymers provided the burst release of lidocaine. However, the cationic hydrophobic polymer (Eudragit E100) retained more lidocaine (approximately 50%) topically than other hydrophobic polymers: Eudragit S100 (anionic) and Eudragit RLPO (cationic copolymer with quaternary ammonium group) ( approximately 25% lidocaine retention) which release lidocaine systematically. Thus, minute changes in functional groups of hydrophobic polymers help tune the lidocaine release topically or systemically. An interaction between HPC and lidocaine as determined by FTIR helps the non-Fickian slower lidocaine release from HPC formulations. However, no interactions between lidocaine and hydrophobic Eudragit polymers explain the Fickian burst release of lidocaine from their formulations. A lipophilic solvent, isostearyl alcohol which when replacing ethanol by 30%, slows the release rate and enhances the topical adsorption of lidocaine. Thus, solvent lipophilicity also modulates drug release properties.

  6. Pharmacokinetic Interactions between Drugs and Botanical Dietary Supplements.

    PubMed

    Sprouse, Alyssa A; van Breemen, Richard B

    2016-02-01

    The use of botanical dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, mechanisms of action, efficacy, and safety. An important but underinvestigated safety concern is the potential for popular botanical dietary supplements to interfere with the absorption, transport, and/or metabolism of pharmaceutical agents. Clinical trials of drug-botanical interactions are the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive preclinical studies. For example, phase 1 clinical trials have confirmed preclinical studies and clinical case reports that St. John's wort (Hypericum perforatum) induces CYP3A4/CYP3A5. However, clinical studies of most botanicals that were predicted to interact with drugs have shown no clinically significant effects. For example, clinical trials did not substantiate preclinical predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and/or CYP3A4. Here, we highlight discrepancies between preclinical and clinical data concerning drug-botanical interactions and critically evaluate why some preclinical models perform better than others in predicting the potential for drug-botanical interactions. Gaps in knowledge are also highlighted for the potential of some popular botanical dietary supplements to interact with therapeutic agents with respect to absorption, transport, and metabolism.

  7. Clinically Relevant Pharmacokinetic Herb-drug Interactions in Antiretroviral Therapy.

    PubMed

    Fasinu, Pius S; Gurley, Bill J; Walker, Larry A

    2015-01-01

    For healthcare professionals, the volume of literature available on herb-drug interactions often makes it difficult to separate experimental/potential interactions from those deemed clinically relevant. There is a need for concise and conclusive information to guide pharmacotherapy in HIV/AIDS. In this review, the bases for potential interaction of medicinal herbs with specific antiretroviral drugs are presented, and several botanicals are discussed for which clinically relevant interactions in humans are established. Such studies have provided, in most cases, sufficient ground to warrant the avoidance of concurrent administration of antiretroviral (ARVs) drugs with St John's wort (Hypericum perforatum), black pepper (Piper species) and grapefruit juice. Other botanicals that require caution in the use with antiretrovirals include African potato (Hypoxis hemerocallidea), ginkgo (Ginkgo biloba), ginseng (Panax species), garlic (Allium sativum), goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum). The knowledge of clinically significant herb-drug interaction will be important in order to avoid herb-induced risk of sub-therapeutic exposure to ARVs (which can lead to viral resistance) or the precipitation of toxicity (which may lead to poor compliance and/or discontinuation of antiretroviral therapy).

  8. Role of biotransformation studies in minimizing metabolism-related liabilities in drug discovery.

    PubMed

    Shu, Yue-Zhong; Johnson, Benjamin M; Yang, Tian J

    2008-01-01

    Metabolism-related liabilities continue to be a major cause of attrition for drug candidates in clinical development. Such problems may arise from the bioactivation of the parent compound to a reactive metabolite capable of modifying biological materials covalently or engaging in redox-cycling reactions leading to the formation of other toxicants. Alternatively, they may result from the formation of a major metabolite with systemic exposure and adverse pharmacological activity. To avert such problems, biotransformation studies are becoming increasingly important in guiding the refinement of a lead series during drug discovery and in characterizing lead candidates prior to clinical evaluation. This article provides an overview of the methods that are used to uncover metabolism-related liabilities in a pre-clinical setting and offers suggestions for reducing such liabilities via the modification of structural features that are used commonly in drug-like molecules.

  9. A high-performance approach to minimizing interactions between inbound and outbound signals in helmet

    NASA Astrophysics Data System (ADS)

    Zhou, Jin; Ayhan, Bulent; Kwan, Chiman; Sands, O. S.

    2012-06-01

    NASA is developing a new generation of audio system for astronauts. The idea is to use directional speakers and microphone arrays. However, since the helmet environment is very reverberant, the inbound signals in the directional speaker may still enter the outbound path (microphone array), resulting in an annoying positive feedback loop. To improve the communication quality between astronauts, it is necessary to develop a digital filtering system to minimize the interactions between inbound and outbound signals. In this paper, we will present the following results. First, we set up experiments under three scenarios: office, bowl, and helmet. Experiments were then performed. Second, 3 adaptive filters known as normalized least mean square (NLMS), affine projection (AP), and recursive least square (RLS) were applied to the experimental data. We also developed a new frequency domain adaptive filter called FDAFSS (frequency domain adaptive filter (FDAF) with spectral subtraction (SS)), which is a combination of FDAF and SS. FDAFSS was compared with LMS, AP, RLS, FDAF, and SS filters and FDAFSS yielded better performance in terms of perceptual speech quality (PESQ). Moreover, FDAFSS is fast and can yield uniform convergence across different frequency bands.

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

    PubMed Central

    Chen, Jiezhong; Raymond, Kenneth

    2006-01-01

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

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

    PubMed

    Chen, Jiezhong; Raymond, Kenneth

    2006-02-15

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

  12. 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

  13. Assessing the Potential for Drug-Nanoparticle Surface Interactions To Improve Drug Penetration into the Skin.

    PubMed

    Cai, X J; Woods, A; Mesquida, P; Jones, S A

    2016-04-04

    There is continued debate as to how nanomaterials enhance the passive diffusion of drugs through the skin. This study examined if drug-nanoparticle surface interactions, which occurred during topical application, had the capability to enhance percutaneous penetration. Atomic force microscopy force adhesion measurements were used to demonstrate that a model drug, tetracaine, strongly adsorbed to the surface of a negatively charged carboxyl-modified polystyrene nanoparticle (NanoPSCOOH) through both its methyl and amine functionalities (up to a 6- and 16-fold greater adhesion force respectively compared with the CH3-CH3 control). These drug-particle adhesion forces were significantly reduced (p < 0.05) to values that were lower than the CH3-CH3 control measurements when tetracaine interacted with a silica nanoparticle (NanoSiO2). This reduction in adhesion was attributed to the lower surface charge of the NanoSiO2 (ca. -23 mV) compared to the NanoPSCOOH (ca. -40 mV), which diminished the electrostatic interactions between positive amine of tetracaine and the negative particle. Mixing NanoPSCOOH with tetracaine on the skin retarded percutaneous drug penetration compared to the control (tetracaine saturated solution without nanoparticles), but the NanoSiO2, which still adsorbed the tetracaine, produced a 3.6-fold enhancement in percutaneous penetration compared to the same control. These data demonstrated the capability of moderate nanoparticle surface interactions that occurred within the application vehicle to promote drug percutaneous penetration.

  14. Human enterovirus 71 protein interaction network prompts antiviral drug repositioning

    PubMed Central

    Han, Lu; Li, Kang; Jin, Chaozhi; Wang, Jian; Li, Qingjun; Zhang, Qiling; Cheng, Qiyue; Yang, Jing; Bo, Xiaochen; Wang, Shengqi

    2017-01-01

    As a predominant cause of human hand, foot, and mouth disease, enterovirus 71 (EV71) infection may lead to serious diseases and result in severe consequences that threaten public health and cause widespread panic. Although the systematic identification of physical interactions between viral proteins and host proteins provides initial information for the recognition of the cellular mechanism involved in viral infection and the development of new therapies, EV71-host protein interactions have not been explored. Here, we identified interactions between EV71 proteins and host cellular proteins and confirmed the functional relationships of EV71-interacting proteins (EIPs) with virus proliferation and infection by integrating a human protein interaction network and by functional annotation. We found that most EIPs had known interactions with other viruses. We also predicted ATP6V0C as a broad-spectrum essential host factor and validated its essentiality for EV71 infection in vitro. EIPs and their interacting proteins were more likely to be targets of anti-inflammatory and neurological drugs, indicating their potential to serve as host-oriented antiviral targets. Thus, we used a connectivity map to find drugs that inhibited EIP expression. We predicted tanespimycin as a candidate and demonstrated its antiviral efficiency in vitro. These findings provide the first systematic identification of EV71-host protein interactions, an analysis of EIP protein characteristics and a demonstration of their value in developing host-oriented antiviral therapies. PMID:28220872

  15. Human enterovirus 71 protein interaction network prompts antiviral drug repositioning.

    PubMed

    Han, Lu; Li, Kang; Jin, Chaozhi; Wang, Jian; Li, Qingjun; Zhang, Qiling; Cheng, Qiyue; Yang, Jing; Bo, Xiaochen; Wang, Shengqi

    2017-02-21

    As a predominant cause of human hand, foot, and mouth disease, enterovirus 71 (EV71) infection may lead to serious diseases and result in severe consequences that threaten public health and cause widespread panic. Although the systematic identification of physical interactions between viral proteins and host proteins provides initial information for the recognition of the cellular mechanism involved in viral infection and the development of new therapies, EV71-host protein interactions have not been explored. Here, we identified interactions between EV71 proteins and host cellular proteins and confirmed the functional relationships of EV71-interacting proteins (EIPs) with virus proliferation and infection by integrating a human protein interaction network and by functional annotation. We found that most EIPs had known interactions with other viruses. We also predicted ATP6V0C as a broad-spectrum essential host factor and validated its essentiality for EV71 infection in vitro. EIPs and their interacting proteins were more likely to be targets of anti-inflammatory and neurological drugs, indicating their potential to serve as host-oriented antiviral targets. Thus, we used a connectivity map to find drugs that inhibited EIP expression. We predicted tanespimycin as a candidate and demonstrated its antiviral efficiency in vitro. These findings provide the first systematic identification of EV71-host protein interactions, an analysis of EIP protein characteristics and a demonstration of their value in developing host-oriented antiviral therapies.

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

    PubMed

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

    2016-02-24

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

  17. Cognitive enhancers (nootropics). Part 1: drugs interacting with receptors.

    PubMed

    Froestl, Wolfgang; Muhs, Andreas; Pfeifer, Andrea

    2012-01-01

    Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer's disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 18 categories according to their mechanism(s) of action, in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease-modifying drugs meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-β and tau. For drugs, whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. The review covers the evolution of research in this field over the last 25 years.

  18. Cognitive enhancers (nootropics). Part 2: drugs interacting with enzymes.

    PubMed

    Froestl, Wolfgang; Muhs, Andreas; Pfeifer, Andrea

    2013-01-01

    Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer's disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 19 categories according to their mechanism(s) of action, in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease modifying drugs meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-β and tau. For drugs whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. This review covers the evolution of research in this field over the last 25 years.

  19. Drug interactions with vortioxetine, a new multimodal antidepressant.

    PubMed

    Spina, Edoardo; Santoro, Vincenza

    2015-01-01

    This article summarized the available knowledge on clinically relevant drug interactions of vortioxetine, a new antidepressant with a “multimodal” serotonergic mechanism of action, recently approved for the treatment of major depressive disorder. Although information is still limited and mainly based on studies performed in healthy volunteers, vortioxetine appears to have a favorable drug interaction profile. Concerning the potential for pharmacokinetic drug interactions, vortioxetine has little to no effect on various cytochrome P450 (CYP) isoforms and therefore is not expected to markedly affect plasma concentrations of other medications metabolized by these enzymes. This is a major advantage when compared to other antidepressants which are known to inhibit the activity of one or more CYP isoforms. On the other hand, dosage adjustments may be required when vortioxetine is coadministered with strong CYP2D6 inhibitors or broad-spectrum CYP inducers. Vortioxetine carries a relatively low risk for pharmacodynamic drug interactions, at least as compared to first-generation antidepressants. Like other antidepressants enhancing serotonergic activity, vortioxetine is associated with a potential risk of serotonin syndrome when used in combination with other serotonergic agents. Based on all available clinical data, vortioxetine has no increased risk of serotonin syndrome when used without other serotoninergic agents and at therapeutic doses.

  20. Studies on pharmacokinetic drug interaction potential of vinpocetine

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Vinpocetine, a semi-synthetic derivative of vincamine, is a popular dietary supplement used for the treatment of several central nervous system related disorders. Despite its wide use, no pharmacokinetic drug interaction studies are reported in literature. Due to increasing use of dietar...

  1. Pharmacokinetic drug interactions in liver disease: An update

    PubMed Central

    Palatini, Pietro; De Martin, Sara

    2016-01-01

    Inhibition and induction of drug-metabolizing enzymes are the most frequent and dangerous drug-drug interactions. They are an important cause of serious adverse events that have often resulted in early termination of drug development or withdrawal of drugs from the market. Management of such interactions by dose adjustment in clinical practice is extremely difficult because of the wide interindividual variability in their magnitude. This review examines the genetic, physiological, and environmental factors responsible for this variability, focusing on an important but so far neglected cause of variability, liver functional status. Clinical studies have shown that liver disease causes a reduction in the magnitude of interactions due to enzyme inhibition, which is proportional to the degree of liver function impairment. The effect of liver dysfunction varies quantitatively according to the nature, reversible or irreversible, of the inhibitory interaction. The magnitude of reversible inhibition is more drastically reduced and virtually vanishes in patients with advanced hepatocellular insufficiency. Two mechanisms, in order of importance, are responsible for this reduction: decreased hepatic uptake of the inhibitory drug and reduced enzyme expression. The extent of irreversible inhibitory interactions is only partially reduced, as it is only influenced by the decreased expression of the inhibited enzyme. Thus, for appropriate clinical management of inhibitory drug interactions, both the liver functional status and the mechanism of inhibition must be taken into consideration. Although the inducibility of drug-metabolizing enzymes in liver disease has long been studied, very conflicting results have been obtained, mainly because of methodological differences. Taken together, the results of early animal and human studies indicated that enzyme induction is substantially preserved in compensated liver cirrhosis, whereas no definitive conclusion as to whether it is

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

    PubMed

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

    2010-03-01

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

  4. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated

    PubMed Central

    Gillman, P K

    2007-01-01

    New data on the pharmacology of tricyclic antidepressants (TCAs), their affinities for human cloned CNS receptors and their cytochrome P450 enzyme inhibition profiles, allow improved deductions concerning their effects and interactions and indicate which of the TCAs are the most useful. The relative toxicity of TCAs continues to be more precisely defined, as do TCA interactions with selective serotonin reuptake inhibitors (SSRIs). TCA interactions with monoamine oxidase inhibitors (MAOIs) have been, historically, an uncertain and difficult question, but are now well understood, although this is not reflected in the literature. The data indicate that nortriptyline and desipramine have the most pharmacologically desirable characteristics as noradrenaline reuptake inhibitors (NRIs), and as drugs with few interactions that are also safe when coadministered with either MAOIs or SSRIs. Clomipramine is the only available antidepressant drug that has good evidence of clinically relevant serotonin and noradrenaline reuptake inhibition (SNRI). These data assist drug selection for monotherapy and combination therapy and predict reliably how and why pharmacodynamic and pharmacokinetic interactions occur. In comparison, two newer drugs proposed to have SNRI properties, duloxetine and venlafaxine, may have insufficient NRI potency to be effective SNRIs. Combinations such as sertraline and nortriptyline may therefore offer advantages over drugs like venlafaxine that have fixed ratios of SRI/NRI effects that are not ideal. However, no TCA/SSRI combination is sufficiently safe to be universally applicable without expert knowledge. Standard texts (e.g. the British National Formulary) and treatment guidelines would benefit by taking account of these new data and understandings. PMID:17471183

  5. Predict drug-protein interaction in cellular networking.

    PubMed

    Xiao, Xuan; Min, Jian-Liang; Wang, Pu; Chou, Kuo-Chen

    2013-01-01

    Involved with many diseases such as cancer, diabetes, neurodegenerative, inflammatory and respiratory disorders, GPCRs (G-protein-coupled receptors) are the most frequent targets for drug development: over 50% of all prescription drugs currently on the market are actually acting by targeting GPCRs directly or indirectly. Found in every living thing and nearly all cells, ion channels play crucial roles for many vital functions in life, such as heartbeat, sensory transduction, and central nervous system response. Their dysfunction may have significant impact to human health, and hence ion channels are deemed as "the next GPCRs". To develop GPCR-targeting or ion-channel-targeting drugs, the first important step is to identify the interactions between potential drug compounds with the two kinds of protein receptors in the cellular networking. In this minireview, we are to introduce two predictors. One is called iGPCR-Drug accessible at http://www.jci-bioinfo.cn/iGPCR-Drug/; the other called iCDI-PseFpt at http://www.jci-bioinfo.cn/iCDI-PseFpt. The former is for identifying the interactions of drug compounds with GPCRs; while the latter for that with ion channels. In both predictors, the drug compound was formulated by the two-dimensional molecular fingerprint, and the protein receptor by the pseudo amino acid composition generated with the grey model theory, while the operation engine was the fuzzy K-nearest neighbor algorithm. For the convenience of most experimental pharmaceutical and medical scientists, a step-bystep guide is provided on how to use each of the two web-servers to get the desired results without the need to follow the complicated mathematics involved originally for their establishment.

  6. 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

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

    PubMed Central

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

    2016-01-01

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

  8. Interaction networks: from protein functions to drug discovery. A review.

    PubMed

    Chautard, E; Thierry-Mieg, N; Ricard-Blum, S

    2009-06-01

    Most genes, proteins and other components carry out their functions within a complex network of interactions and a single molecule can affect a wide range of other cell components. A global, integrative, approach has been developed for several years, including protein-protein interaction networks (interactomes). In this review, we describe the high-throughput methods used to identify new interactions and to build large interaction datasets. The minimum information required for reporting a molecular interaction experiment (MIMIx) has been defined as a standard for storing data in publicly available interaction databases. Several examples of interaction networks from molecular machines (proteasome) or organelles (phagosome, mitochondrion) to whole organisms (viruses, bacteria, yeast, fly, and worm) are given and attempts to cover the entire human interaction network are discussed. The methods used to perform the topological analysis of interaction networks and to extract biological information from them are presented. These investigations have provided clues on protein functions, signalling and metabolic pathways, and physiological processes, unraveled the molecular basis of some diseases (cancer, infectious diseases), and will be very useful to identify new therapeutic targets and for drug discovery. A major challenge is now to integrate data from different sources (interactome, transcriptome, phenome, localization) to switch from static to dynamic interaction networks. The merging of a viral interactome and the human interactome has been used to simulate viral infection, paving the way for future studies aiming at providing molecular basis of human diseases.

  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. 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

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

    PubMed

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

    2015-07-21

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

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

    PubMed

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

    2007-09-10

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

  13. Interaction of Approved Drugs with Synaptic Vesicle Protein 2A.

    PubMed

    Danish, Azeem; Namasivayam, Vigneshwaran; Schiedel, Anke C; Müller, Christa E

    2017-04-01

    Levetiracetam (LEV) and its recently approved derivative brivaracetam are anti-epileptic drugs with a unique mechanism of action. The synaptic vesicle protein 2A (SV2A) was previously identified as their main target. In the current study, we tested a collection of 500 approved drugs for interaction with the human SV2A protein expressed in Chinese hamster ovary cells. Competition binding studies were performed using cell lysates with high SV2A expression and [(3) H]brivaracetam as a radioligand. A hit rate of 3% was obtained, defined as compounds that inhibited radioligand binding by more than 90% at a screening concentration of 20 μM. Subsequent concentration-inhibition curves revealed the antihistaminic prodrug loratadine (Ki  = 1.16 μM) and the antimalarial drug quinine (Ki  = 2.03 μM) to be the most potent SV2A protein ligands of the investigated drug library. Both compounds were similarly potent as LEV (Ki  = 1.74 μM), providing structurally novel scaffolds for SV2A ligands. A pharmacophore model was established, which indicated steric and electronic conformities of brivaracetam with the new SV2A ligands, and preliminary structure-activity relationships were determined. The anti-convulsive effects of the natural product quinine may - at least in part - be explained by interaction with SV2A. Loratadine and quinine represent new lead structures for anti-epileptic drug development.

  14. The interaction of encapsulated pharmaceutical drugs with a silica matrix.

    PubMed

    Morais, Everton C; Correa, Gabriel G; Brambilla, Rodrigo; Radtke, Claudio; Baibich, Ione Maluf; dos Santos, João Henrique Z

    2013-03-01

    A series of seven drugs, namely, fluoxetine, gentamicin, lidocaine, morphine, nifedipine, paracetamol and tetracycline, were encapsulated. The encapsulated systems were characterized using a series of complementary techniques: Fourier-transform infrared spectroscopy (FT-IR), diffusive reflectance spectroscopy in the UV-vis region (DRS) and X-ray photoelectron spectroscopy (XPS). According to the DRS spectra, most of the encapsulated systems showed a band shift of the maximum absorption when compared with the corresponding bare pharmaceutical. Additionally, after encapsulation, the drugs exhibited infrared band shifts toward higher wavenumbers, which in turn provided insight into potential sites for interaction with the silica framework. The amine group showed a band shift in the spectra of almost all the drugs (except nifedipine and tetracycline). This finding indicates the possibility of a hydrogen bonding interaction between the drug and the silica via electron donation from the amine group to the silica framework. XPS confirmed this interaction between the pharmaceuticals and the silica through the amine group. A correlation was observed between the textural characteristics of the solids and the spectroscopic data, suggesting that the amine groups from the pharmaceuticals were more perturbed upon encapsulation.

  15. Relating drug–protein interaction network with drug side effects

    PubMed Central

    Mizutani, Sayaka; Pauwels, Edouard; Stoven, Véronique; Goto, Susumu; Yamanishi, Yoshihiro

    2012-01-01

    Motivation: Identifying the emergence and underlying mechanisms of drug side effects is a challenging task in the drug development process. This underscores the importance of system–wide approaches for linking different scales of drug actions; namely drug-protein interactions (molecular scale) and side effects (phenotypic scale) toward side effect prediction for uncharacterized drugs. Results: We performed a large-scale analysis to extract correlated sets of targeted proteins and side effects, based on the co-occurrence of drugs in protein-binding profiles and side effect profiles, using sparse canonical correlation analysis. The analysis of 658 drugs with the two profiles for 1368 proteins and 1339 side effects led to the extraction of 80 correlated sets. Enrichment analyses using KEGG and Gene Ontology showed that most of the correlated sets were significantly enriched with proteins that are involved in the same biological pathways, even if their molecular functions are different. This allowed for a biologically relevant interpretation regarding the relationship between drug–targeted proteins and side effects. The extracted side effects can be regarded as possible phenotypic outcomes by drugs targeting the proteins that appear in the same correlated set. The proposed method is expected to be useful for predicting potential side effects of new drug candidate compounds based on their protein-binding profiles. Supplementary information: Datasets and all results are available at http://web.kuicr.kyoto-u.ac.jp/supp/smizutan/target-effect/. Availability: Software is available at the above supplementary website. Contact: yamanishi@bioreg.kyushu-u.ac.jp, or goto@kuicr.kyoto-u.ac.jp PMID:22962476

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

    PubMed

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

    2014-05-01

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

  17. 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.

  18. Interactions between clinically used drugs and oral contraceptives.

    PubMed Central

    Bolt, H M

    1994-01-01

    Metabolism of contraceptive compounds may be influenced by various drugs. Of clinical importance is induction by barbiturates, by diphenylhydantoin, and especially by rifampicin, of enzymes that are responsible for degradation of estrogens. The major target is the hepatic microsomal estrogen-2-hydroxylase (cytochrome P450 3A4). Another type of interaction of drugs with disposition and effectiveness of estrogens is impairment of their enterohepatic circulation. This may be due to absorption of biliary estrogen conjugates (e.g., by cholestyramine) or to insufficient cleavage of the conjugate by intestinal bacteria, the latter being observed after administration of antibiotics (e.g., ampicillin, neomycin). PMID:7698081

  19. Stress, alcohol and drug interaction: an update of human research

    PubMed Central

    Uhart, Magdalena; Wand, Gary S.

    2008-01-01

    A challenging question that continues unanswered in the field of addiction is why some individuals are more vulnerable to substance use disorders than others. Numerous risk factors for alcohol and other drugs of abuse, including exposure to various forms of stress, have been identified in clinical studies. However, the neurobiological mechanisms that underlie this relationship remain unclear. Critical neurotransmitters, hormones and neurobiological sites have been recognized, which may provide the substrates that convey individual differences in vulnerability to addiction. With the advent of more sophisticated measures of brain function in humans, such as functional imaging technology, the mechanisms and neural pathways involved in the interactions between drugs of abuse, the mesocorticolimbic dopamine system and stress systems are beginning to be characterized. This review provides a neuroadaptive perspective regarding the role of the hormonal and brain stress systems in drug addiction with a focus on the changes that occur during the transition from occasional drug use to drug dependence. We also review factors that contribute to different levels of hormonal/brain stress activation, which has implications for understanding individual vulnerability to drug dependence. Ultimately, these efforts may improve our chances of designing treatment strategies that target addiction at the core of the disorder. PMID:18855803

  20. Interaction of Drug or Food with Drug Transporters in Intestine and Liver.

    PubMed

    Nakanishi, Takeo; Tamai, Ikumi

    2015-01-01

    Oral bioavailability (F) is determined as fraction of the drug dose absorbed through the gastrointestinal membranes (Fa), the unmetabolized fraction of the absorbed dose that passes through the gut into the portal blood (Fg), and the hepatic first pass availability (Fh), namely F is expressed as the product of Fa, Fg and Fh (F = Fa.Fg.Fh). Current evidence suggests that transporter proteins play a role in intestinal absorption and hepatobiliary clearance of drugs. Among those transporters, this review will focus on PEPT1 and OATP2B1 as influx transporter and p-glycoprotein (P-gp) and BCRP as efflux transporter in intestinal epithelial cells, and on OATP1B1 and 1B3 as influx transporter and MRP2 as efflux transporter in hepatocytes, respectively, because drug-drug (DDI) and -food (DFI) interactions on these transporter are considered to affect bioavailability of their substrate drugs. DDI and DFI may reduce systemic exposure to drug by blocking influx transporters in intestine, but increase it by modulating influx and efflux transporters in liver and efflux transporters in intestines. Namely, drug disposition and efficacy are likely affected by DDI and DFI, resulting in treatment failures or increase in adverse effect. Therefore, it is of significantly importance to understand precise mechanism of DDI and DFI. This review will present information about transporter-based DDI and DFI in the processes of intestinal absorption and hepatic clearance of drugs, and discuss about their clinical implication.

  1. Drug metabolism and liver disease: a drug-gene-environment interaction.

    PubMed

    Zgheib, Nathalie K; Branch, Robert A

    2017-02-01

    Despite the central role of the liver in drug metabolism, surprisingly there is lack of certainty in anticipating the extent of modification of the clearance of a given drug in a given patient. The intent of this review is to provide a conceptual framework in considering the impact of liver disease on drug disposition and reciprocally the impact of drug disposition on liver disease. It is proposed that improved understanding of the situation is gained by considering the issue as a special example of a drug-gene-environment interaction. This requires an integration of knowledge of the drug's properties, knowledge of the gene products involved in its metabolism, and knowledge of the pathophysiology of its disposition. This will enhance the level of predictability of drug disposition and toxicity for a drug of interest in an individual patient. It is our contention that advances in pharmacology, pharmacogenomics, and hepatology, together with concerted interests in the academic, regulatory, and pharmaceutical industry communities provide an ideal immediate environment to move from a qualitative reactive approach to quantitative proactive approach in individualizing patient therapy in liver disease.

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

    PubMed

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

    2012-01-01

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

  3. Clinically significant drug interactions with antacids: an update.

    PubMed

    Ogawa, Ryuichi; Echizen, Hirotoshi

    2011-10-01

    One may consider that drug-drug interactions (DDIs) associated with antacids is an obsolete topic because they are prescribed less frequently by medical professionals due to the advent of drugs that more effectively suppress gastric acidity (i.e. histamine H(2)-receptor antagonists [H2RAs] and proton pump inhibitors [PPIs]). Nevertheless, the use of antacids by ambulant patients may be ever increasing, because they are freely available as over-the-counter (OTC) drugs. Antacids consisting of weak basic substances coupled with polyvalent cations may alter the rate and/or the extent of absorption of concomitantly administered drugs via different mechanisms. Polyvalent cations in antacid formulations may form insoluble chelate complexes with drugs and substantially reduce their bioavailability. Clinical studies demonstrated that two classes of antibacterials (tetracyclines and fluoroquinolones) are susceptible to clinically relevant DDIs with antacids through this mechanism. Countermeasures against this type of DDI include spacing out the dosing interval - taking antacid either 4 hours before or 2 hours after administration of these antibacterials. Bisphosphonates may be susceptible to DDIs with antacids by the same mechanism, as described in the prescription information of most bisphosphonates, but no quantitative data about the DDIs are available. For drugs with solubility critically dependent on pH, neutralization of gastric fluid by antacids may alter the dissolution of these drugs and the rate and/or extent of their absorption. However, the magnitude of DDIs elicited by antacids through this mechanism is less than that produced by H2RAs or PPIs; therefore, the clinical relevance of such DDIs is often obscure. Magnesium ions contained in some antacid formulas may increase gastric emptying, thereby accelerating the rate of absorption of some drugs. However, the clinical relevance of this is unclear in most cases because the difference in plasma drug concentration

  4. Idiosyncratic Drug-Induced Liver Injury: Is Drug-Cytokine Interaction the Linchpin?

    PubMed

    Roth, Robert A; Maiuri, Ashley R; Ganey, Patricia E

    2017-02-01

    Idiosyncratic drug-induced liver injury continues to be a human health problem in part because drugs that cause these reactions are not identified in current preclinical testing and because progress in prevention is hampered by incomplete knowledge of mechanisms that underlie these adverse responses. Several hypotheses involving adaptive immune responses, inflammatory stress, inability to adapt to stress, and multiple, concurrent factors have been proposed. Yet much remains unknown about how drugs interact with the liver to effect death of hepatocytes. Evidence supporting hypotheses implicating adaptive or innate immune responses in afflicted patients has begun to emerge and is bolstered by results obtained in experimental animal models and in vitro systems. A commonality in adaptive and innate immunity is the production of cytokines, including interferon-γ (IFNγ). IFNγ initiates cell signaling pathways that culminate in cell death or inhibition of proliferative repair. Tumor necrosis factor-α, another cytokine prominent in immune responses, can also promote cell death. Furthermore, tumor necrosis factor-α interacts with IFNγ, leading to enhanced cellular responses to each cytokine. In this short review, we propose that the interaction of drugs with these cytokines contributes to idiosyncratic drug-induced liver injury, and mechanisms by which this could occur are discussed.

  5. Minimizing Cardiovascular Adverse Effects of Atypical Antipsychotic Drugs in Patients with Schizophrenia

    PubMed Central

    Khasawneh, Fadi T.; Shankar, Gollapudi S.

    2014-01-01

    The use of atypical antipsychotic agents has rapidly increased in the United States and worldwide in the last decade. Nonetheless, many health care practitioners do not appreciate the significance of the cardiovascular side effects that may be associated with their use and the means to minimize them. Thus, atypical antipsychotic medications can cause cardiovascular side effects such as arrhythmias and deviations in blood pressure. In rare cases, they may also cause congestive heart failure, myocarditis, and sudden death. Patients with schizophrenia have a higher risk of cardiovascular mortality than healthy individuals, possibly because of excessive smoking, the underlying disorder itself, or a combination of both factors. Increased awareness of these potential complications can allow pharmacists and physicians to better manage and monitor high risk patients. Accurate assessments are very important to avoid medications from being given to patients inappropriately. Additionally, monitoring patients regularly via blood draws and checking blood pressure, heart rate, and electrocardiogram can help catch any clinical problems and prevent further complications. Finally, patient and family-member education, which pharmacists in particular can play key roles in, is central for the management and prevention of side effects, which is known to reflect positively on morbidity and mortality in these patients. PMID:24649390

  6. An antibiotic protocol to minimize emergence of drug-resistant tuberculosis

    NASA Astrophysics Data System (ADS)

    de Espíndola, Aquino L.; Girardi, Daniel; Penna, T. J. P.; Bauch, Chris T.; Troca Cabella, Brenno C.; Martinez, Alexandre Souto

    2014-04-01

    A within-host model of the spread of tuberculosis is proposed here where the emergence of drug resistance and bacterial dormancy are simultaneously combined. We consider both sensitive and resistant strains of tuberculosis pathogens as well as a dormant state of these bacteria. The dynamics of the within-host system is modeled by a set of coupled differential equations which are numerically solved to find a relation between the within-host bacterial populations and the host health states. The values of the parameters were taken from the current literature when available; a sensitivity analysis was performed for the others. Antibiotic treatment for standard, intermittent and oscillating intermittent protocols is analyzed for different conditions. Our results suggest that the oscillating protocol is the most effective one, that would imply a lower treatment cost.

  7. 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

  8. Modeling Drug-Carrier Interaction in the Drug Release from Nanocarriers

    PubMed Central

    Zeng, Like; An, Lingling; Wu, Xiaoyi

    2011-01-01

    Numerous nanocarriers of various compositions and geometries have been developed for the delivery and release of therapeutic and imaging agents. Due to the high specific surface areas of nanocarriers, different mechanisms such as ion pairing and hydrophobic interaction need to be explored for achieving sustained release. Recently, we developed a three-parameter model that considers reversible drug-carrier interaction and first-order drug release from liposomes. A closed-form analytical solution was obtained. Here, we further explore the ability of the model to capture the release of bioactive molecules such as drugs and growth factors from various nanocarriers. A parameter study demonstrates that the model is capable of resembling major categories of drug release kinetics. We further fit the model to 60 sets of experimental data from various drug release systems, including nanoparticles, hollow particles, fibers, and hollow fibers. Additionally, bootstrapping is used to evaluate the accuracy of parameter determination and validate the model in selected cases. The simplicity and universality of the model and the clear physical meanings of each model parameter render the model useful for the design and development of new drug delivery systems. PMID:21845225

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

    PubMed

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

    2013-07-01

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

  10. Quantitative structure-interaction relationship analysis of 1,4-dihydropyridine drugs in concomitant administration with grapefruit juice.

    PubMed

    Uesawa, Y; Mohri, K

    2012-03-01

    Quantitative structure-interaction relationship (QSIR) analyses of 1,4-dihydropyridine drugs were performed on grapefruit juice interaction potentials to characterize the interaction and evaluate drugs not yet tested in clinical research. AUC ratios of drugs with and without grapefruit juice ingestion were estimated as grapefruit juice interaction potentials from clinical studies on dihydropyridine drugs such as amlodipine, azelnidipine, benidipine, cilnidipine, felodipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, and pranidipine. The minimal energy conformation in each dihydropyridine drug was searched for using Merck Molecular Force Field (MMFFaq), and then geometry optimization was performed by density-functional-theory (DFT) calculation (B3LYP/6-31G**). The geometric, electronic, and physicochemical features including molecular size, dipole moment, total energy, HOMO/LUMO energies, and logP values were then obtained. Dragon descriptors were also calculated by optimized 3D-structures. The relation between the potentials and over 1000 of the molecular properties was investigated using statistical techniques including partial least squares analysis with genetic algorithm (GA-PLS) to a variable subset selection. Some PLS regression equations including logP values and dragon descriptors as explanatory variables were constructed in which the maximal contribution coefficient was 94%. These models could be applied to estimate the interaction potentials of other dihydropyridine drugs that have gone unreported in interactions with drugs such as aranidipine, barnidipine, clevidipine, lemildipine, lercanidipine, niguldipine, niludipine, and nilvadipine. In the assessment of major dihydropyridines, amlodipine was found to be the safest drug to avoid interactions among the drugs investigated in the present study.

  11. Diabetes in the elderly: drug use and the risk of drug interaction.

    PubMed

    Prado, Maria Aparecida Medeiros Barros do; Francisco, Priscila Maria Stolses Bergamo; Barros, Marilisa Berti de Azevedo

    2016-11-01

    This study sought to outline the sociodemographic and health profile of elderly persons with reported diabetes, to assess the knowledge and practices regarding treatment options and describe the use of medications and potential risks for drug interactions (DI) in this subgroup. In 2008,a cross-sectional study was conducted of 1,517 elderly citizens in Campinas in which the prevalence of diabetes was estimated and its associations assessed using the Rao-Scott test (p < 0,05).The potential drug interactions were evaluated using the Micromedex® database. Diabetes prevalence was 21.7%, without significant difference between the sexes. A higher percentage of elderly diabetics was found aged over 70, with less schooling, per capita family income of less than 1 minimum wage and no occupational activity. The average drug intake was 3.9 in the previous 3 days. Possible interactions were identified in 413 cases and 53.1%, 7.8% and 7.2% of the subjects presented moderate, minor and serious risk of DI, respectively. The importance of adopting a healthy diet and physical activity for weight reduction, disease and complication control is stressed. The need for attention to the potential for drug interactions and the use of inappropriate medications among the elderly is highlighted.

  12. Pharmacokinetic Herb-Drug Interactions: Insight into Mechanisms and Consequences.

    PubMed

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

    2016-04-01

    Herbal medicines are currently in high demand, and their popularity is steadily increasing. Because of their perceived effectiveness, fewer side effects and relatively low cost, they are being used for the management of numerous medical conditions. However, they are capable of affecting the pharmacokinetics and pharmacodynamics of coadministered conventional drugs. These interactions are particularly of clinically relevance when metabolizing enzymes and xenobiotic transporters, which are responsible for the fate of many drugs, are induced or inhibited, sometimes resulting in unexpected outcomes. This article discusses the general use of herbal medicines in the management of several ailments, their concurrent use with conventional therapy, mechanisms underlying herb-drug interactions (HDIs) as well as the drawbacks of herbal remedy use. The authors also suggest means of surveillance and safety monitoring of herbal medicines. Contrary to popular belief that "herbal medicines are totally safe," we are of the view that they are capable of causing significant toxic effects and altered pharmaceutical outcomes when coadministered with conventional medicines. Due to the paucity of information as well as sometimes conflicting reports on HDIs, much more research in this field is needed. The authors further suggest the need to standardize and better regulate herbal medicines in order to ensure their safety and efficacy when used alone or in combination with conventional drugs.

  13. Herb-drug interactions. Interactions between saw palmetto and prescription medications.

    PubMed

    Bressler, Rubin

    2005-11-01

    Patients over age 50 typically present with one chronic disease per decade. Each chronic disease typically requires long-term drug therapy, meaning most older patients require several drugs to maintain health. Simultaneously, use of complementary and alternative medicine (CAM) has increased in the United States in the last 20 years, reaching 36% in 2002; herbal medicine use accounts for approximately 22% of all CAM use. Older adults often add herbal medicines to prescription medications, yet do not always inform their physicians. The drug metabolizing enzyme systems process all compounds foreign to the body, including prescription and herbal medications. Therefore use of both medicinals simultaneously has a potential for adverse interactions. This review, which discusses saw palmetto, is the last in a series covering the documented interactions among the top 5 efficacious herbal medicines and prescription drugs.

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

    PubMed

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

    2016-02-01

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

  15. Cost-effectiveness of one-time genetic testing to minimize lifetime adverse drug reactions.

    PubMed

    Alagoz, O; Durham, D; Kasirajan, K

    2016-04-01

    We evaluated the cost-effectiveness of one-time pharmacogenomic testing for preventing adverse drug reactions (ADRs) over a patient's lifetime. We developed a Markov-based Monte Carlo microsimulation model to represent the ADR events in the lifetime of each patient. The base-case considered a 40-year-old patient. We measured health outcomes in life years (LYs) and quality-adjusted LYs (QALYs) and estimated costs using 2013 US$. In the base-case, one-time genetic testing had an incremental cost-effectiveness ratio (ICER) of $43,165 (95% confidence interval (CI) is ($42,769,$43,561)) per additional LY and $53,680 per additional QALY (95% CI is ($53,182,$54,179)), hence under the base-case one-time genetic testing is cost-effective. The ICER values were most sensitive to the average probability of death due to ADR, reduction in ADR rate due to genetic testing, mean ADR rate and cost of genetic testing.

  16. Cradle-to-cradle stewardship of drugs for minimizing their environmental disposition while promoting human health. II. Drug disposal, waste reduction, and future directions.

    PubMed Central

    Daughton, Christian G

    2003-01-01

    Since the 1980s, the occurrence of pharmaceuticals and personal care products (PPCPs) as trace environmental pollutants, originating primarily from consumer use and actions rather than manufacturer effluents, continues to become more firmly established. The growing, worldwide importance of freshwater resources underscores the need for ensuring that any aggregate or cumulative impacts on (or from) water supplies are minimized. Despite a paucity of effects data from long-term, simultaneous exposure at low doses to multiple xenobiotics (particularly non-target-organism exposure to PPCPs), a wide range of proactive actions could be implemented for reducing or minimizing the introduction of PPCPs to the environment. Most of these actions fall under what could be envisioned as a holistic stewardship program--overseen by the health care industry and consumers alike. Significantly, such a stewardship program would benefit not just the environment--additional, collateral benefits could automatically accrue, including the lessening of medication expense for the consumer and improving patient health and consumer safety. In this article (the second of two parts describing the "green pharmacy") I focus on those actions and activities tied more closely to the end user (e.g., the patient) and issues associated with drug disposal/recycling that could prove useful in minimizing the environmental disposition of PPCPs. I also outline some recommendations and suggestions for further research and pose some considerations regarding the future. In this mini-monograph I attempt to capture cohesively for the first time the wide spectrum of actions available for minimizing the release of PPCPs to the environment. A major objective is to generate an active dialog or debate across the many disciplines that must become actively involved to design and implement a successful approach to life-cycle stewardship of PPCPs. PMID:12727607

  17. Outliers on the dose-response curve: how to minimize this problem using therapeutic drug monitoring, an underutilized tool in psychiatry.

    PubMed

    Preskorn, Sheldon H

    2010-05-01

    This column continues the discussion of outliers on the dose-response curve begun in earlier columns. It focuses on therapeutic drug monitoring (TDM) as an underutilized tool in psychiatry to minimize this problem. The scientific rationale for dose adjustment based on TDM is presented and its efficiency is contrasted with dose adjustment based on clinical assessment of response. In current practice, the use of TDM with psychiatric drugs is generally restricted to drugs with narrow therapeutic windows or drugs imported into psychiatry from neurology where TDM is more commonly used. Examples of each of these types of drugs are cited.

  18. 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

  19. Quantitative Prediction of Drug–Drug Interactions Involving Inhibitory Metabolites in Drug Development: How Can Physiologically Based Pharmacokinetic Modeling Help?

    PubMed Central

    Chen, Y; Mao, J; Lin, J; Yu, H; Peters, S; Shebley, M

    2016-01-01

    This subteam under the Drug Metabolism Leadership Group (Innovation and Quality Consortium) investigated the quantitative role of circulating inhibitory metabolites in drug–drug interactions using physiologically based pharmacokinetic (PBPK) modeling. Three drugs with major circulating inhibitory metabolites (amiodarone, gemfibrozil, and sertraline) were systematically evaluated in addition to the literature review of recent examples. The application of PBPK modeling in drug interactions by inhibitory parent–metabolite pairs is described and guidance on strategic application is provided. PMID:27642087

  20. Effects of drug-carrier interactions on drug dissolution from binary and ternary matrices

    NASA Astrophysics Data System (ADS)

    Iqbal, Zafar

    For nearly five decades, pharmaceutical researchers have studied solid solutions of drugs in polymers as a potential means to enhance the dissolution of drugs with poor aqueous solubility. This has become of greater importance in recent years because most new potential drug compounds (new chemical entities) exhibit poor water solubility and present great challenges to scientists who must design dosage forms from which the drugs are bioavailable. During the formulation of a solid solution, the drug undergoes physical but not chemical alterations that increase its chemical potential in the formulation relative to that of the pure drug in its stable form. This increased chemical potential is responsible for enhanced dissolution as well as physical instabilities, such as amorphous to crystalline conversions and precipitation within the solid state. The chemical potential is derived from the Gibbs free energy, so it is reasonable to explain the behavior of solid solution systems in terms of thermodynamics. Solid solutions and dispersions have been extensively studied by pharmaceutical scientists, both with regard to manufacturing aspects and the proposal of various models in attempts to explain the physical bases for how these systems work. Recently, Dave and Bellantone proposed a model based on the thermodynamic changes resulting from the formulation of binary solid solutions of a drug in the polymer PVP. Their model introduced a modification of the F-H theory, which was used to quantify the drug-polymer interaction energies and calculate the entropy of mixing of the drug and polymer. In this work, the model of Dave and Bellantone was extended to include three-component systems, consisting of one drug mixed in a carrier matrix consisting of mixture of two polymers or a polymer and a surfactant. For this research, solid solutions were formed using various drug weight fractions in the formulations. The study focused on the following points: (1) Prepare solid solution

  1. Concept of interactions between consumable substances in Ayurveda with special reference to foods and drugs.

    PubMed

    Sarkar, Prasanta Kumar; Chaudhari, Supriyo; Chattopadhyay, Abichal

    2013-01-01

    Ayurvedic medicines are available in the market as over-the-counter products. Today people use prescription and nonprescription medicines along with Ayurvedic medicines for quick relief from ailments. In the ancient texts of Ayurveda, the concept of interactions with various examples of food interactions and food-drug interactions are mentioned. Recent studies and publications reported drug interactions of Ayurveda medicines and modern drugs. In the present review article, the concept of interactions mentioned in the Ayurvedic texts along with the examples of food interactions, food-drug interactions and the recent research work and publications indicating the interactions of the Ayurvedic drugs and drug interactions of Ayurvedic medicines and modern drugs are compiled. This will help the consumer of the prescription and nonprescription medicines with the Ayurvedic medicines to be cautious about the probable interactions.

  2. How Minimal Grade Goals and Self-Control Capacity Interact in Predicting Test Grades

    ERIC Educational Resources Information Center

    Bertrams, Alex

    2012-01-01

    The present research examined the prediction of school students' grades in an upcoming math test via their minimal grade goals (i.e., the minimum grade in an upcoming test one would be satisfied with). Due to its significance for initiating and maintaining goal-directed behavior, self-control capacity was expected to moderate the relation between…

  3. Investigating the Evolution of Ingroup Favoritism Using a Minimal Group Interaction Paradigm: The Effects of Inter- and Intragroup Interdependence

    PubMed Central

    Quayle, Michael; Tredoux, Colin G.; Titlestad, Kim; Tooke, Larry

    2016-01-01

    We investigated the effect of structural interdependencies between groups (especially inequality), and interdependencies between individuals on ingroup favoritism in minimal group situations. Previous research has attempted to determine whether ingroup favoritism is produced by categorization or intragroup interdependencies (reciprocation expectations), but recent literature suggests that it is not possible to tease these influences apart. We report two studies that investigate how ingroup favoritism evolves over time in social interaction. The levels of ingroup favoritism were affected by categorization and inequality, and the level of ingroup favoritism changed over time, increasing or decreasing depending on the nature of the initial intergroup structure. We conclude by providing two explanations for this change: emergent norms, and changes to the intergroup situation produced by interaction. Our experiments confirm the value of studying the evolution of minimal group behavior, especially for explaining why low status groups act to preserve intergroup inequalities. PMID:27851791

  4. Nanosized Drug Delivery Systems in Gastrointestinal Targeting: Interactions with Microbiota

    PubMed Central

    Karavolos, Michail; Holban, Alina

    2016-01-01

    The new age of nanotechnology has signaled a stream of entrepreneurial possibilities in various areas, form industry to medicine. Drug delivery has benefited the most by introducing nanostructured systems in the transport and controlled release of therapeutic molecules at targeted sites associated with a particular disease. As many nanosized particles reach the gastrointestinal tract by various means, their interactions with the molecular components of this highly active niche are intensively investigated. The well-characterized antimicrobial activities of numerous nanoparticles are currently being considered as a reliable and efficient alternative to the eminent world crisis in antimicrobial drug discovery. The interactions of nanosystems present in the gastrointestinal route with host microbiota is unavoidable; hence, a major research initiative is needed to explore the mechanisms and effects of these nanomaterials on microbiota and the impact that microbiota may have in the outcome of therapies entailing drug delivery nanosystems through the gastrointestinal route. These coordinated studies will provide novel techniques to replace or act synergistically with current technologies and help develop new treatments for major diseases via the discovery of unique antimicrobial molecules. PMID:27690060

  5. Comparison of the interaction between lactoferrin and isomeric drugs

    NASA Astrophysics Data System (ADS)

    Guo, Ming; Lu, Xiaowang; Wang, Yan; Brodelius, Peter E.

    2017-02-01

    The binding properties of pentacyclic triterpenoid isomeric drugs, i.e. ursolic acid (UA) and oleanolic acid (OA), to bovine lactoferrin (BLF) have been studied by molecule modeling, fluorescence spectroscopy, UV-visible absorbance spectroscopy and infrared spectroscopy (IR). Molecular docking, performed to reveal the possible binding mode or mechanism, suggested that hydrophobic interaction and hydrogen bonding play important roles to stabilize the complex. The results of spectroscopic measurements showed that the two isomeric drugs both strongly quenched the intrinsic fluorescence of BLF through a static quenching procedure although some differences between UA and OA binding strength and non-radiation energy transfer occurred within the molecules. The number of binding sites was 3.44 and 3.10 for UA and OA, respectively, and the efficiency of Förster energy transfer provided a distance of 0.77 and 1.21 nm for UA and OA, respectively. The conformation transformation of BLF affected by the drugs conformed to the "all-or-none" pattern. In addition, the changes of the ratios of α-helices, β-sheets and β-turns of BLF during the process of the interaction were obtained. The results of the experiments in combination with the calculations showed that there are two modes of pentacyclic triterpenoid binding to BLF instead of one binding mode only governed by the principle of the lowest bonding energy.

  6. Comparison of the interaction between lactoferrin and isomeric drugs.

    PubMed

    Guo, Ming; Lu, Xiaowang; Wang, Yan; Brodelius, Peter E

    2017-02-15

    The binding properties of pentacyclic triterpenoid isomeric drugs, i.e. ursolic acid (UA) and oleanolic acid (OA), to bovine lactoferrin (BLF) have been studied by molecule modeling, fluorescence spectroscopy, UV-visible absorbance spectroscopy and infrared spectroscopy (IR). Molecular docking, performed to reveal the possible binding mode or mechanism, suggested that hydrophobic interaction and hydrogen bonding play important roles to stabilize the complex. The results of spectroscopic measurements showed that the two isomeric drugs both strongly quenched the intrinsic fluorescence of BLF through a static quenching procedure although some differences between UA and OA binding strength and non-radiation energy transfer occurred within the molecules. The number of binding sites was 3.44 and 3.10 for UA and OA, respectively, and the efficiency of Förster energy transfer provided a distance of 0.77 and 1.21nm for UA and OA, respectively. The conformation transformation of BLF affected by the drugs conformed to the "all-or-none" pattern. In addition, the changes of the ratios of α-helices, β-sheets and β-turns of BLF during the process of the interaction were obtained. The results of the experiments in combination with the calculations showed that there are two modes of pentacyclic triterpenoid binding to BLF instead of one binding mode only governed by the principle of the lowest bonding energy.

  7. Pharmacokinetics, drug interactions, and tolerability of paroxetine and paroxetine CR.

    PubMed

    DeVane, C Lindsay

    2003-01-01

    The development of paroxetine hydrochloride began in the late 1970s. An abundance of data have been accumulated from clinical investigations demonstrating the efficacy of paroxetine in the treatment of major depression and anxiety disorders. The published literature contains a substantial amount of supportive data documenting the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of paroxetine. The role of paroxetine in clinically significant drug-drug interactions, especially involving metabolic inhibitory effects on the substrates of cytochrome p450 2D6, has long been suspected, but only isolated cases provide any evidence. Published data for widespread patient morbidity from drug interactions with paroxetine are almost nonexistent. Considerations of the pharmacokinetic properties of paroxetine support a rationale for the development of new dosage forms that maintain the efficacy yet improve the tolerability profile of the selective serotonin reuptake inhibitors. Paroxetine controlled-release is an enteric-coated formulation with release features that may enhance clinical outcome by modifying absorption-related pharmacokinetics, improving tolerability, and maintaining therapeutic benefits

  8. A fatal drug interaction between oxycodone and clonazepam.

    PubMed

    Burrows, David L; Hagardorn, Andrea N; Harlan, Gretel C; Wallen, Ellen D B; Ferslew, Kenneth E

    2003-05-01

    A case is presented of a fatal drug interaction caused by ingestion of oxycodone (Oxycontin) and clonazepam (Klonapin). Oxycodone is an opium alkaloid used in long-term pain management therapy. Clonazepam is a benzodiazepine used for the treatment of seizures and panic disorders. The Drug Abuse Warning Network (DAWN) has reported an increase of 108% in the last two years of emergency department episodes related to Oxycontin. Six billion prescriptions were written for Oxycontin in the year 2000, an 18-fold increase from four years previous (1). Oxycontin has recently gained enormous notoriety at the local and national levels; however, there are very few previously documented cases of lethal drug interactions between oxycodone and clonazepam. Synergistic effects between these two drugs are postulated to arise from different agonistic mechanisms producing similar physiological changes. It is also theorized that clonazepam may inhibit the metabolism of oxycodone. A 38-year-old white female was found dead in Jefferson County, Tennessee in March of 2001. The deceased had physical evidence of previous drug abuse and positive serological findings of hepatitis B and C. Prescription pill bottles filled under the name of the deceased, as well as another name, were found with the body. Serum, urine and gastric contents from the deceased were screened for numerous drugs and metabolites using a combination of thin layer chromatography and immunoassay techniques (EMIT and FPIA). Analysis of biological specimens from the deceased revealed the presence of: benzodiazepines, opiates (oxycodone), and trazodone metabolites in the serum; cannabinoids, benzodiazepines, opiates (oxycodone), trazodone, trazodone metabolites, nicotine, and nicotine metabolite in the urine; and benzodiazepines, opiates (oxycodone), nicotine, and nicotine metabolite in the gastric contents. Quantitative analyses for clonazepam was performed by high performance liquid chromatography (HPLC) and revealed a

  9. How pre-marketing data can be used for predicting the weight of drug interactions in clinical practice.

    PubMed

    Caccia, Silvio; Pasina, Luca; Nobili, Alessandro

    2013-04-01

    Unexpected drug interactions have led to the withdrawal of many drugs, raising concern about the gap between what is known at the time of approval and the risk of serious effects in the longer term, particularly in high-risk populations generally excluded from drug development. This is because the majority of drug interaction studies are done using in vitro methods, or in healthy young volunteers who may not reflect the complexity of patients, and the settings in which the drug will be used in clinical practice. Pre-marketing interaction studies should therefore be designed to make information easily accessible and clinically transferable. They should be adequate in terms of sample size, population, comorbidity, phenotyping and/or genotyping, end-points and outcome measures, and conducted in conditions of dose, route and timing of co-administration that reproduce the proposed therapeutic indications of the new drug. Although young volunteers have the advantage of minimizing some confounding effects introduced by diseases or polypharmacy, patients drawn from populations for whom the drug is intended would be more relevant and accurate, providing the studies are feasible and safe.

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

    PubMed

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

    2006-12-01

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

  11. 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

  12. Pharmacokinetic interaction of some antitubercular drugs with caraway: implications in the enhancement of drug bioavailability.

    PubMed

    Sachin, B S; Monica, P; Sharma, S C; Satti, N K; Tikoo, M K; Tikoo, A K; Suri, K A; Gupta, B D; Johri, R K

    2009-04-01

    This study deals with the pharmacokinetic interaction of selected anti-TB drugs with a natural product (CC-1a) derived from caraway (Carum carvi, L.) seed. CC-1a, chemically standardized butanolic fraction, enhanced the plasma levels of rifampicin, pyrazinamide, and isoniazid in Wistar rat, resulting in increased bioavailability indices (C(max) and AUC) of the drugs. Moreover, a 40% reduced dose regimen of these drugs, which additionally contained CC-1a, was equivalent in terms of C(max) and AUC to a normal dose regimen. A permeation-enhancing property of CC-1a across small intestinal absorptive surface was found to be a contributing factor in its bioavailability enhancing profile.

  13. Drug interaction between ethanol and 3,4-methylenedioxymethamphetamine ("ecstasy").

    PubMed

    Upreti, Vijay V; Eddington, Natalie D; Moon, Kwan-Hoon; Song, Byoung-Joon; Lee, Insong J

    2009-07-24

    Alcohol (ethanol) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are frequently co-abused, but recent findings indicate a harmful drug interaction between these two agents. In our previous study, we showed that MDMA exposure inhibits the activity of the acetaldehyde (ACH) metabolizing enzyme, aldehyde dehydrogenase2 (ALDH2). Based on this finding, we hypothesized that the co-administration of MDMA and ethanol would reduce the metabolism of ACH and result in increased accumulation of ACH. Rats were treated with MDMA or vehicle and then administered a single dose of ethanol. Liver ALDH2 activity decreased by 35% in the MDMA-treated rats compared to control rats. The peak concentration and the area under the concentration versus time curve of plasma ACH were 31% and 59% higher, respectively, in the MDMA-ethanol group compared to the ethanol-only group. In addition, the MDMA-ethanol group had 80% higher plasma transaminase levels than the ethanol-only group, indicating greater hepatocellular damage. Our results not only support a drug interaction between MDMA and ethanol but a novel underlying mechanism for the interaction.

  14. Interactions between carbon nanotubes and bioactives: a drug delivery perspective.

    PubMed

    Mehra, Neelesh Kumar; Palakurthi, Srinath

    2016-04-01

    Applications of carbon nanotubes (CNTs) in the biomedical arena have gained increased attention over the past decade. Surface engineering of CNTs by covalent and noncovalent modifications enables site-specific drug delivery and targeting. CNTs are available as single-, double-, triple-, and multiwalled carbon nanotubes (SWCNTs, DWCNTs, TWCNTs, and MWCNTs, respectively) and have unique physicochemical properties, including a high surface area, high loading efficiency, good biocompatibility, low toxicity, ultra lightweight, rich surface chemistry, non-immunogenicity, and photoluminescence. In this review, we highlight current understanding of the different types of physical and chemical interaction that occur between therapeutics and CNTs, and the potential application of the latter in drug delivery and imaging. Such understanding will aid exploration of the utility of multifunctional CNTs as pharmaceutical nanocarriers, and potential safety and toxicity issues.

  15. The drug-minded protein interaction database (DrumPID) for efficient target analysis and drug development.

    PubMed

    Kunz, Meik; Liang, Chunguang; Nilla, Santosh; Cecil, Alexander; Dandekar, Thomas

    2016-01-01

    The drug-minded protein interaction database (DrumPID) has been designed to provide fast, tailored information on drugs and their protein networks including indications, protein targets and side-targets. Starting queries include compound, target and protein interactions and organism-specific protein families. Furthermore, drug name, chemical structures and their SMILES notation, affected proteins (potential drug targets), organisms as well as diseases can be queried including various combinations and refinement of searches. Drugs and protein interactions are analyzed in detail with reference to protein structures and catalytic domains, related compound structures as well as potential targets in other organisms. DrumPID considers drug functionality, compound similarity, target structure, interactome analysis and organismic range for a compound, useful for drug development, predicting drug side-effects and structure-activity relationships.Database URL:http://drumpid.bioapps.biozentrum.uni-wuerzburg.de.

  16. The drug-minded protein interaction database (DrumPID) for efficient target analysis and drug development

    PubMed Central

    Kunz, Meik; Liang, Chunguang; Nilla, Santosh; Cecil, Alexander; Dandekar, Thomas

    2016-01-01

    The drug-minded protein interaction database (DrumPID) has been designed to provide fast, tailored information on drugs and their protein networks including indications, protein targets and side-targets. Starting queries include compound, target and protein interactions and organism-specific protein families. Furthermore, drug name, chemical structures and their SMILES notation, affected proteins (potential drug targets), organisms as well as diseases can be queried including various combinations and refinement of searches. Drugs and protein interactions are analyzed in detail with reference to protein structures and catalytic domains, related compound structures as well as potential targets in other organisms. DrumPID considers drug functionality, compound similarity, target structure, interactome analysis and organismic range for a compound, useful for drug development, predicting drug side-effects and structure–activity relationships. Database URL: http://drumpid.bioapps.biozentrum.uni-wuerzburg.de PMID:27055828

  17. Methods for Elucidation of DNA-Anticancer Drug Interactions and their Applications in the Development of New Drugs.

    PubMed

    Misiak, Majus; Mantegazza, Francesco; Beretta, Giovanni L

    2016-01-01

    DNA damaging agents including anthracyclines, camptothecins and platinum drugs are among most frequently used drugs in the chemotherapeutic routine. Due to their relatively low selectivity for cancer cells, administration of these drugs is associated with adverse side effects, inherent genotoxicity with risk of developing secondary cancers. Development of new drugs, which could be spared of these drawbacks and characterize by improved antitumor efficacy, remains challenging yet vitally important task. These properties are in large part dictated by the selectivity of interaction between the drug and DNA and in this way the studies aimed at elucidating the complex interactions between ligand and DNA represent a key step in the drug development. Studies of the drug-DNA interactions encompass determination of DNA sequence specificity and mode of DNA binding as well as kinetic, dynamic and structural parameters of binding. Here, we consider the types of interactions between small molecule ligands and polynucleotides, how they are affected by DNA sequence and structure, and what is their significance for the antitumor activity. Based on this knowledge, we discuss the wide array of experimental techniques available to researchers for studying drug-DNA interactions, which include absorption and emission spectroscopies, NMR, magnetic and optical tweezers or atomic force microscopy. We show, using the clinical and experimental anticancer drugs as examples, how these methods provide various types of information and at the same time complement each other to provide full picture of drug- DNA interaction and aid in the development of new drugs.

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  20. Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues

    PubMed Central

    Madaan, Kanika; Kumar, Sandeep; Poonia, Neelam; Lather, Viney; Pandita, Deepti

    2014-01-01

    Dendrimers are the emerging polymeric architectures that are known for their defined structures, versatility in drug delivery and high functionality whose properties resemble with biomolecules. These nanostructured macromolecules have shown their potential abilities in entrapping and/or conjugating the high molecular weight hydrophilic/hydrophobic entities by host-guest interactions and covalent bonding (prodrug approach) respectively. Moreover, high ratio of surface groups to molecular volume has made them a promising synthetic vector for gene delivery. Owing to these properties dendrimers have fascinated the researchers in the development of new drug carriers and they have been implicated in many therapeutic and biomedical applications. Despite of their extensive applications, their use in biological systems is limited due to toxicity issues associated with them. Considering this, the present review has focused on the different strategies of their synthesis, drug delivery and targeting, gene delivery and other biomedical applications, interactions involved in formation of drug-dendrimer complex along with characterization techniques employed for their evaluation, toxicity problems and associated approaches to alleviate their inherent toxicity. PMID:25035633

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

    PubMed

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

    2012-07-01

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

  2. 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

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

    PubMed Central

    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

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

    PubMed

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

    2014-07-01

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

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

    PubMed

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

    2015-11-27

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

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

    PubMed

    Barr, John T; Jones, Jeffrey P

    2011-12-01

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

  7. Pharmacokinetic Interactions between Drugs and Botanical Dietary Supplements

    PubMed Central

    Sprouse, Alyssa A.

    2016-01-01

    The use of botanical dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, mechanisms of action, efficacy, and safety. An important but underinvestigated safety concern is the potential for popular botanical dietary supplements to interfere with the absorption, transport, and/or metabolism of pharmaceutical agents. Clinical trials of drug–botanical interactions are the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive preclinical studies. For example, phase 1 clinical trials have confirmed preclinical studies and clinical case reports that St. John’s wort (Hypericum perforatum) induces CYP3A4/CYP3A5. However, clinical studies of most botanicals that were predicted to interact with drugs have shown no clinically significant effects. For example, clinical trials did not substantiate preclinical predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and/or CYP3A4. Here, we highlight discrepancies between preclinical and clinical data concerning drug–botanical interactions and critically evaluate why some preclinical models perform better than others in predicting the potential for drug–botanical interactions. Gaps in knowledge are also highlighted for the potential of some popular botanical dietary supplements to interact with therapeutic agents with respect to absorption, transport, and metabolism. PMID:26438626

  8. Toward standardized reporting of drug interactions: the READI checklist for anecdotal reports.

    PubMed

    Aronson, Jeffrey K

    2015-01-01

    Anecdotal reports contribute 30% of the literature on adverse drug reactions and interactions. However, the quality of such reports has not been uniformly high. Standardized reporting of clinical studies is of increasing interest, including the CARE guidelines on reporting anecdotal cases in general. Although there are guidelines on evaluating and managing drug-drug interactions, there are none recommending methods for reporting suspected drug interactions. Here, based on published guidelines for reporting suspected adverse drug reactions, I propose a checklist for reporting details of suspected drug interactions, the REporting Anecdotal Drug Interactions (READI) checklist, hoping to stimulate discussion and improve reporting of suspected drug interactions. The checklist includes items relating, among others, to the patient affected, the drugs involved, and the outcome.

  9. Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection

    PubMed Central

    Ndieyira, Joseph W.; Watari, Moyu; McKendry, Rachel A.

    2013-01-01

    The cantilever sensor, which acts as a transducer of reactions between model bacterial cell wall matrix immobilized on its surface and antibiotic drugs in solution, has shown considerable potential in biochemical sensing applications with unprecedented sensitivity and specificity1-5. The drug-target interactions generate surface stress, causing the cantilever to bend, and the signal can be analyzed optically when it is illuminated by a laser. The change in surface stress measured with nano-scale precision allows disruptions of the biomechanics of model bacterial cell wall targets to be tracked in real time. Despite offering considerable advantages, multiple cantilever sensor arrays have never been applied in quantifying drug-target binding interactions. Here, we report on the use of silicon multiple cantilever arrays coated with alkanethiol self-assembled monolayers mimicking bacterial cell wall matrix to quantitatively study antibiotic binding interactions. To understand the impact of vancomycin on the mechanics of bacterial cell wall structures1,6,7. We developed a new model1 which proposes that cantilever bending can be described by two independent factors; i) namely a chemical factor, which is given by a classical Langmuir adsorption isotherm, from which we calculate the thermodynamic equilibrium dissociation constant (Kd) and ii) a geometrical factor, essentially a measure of how bacterial peptide receptors are distributed on the cantilever surface. The surface distribution of peptide receptors (p) is used to investigate the dependence of geometry and ligand loading. It is shown that a threshold value of p ~10% is critical to sensing applications. Below which there is no detectable bending signal while above this value, the bending signal increases almost linearly, revealing that stress is a product of a local chemical binding factor and a geometrical factor combined by the mechanical connectivity of reacted regions and provides a new paradigm for design of

  10. 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.

  11. Biomembrane models and drug-biomembrane interaction studies: Involvement in drug design and development

    PubMed Central

    Pignatello, R.; Musumeci, T.; Basile, L.; Carbone, C.; Puglisi, G.

    2011-01-01

    Contact with many different biological membranes goes along the destiny of a drug after its systemic administration. From the circulating macrophage cells to the vessel endothelium, to more complex absorption barriers, the interaction of a biomolecule with these membranes largely affects its rate and time of biodistribution in the body and at the target sites. Therefore, investigating the phenomena occurring on the cell membranes, as well as their different interaction with drugs in the physiological or pathological conditions, is important to exploit the molecular basis of many diseases and to identify new potential therapeutic strategies. Of course, the complexity of the structure and functions of biological and cell membranes, has pushed researchers toward the proposition and validation of simpler two- and three-dimensional membrane models, whose utility and drawbacks will be discussed. This review also describes the analytical methods used to look at the interactions among bioactive compounds with biological membrane models, with a particular accent on the calorimetric techniques. These studies can be considered as a powerful tool for medicinal chemistry and pharmaceutical technology, in the steps of designing new drugs and optimizing the activity and safety profile of compounds already used in the therapy. PMID:21430952

  12. Investigating antimalarial drug interactions of emetine dihydrochloride hydrate using CalcuSyn-based interactivity calculations

    PubMed Central

    Matthews, Holly; Deakin, Jon; Rajab, May; Idris-Usman, Maryam

    2017-01-01

    The widespread introduction of artemisinin-based combination therapy has contributed to recent reductions in malaria mortality. Combination therapies have a range of advantages, including synergism, toxicity reduction, and delaying the onset of resistance acquisition. Unfortunately, antimalarial combination therapy is limited by the depleting repertoire of effective drugs with distinct target pathways. To fast-track antimalarial drug discovery, we have previously employed drug-repositioning to identify the anti-amoebic drug, emetine dihydrochloride hydrate, as a potential candidate for repositioned use against malaria. Despite its 1000-fold increase in in vitro antimalarial potency (ED50 47 nM) compared with its anti-amoebic potency (ED50 26–32 uM), practical use of the compound has been limited by dose-dependent toxicity (emesis and cardiotoxicity). Identification of a synergistic partner drug would present an opportunity for dose-reduction, thus increasing the therapeutic window. The lack of reliable and standardised methodology to enable the in vitro definition of synergistic potential for antimalarials is a major drawback. Here we use isobologram and combination-index data generated by CalcuSyn software analyses (Biosoft v2.1) to define drug interactivity in an objective, automated manner. The method, based on the median effect principle proposed by Chou and Talalay, was initially validated for antimalarial application using the known synergistic combination (atovaquone-proguanil). The combination was used to further understand the relationship between SYBR Green viability and cytocidal versus cytostatic effects of drugs at higher levels of inhibition. We report here the use of the optimised Chou Talalay method to define synergistic antimalarial drug interactivity between emetine dihydrochloride hydrate and atovaquone. The novel findings present a potential route to harness the nanomolar antimalarial efficacy of this affordable natural product. PMID:28257497

  13. Lipid-Drug Interaction and Colligative Properties in Phospholipid Vesicles.

    PubMed

    Banerjee; Bennouna; Ferreira-Marques; Ruysschaert; Caspers

    1999-11-01

    Imipramine penetration into the lipid core of a membrane was demonstrated through measurements on lipid monolayers (surface pressure and surface potential). The surface pressure measurements allow us to calculate the intrinsic binding constant (partition coefficient) for the lipid-Imipramine interaction. This latter value is in correct agreement with the results obtained by electrophoretic mobility measurements on liposomes. In addition, it was observed that the same mole fraction of "lipid-soluble drug" (Chlorpromazine or Imipramine) incorporated in a given lipidic phase (DPPC) induced the same shift in the transition temperature. Copyright 1999 Academic Press.

  14. A Look at an Interactive Classroom-Based Drug Abuse Prevention Program: Interactive Contents and Suggestions for Research

    ERIC Educational Resources Information Center

    Sussman, Steve; Rohrbach, Louise A.; Patel, Ravi; Holiday, Karen

    2003-01-01

    Interactivity has been shown to be a critical element of effective drug abuse prevention programs. This study examined the contents of Project Towards No Drug Abuse, a program that has revealed strong effects only when delivered in a highly interactive version. Types of teacher and student interactive messages were identified. It is speculated…

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  17. 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

  18. Computational Discovery of Putative Leads for Drug Repositioning through Drug-Target Interaction Prediction

    PubMed Central

    2016-01-01

    De novo experimental drug discovery is an expensive and time-consuming task. It requires the identification of drug-target interactions (DTIs) towards targets of biological interest, either to inhibit or enhance a specific molecular function. Dedicated computational models for protein simulation and DTI prediction are crucial for speed and to reduce the costs associated with DTI identification. In this paper we present a computational pipeline that enables the discovery of putative leads for drug repositioning that can be applied to any microbial proteome, as long as the interactome of interest is at least partially known. Network metrics calculated for the interactome of the bacterial organism of interest were used to identify putative drug-targets. Then, a random forest classification model for DTI prediction was constructed using known DTI data from publicly available databases, resulting in an area under the ROC curve of 0.91 for classification of out-of-sampling data. A drug-target network was created by combining 3,081 unique ligands and the expected ten best drug targets. This network was used to predict new DTIs and to calculate the probability of the positive class, allowing the scoring of the predicted instances. Molecular docking experiments were performed on the best scoring DTI pairs and the results were compared with those of the same ligands with their original targets. The results obtained suggest that the proposed pipeline can be used in the identification of new leads for drug repositioning. The proposed classification model is available at http://bioinformatics.ua.pt/software/dtipred/. PMID:27893735

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

    PubMed Central

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

    2015-01-01

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

  20. 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.

  1. Minimization of operator-balance interactive warmup by use of an alter ego heat source

    NASA Astrophysics Data System (ADS)

    Braudaway, D. W.

    Operator-equipment interaction is a well-known but frustrating part of many high precision measurements. Deterioration in performance of a high-precision balance required testing to identify the cause of the problem and to establish effectiveness of the solution. An unexpected result of the tests was a clear characterization of a significant operator-balance thermal interaction and verification of the empirically determined warmup requirement. The repeatability of the interactive effect inspired development of a replacement for the operator using an alter ego heat source.

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

    PubMed Central

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

    2017-01-01

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

  3. Monotonic single-index models to assess drug interactions.

    PubMed

    Wan, Yubing; Datta, Susmita; Lee, J Jack; Kong, Maiying

    2017-02-20

    Although single-index models have been extensively studied, the monotonicity of the link function f in the single-index model is rarely studied. In many situations, it is desirable that f is monotonic, which results in a monotonic single-index model that can be very useful in economics and biometrics. In this article, we propose a monotonic single-index model in which the link function is constructed using penalized I-splines along with constraints on coefficients to achieve monotonicity of the link function f. An algorithm to estimate the single-index parameters and the link function is developed, and the sandwich estimate of the variance of the index parameters is provided. We propose to apply this monotonic single-index model to estimate the dose-response surface and assess drug interactions while considering the variability of the observed data. An extensive simulation study was carried out to evaluate the performance of the proposed monotonic single-index model. A case study is provided to illustrate the application of the proposed model to estimate the dose-response surface and assess drug interactions. Both the simulation and case study show that the proposed monotonic single-index model works very well. Copyright © 2016 John Wiley & Sons, Ltd.

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

    PubMed

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

    2013-11-01

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

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

    PubMed

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

    2016-09-14

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

  6. Discovering drug–drug interactions: a text-mining and reasoning approach based on properties of drug metabolism

    PubMed Central

    Tari, Luis; Anwar, Saadat; Liang, Shanshan; Cai, James; Baral, Chitta

    2010-01-01

    Motivation: Identifying drug–drug interactions (DDIs) is a critical process in drug administration and drug development. Clinical support tools often provide comprehensive lists of DDIs, but they usually lack the supporting scientific evidences and different tools can return inconsistent results. In this article, we propose a novel approach that integrates text mining and automated reasoning to derive DDIs. Through the extraction of various facts of drug metabolism, not only the DDIs that are explicitly mentioned in text can be extracted but also the potential interactions that can be inferred by reasoning. Results: Our approach was able to find several potential DDIs that are not present in DrugBank. We manually evaluated these interactions based on their supporting evidences, and our analysis revealed that 81.3% of these interactions are determined to be correct. This suggests that our approach can uncover potential DDIs with scientific evidences explaining the mechanism of the interactions. Contact: luis.tari@roche.com PMID:20823320

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

    PubMed Central

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

    2015-01-01

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

  8. Interaction of zanamivir with DNA and RNA: Models for drug DNA and drug RNA bindings

    NASA Astrophysics Data System (ADS)

    Nafisi, Shohreh; Kahangi, Fatemeh Ghoreyshi; Azizi, Ebrahim; Zebarjad, Nader; Tajmir-Riahi, Heidar-Ali

    2007-03-01

    Zanamivir (ZAN) is the first of a new generation of influenza virus-specific drugs known as neuraminidase inhibitors, which acts by interfering with life cycles of influenza viruses A and B. It prevents the virus spreading infection to other cells by blocking the neuraminidase enzyme present on the surface of the virus. The aim of this study was to examine the stability and structural features of calf thymus DNA and yeast RNA complexes with zanamivir in aqueous solution, using constant DNA or RNA concentration (12.5 mM) and various zanamivir/polynucleotide ( P) ratios of 1/20, 1/10, 1/4, and 1/2. FTIR and UV-visible spectroscopy are used to determine the drug external binding modes, the binding constant and the stability of zanamivir-DNA and RNA complexes in aqueous solution. Structural analysis showed major interaction of zanamivir with G-C (major groove) and A-T (minor groove) base pairs and minor perturbations of the backbone PO 2 group with overall binding constants of Kzanamivir-DNA = 1.30 × 10 4 M -1 and Kzanamivir-RNA = 1.38 × 10 4 M -1. The drug interaction induces a partial B to A-DNA transition, while RNA remains in A-conformation.

  9. The interaction of a binary/ternary interactive mixture of hydrophobic-hydrophilic materials on the drug distribution and drug release performance in the tablet formulation

    NASA Astrophysics Data System (ADS)

    Ainurofiq, A.; Choiri, S.

    2017-02-01

    The aim of this research was to optimize and determine an interaction of a binary/ternary mixture of hydrophobic-hydrophilic materials (H-HM) on the drug distribution, tablet characteristics, and drug release performance. The interactive mixture (IM) between carrier and H-HM was conducted using a carrier, Pruv and Cab-O-Sil as hydrophilic materials, magnesium stearate as a hydrophobic material, and a micronized nifedipine as a drug model. These interactions between binary and ternary mixtures of H-HM were assessed by a simplex centroid design (SCD) approach. The homogeneity of IM between drug and carrier was achieved at more time of mixing time. Unique effects and interactions of H-HM were observed on the drug distribution and drug release. Furthermore, the SCD had successfully determined the optimum design space of IM in the ternary mixture of H-HM.

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

    PubMed

    Zhang, Tao

    2015-09-18

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

  11. "Triple-punch" strategy for triple negative breast cancer therapy with minimized drug dosage and improved antitumor efficacy.

    PubMed

    Su, Shishuai; Tian, Yanhua; Li, Yiye; Ding, Yanping; Ji, Tianjiao; Wu, Meiyu; Wu, Yan; Nie, Guangjun

    2015-02-24

    Effective therapeutics against triple negative breast cancer (TNBC), which has no standard-of-care therapy, needs to be developed urgently. Here we demonstrated a strategy of integrating indocyanine green (ICG), paclitaxel (PTX), and survivin siRNA into one thermosensitive poly(2-(2-methoxyethoxy)ethyl methacrylate-co-oligo(ethylene glycol) methacrylate)-co-2-(dimethylamino)ethyl methacrylate-b-poly(D,L-lactide-co-glycolide) (P (MEO2MA-co-OEGMA-co-DMAEMA)-b-PLGA) nanoparticle (NP-IPS) for triple-punch strategy against TNBC. The NP-IPS significantly enhanced the stability of ICG. Controlled release of the PTX in tumor regions was triggered by the hyperthermia produced by laser irradiated ICG. The NP-IPS exhibited remarkable antitumor efficacy (almost complete ablation of the tumor xenografts) due to the combinational effects of chemotherapy, photothermal therapy, and gene therapy with low drug dose (ICG, 0.32 μmol/kg; PTX, 0.54 μmol/kg; siRNA, 1.5 mg/kg) and minimal side effects. Taken together, our current study demonstrates a nanoplatform for triple-therapy, which reveals a promising strategy for TNBC treatment.

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

    PubMed Central

    Bokharaeian, Behrouz; Diaz, Alberto; Chitsaz, Hamidreza

    2016-01-01

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

  13. 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.

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

    PubMed Central

    Rodrigues, Maria Cristina Soares; de Oliveira, Cesar

    2016-01-01

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

  15. Interaction of proton pump inhibitors with cytochromes P450: consequences for drug interactions.

    PubMed Central

    Meyer, U. A.

    1996-01-01

    Omeprazole, lansoprazole and pantoprazole are metabolized by several human cytochromes P450, most prominently by CYP2C19 and CYP3A4. Only pantoprazole is also metabolized by a sulfotransferase. Differences in the quantitative contribution of these enzymes and in the relative affinities of the substrates explain some of the observed interactions with carbamazepin, diazepam, phenytoin and theophylline and of the impact of the CYP2C19 (mephenytoin) genetic polymorphism. Of these drugs, pantoprazole has the lowest potential for interactions, both in vitro and in human volunteer studies. PMID:9165689

  16. Structural biology and drug discovery for protein-protein interactions.

    PubMed

    Jubb, Harry; Higueruelo, Alicia P; Winter, Anja; Blundell, Tom L

    2012-05-01

    Although targeting protein-protein interfaces of regulatory multiprotein complexes has become a significant focus in drug discovery, it continues to pose major challenges. Most interfaces would be classed as 'undruggable' by conventional analyses, as they tend to be large, flat and featureless. Over the past decade, encouragement has come from the discovery of hotspots that contribute much of the free energy of interaction, and this has led to the development of tethering methods that target small molecules to these sites, often inducing adaptive changes. Equally important has been the recognition that many protein-protein interactions involve a continuous epitope of one partner and a well-defined groove or series of specific small pockets. These observations have stimulated the development of stapled α-helical peptides and other proteomimetic approaches. They have also led to the realisation that fragments might gain low-affinity 'footholds' on some protein-protein interfaces, and that these fragments might be elaborated to useful modulators of the interactions.

  17. Management of drug and food interactions with azole antifungal agents in transplant recipients.

    PubMed

    Dodds-Ashley, Elizabeth

    2010-08-01

    Azole antifungal agents are frequently used in hematopoietic stem cell and solid organ transplant recipients for prevention or treatment of invasive fungal infections. However, because of metabolism by or substrate activity for various isoenzymes of the cytochrome P450 system and/or P-glycoprotein, azole antifungals have the potential to interact with many of the drugs commonly used in these patient populations. Thus, to identify drug interactions that may result between azole antifungals and other drugs, we conducted a literature search of the MEDLINE database (1966-December 2009) for English-language articles on drug interaction studies involving the azole antifungal agents fluconazole, itraconazole, voriconazole, and posaconazole. Another literature search between each of the azoles and the immunosuppressants cyclosporine, tacrolimus, and sirolimus, as well as the corticosteroids methylprednisolone, dexamethasone, prednisolone, and prednisone, was also conducted. Concomitant administration of azoles and immunosuppressive agents may cause clinically significant drug interactions resulting in extreme immunosuppression or toxicity. The magnitude and duration of an interaction between azoles and immunosuppressants are not class effects of the azoles, but differ between drug combinations and are subject to interpatient variability. Drug interactions in the transplant recipient receiving azole therapy may also occur with antibiotics, chemotherapeutic agents, and acid-suppressive therapies, among other drugs. Initiation of an azole antifungal in transplant recipients nearly ensures a drug-drug interaction, but often these drugs are required. Management of these interactions first involves knowledge of the potential drug interaction, appropriate dosage adjustments when necessary, and therapeutic or clinical monitoring at an appropriate point in therapy to assess the drug-drug interaction (e.g., immunosuppressive drug concentrations, signs and symptoms of toxicity

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

    PubMed Central

    Zhang, Nan; Liu, Yong; Jeong, Hyunyoung

    2015-01-01

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

  19. RFDT: A Rotation Forest-based Predictor for Predicting Drug-Target Interactions using Drug Structure and Protein Sequence Information.

    PubMed

    Wang, Lei; You, Zhu-Hong; Chen, Xing; Yan, Xin; Liu, Gang; Zhang, Wei

    2016-11-14

    Identification of interaction between drugs and target proteins plays an important role in discovering new drug candidates. However, through the experimental method to identify the drug-target interactions remain to be extremely time-consuming, expensive and challenging even nowadays. Therefore, it is urgent to develop new computational methods to predict potential drug-target interactions (DTI). In this article, a novel computational model is developed for predicting potential drug-target interactions under the theory that each drug-target interaction pair can be represented by the structural properties from drugs and evolutionary information derived from proteins. Specifically, the protein sequences are encoded as Position-Specific Scoring Matrix (PSSM) descriptor which contains information of biological evolutionary and the drug molecules are encoded as fingerprint feature vector which represents the existence of certain functional groups or fragments. Four benchmark datasets involving enzymes, ion channels, GPCRs and nuclear receptors, are independently used for establishing predictive models with Rotation Forest (RF) model. The proposed method achieved the prediction accuracy of 91.3%, 89.1%, 84.1% and 71.1% for four datasets respectively. In order to make our method more persuasive, we compared our classifier with the state-of-the-art Support Vector Machine (SVM) classifier. We also compared the proposed method with other excellent methods. Experimental results demonstrate that the proposed method is effective in the prediction of DTI, and can provide assistance for new drug research and development.

  20. The Two Faces of Social Interaction Reward in Animal Models of Drug Dependence.

    PubMed

    El Rawas, Rana; Saria, Alois

    2016-03-01

    Drug dependence is a serious health and social problem. Social factors can modify vulnerability to developing drug dependence, acting as risk factors or protective factors. Whereas stress and peer environment that encourage substance use may increase drug taking, strong attachments between family members and peer environment that do not experience drug use may protect against drug taking and, ultimately, drug dependence. The rewarding effects of drug abuse and social interaction can be evaluated using animal models. In this review we focus on evaluating social interaction reward in the conditioned place preference paradigm. We give an overview of how social interaction, if made available within the drug context, may facilitate, promote and interact with the drug's effects. However, social interaction, if offered alternatively outside the drug context, may have pronounced protective effects against drug abuse and relapse. We also address the importance of the weight difference parameter between the social partners in determining the positive or "agonistic" versus the hostile or "antagonistic" social interaction. We conclude that understanding social interaction reward and its subsequent effects on drug reward is sorely needed for therapeutic interventions against drug dependence.

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

    PubMed

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

    2014-01-01

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

  2. Drug interactions and hepatitis produced by some macrolide antibiotics.

    PubMed

    Pessayre, D; Larrey, D; Funck-Brentano, C; Benhamou, J P

    1985-07-01

    Drug interactions involving macrolides have been mainly reported in subjects receiving troleandomycin and in a few receiving erythromycin derivatives. In rats and in humans, troleandomycin, erythromycin and erythromycin derivatives induce microsomal enzymes; the induced isozymes of cytochrome P-450 have a high activity for these macrolides but a poor activity with several other substrates. These isozymes actively demethylate and oxidize these macrolides into nitrosoalkanes which form stable, inactive complexes with the iron of cytochrome P-450. Eventually, the oxidative metabolism of other drugs may be decreased. These effects are marked after administration of troleandomycin, moderate after administration of erythromycin derivatives and absent (or negligible) after administration of spiramycin, josamycin or midecamycin. A second adverse effect of the administration of troleandomycin or erythromycin derivatives is the possible occurrence of hepatitis. Mild hepatic dysfunction is fairly frequent and may be toxic in type. In contrast, jaundice is common, is frequently associated with hypersensitivity, and promptly recurs when the drug is readministered. Troleandomycin and erythromycin derivatives, which form nitrosoalkanes, produce hepatitis, whereas josamycin, midecamycin and spiramycin, which do not form cytochrome P-450-nitrosoalkane complexes, rarely, if ever, produce hepatitis. Nitrosoalkanes are unstable intermediates which react with glutathione but also with cysteine and might covalently bind to the SH-groups of proteins. The following mechanism might be proposed as a hypothetical attempt to link up these various observations. The macrolide (or its reactive metabolite) may have discrete toxicity; in several subjects, this may produce minor liver lesions and a mildly raised aminotransferase activity. Necrosis of a few hepatocytes may release into the circulation plasma membrane proteins altered by the covalent binding of metabolites. Such modified liver

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

    PubMed

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

    2013-02-01

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

  4. Hemodynamic changes by drug interaction of adrenaline with chlorpromazine.

    PubMed

    Higuchi, Hitoshi; Yabuki, Akiko; Ishii-Maruhama, Minako; Tomoyasu, Yumiko; Maeda, Shigeru; Miyawaki, Takuya

    2014-01-01

    Adrenaline (epinephrine) is included in dental local anesthesia for the purpose of vasoconstriction. In Japan, adrenaline is contraindicated for use in patients receiving antipsychotic therapy, because the combination of adrenaline and an antipsychotic is considered to cause severe hypotension; however, there is insufficient evidence supporting this claim. The purpose of the present study was to clarify the changes in hemodynamics caused by drug interaction between adrenaline and an antipsychotic and to evaluate the safety of the combined use of adrenaline and an antipsychotic in an animal study. Male Sprague-Dawley rats were anesthetized with sodium pentobarbital. A catheter was inserted into the femoral artery to measure blood pressure and pulse rate. Rats were pretreated by intraperitoneal injection of chlorpromazine or chlorpromazine and propranolol, and after 20 minutes, saline or 1 of 3 different doses of adrenaline was administered by intraperitoneal injection. Changes in the ratio of mean arterial blood pressure and pulse rate were measured after the injection of adrenaline. Significant hypotension and tachycardia were observed after the injection of adrenaline in the chlorpromazine-pretreated rats. These effects were in a dose-dependent manner, and 100 μg/kg adrenaline induced significant hemodynamic changes. Furthermore, in the chlorpromazine and propranolol-pretreated rats, modest hypertension was induced by adrenaline, but hypotension and tachycardia were not significantly shown. Hypotension was caused by a drug interaction between adrenaline and chlorpromazine through the activation of the β-adrenergic receptor and showed a dose-dependent effect. Low-dose adrenaline similar to what might be used in human dental treatment did not result in a significant homodynamic change.

  5. Minimizing density functional failures for non-covalent interactions beyond van der Waals complexes.

    PubMed

    Corminboeuf, Clemence

    2014-11-18

    CONSPECTUS: Kohn-Sham density functional theory offers a powerful and robust formalism for investigating the electronic structure of many-body systems while providing a practical balance of accuracy and computational cost unmatched by other methods. Despite this success, the commonly used semilocal approximations have difficulties in properly describing attractive dispersion interactions that decay with R(-6) at large intermolecular distances. Even in the short to medium range, most semilocal density functionals fail to give an accurate description of weak interactions. The omnipresence of dispersion interactions, which are neglected in the most popular electronic structure framework, has stimulated intense developments during the past decade. In this Account, we summarize our effort to develop and implement dispersion corrections that dramatically reduce the failures of both inter- and intramolecular interaction energies. The proposed schemes range from improved variants of empirical atom pairwise dispersion correction (e.g., dD10) to robust formulations dependent upon the electron density. Emphasis has been placed on introducing more physics into a modified Tang and Toennies damping function and deriving accurate dispersion coefficients. Our most sophisticated and established density-dependent correction, dDsC, is based on a simple generalized gradient approximation (GGA)-like reformulation of the exchange hole dipole moment introduced by Becke and Johnson. Akin to its empirical precursor, dDsC dramatically improves the interaction energy of a variety of standard density functionals simultaneously for typical intermolecular complexes and shorter-range interactions occurring within molecules. The broad applicability and robustness of the dDsC scheme is demonstrated on various representative reaction energies, geometries, and molecular dynamic simulations. The suitability of the a posteriori correction is also established through comparisons with the more

  6. Minimally-Invasive Gene Transfection by Chemical and Physical Interaction of Atmospheric Pressure Plasma Flow

    NASA Astrophysics Data System (ADS)

    Kaneko, Toshiro

    2014-10-01

    Non-equilibrium atmospheric pressure plasma irradiated to the living-cell is investigated for medical applications such as gene transfection, which is expected to play an important role in molecular biology, gene therapy, and creation of induced pluripotent stem (iPS) cells. However, the conventional gene transfection using the plasma has some problems that the cell viability is low and the genes cannot be transferred into some specific lipid cells, which is attributed to the unknown mechanism of the gene transfection using the plasma. Therefore, the time-controlled atmospheric pressure plasma flow is generated and irradiated to the living-cell suspended solution for clarifying the transfection mechanism toward developing highly-efficient and minimally- invasive gene transfection system. In this experiment, fluorescent dye YOYO-1 is used as the simulated gene and LIVE/DEAD Stain is simultaneously used for cell viability assay. By the fluorescence image, the transfection efficiency is calculated as the ratio of the number of transferred and surviving cells to total cell count. It is clarified that the transfection efficiency is significantly increased by the short-time (<4 sec) and short-distance (<40 mm) plasma irradiation, and the high transfection efficiency of 53% is realized together with the high cell viability (>90%). This result indicates that the physical effects such as the electric field caused by the charged particles arriving at the surface of the cell membrane, and chemical effects associated with plasma-activated products in solution act synergistically to enhance the cell-membrane transport with low-damage. This work was supported by JSPS KAKENHI Grant Number 24108004.

  7. Predicting drug-target interaction for new drugs using enhanced similarity measures and super-target clustering.

    PubMed

    Shi, Jian-Yu; Yiu, Siu-Ming; Li, Yiming; Leung, Henry C M; Chin, Francis Y L

    2015-07-15

    Predicting drug-target interaction using computational approaches is an important step in drug discovery and repositioning. To predict whether there will be an interaction between a drug and a target, most existing methods identify similar drugs and targets in the database. The prediction is then made based on the known interactions of these drugs and targets. This idea is promising. However, there are two shortcomings that have not yet been addressed appropriately. Firstly, most of the methods only use 2D chemical structures and protein sequences to measure the similarity of drugs and targets respectively. However, this information may not fully capture the characteristics determining whether a drug will interact with a target. Secondly, there are very few known interactions, i.e. many interactions are "missing" in the database. Existing approaches are biased towards known interactions and have no good solutions to handle possibly missing interactions which affect the accuracy of the prediction. In this paper, we enhance the similarity measures to include non-structural (and non-sequence-based) information and introduce the concept of a "super-target" to handle the problem of possibly missing interactions. Based on evaluations on real data, we show that our similarity measure is better than the existing measures and our approach is able to achieve higher accuracy than the two best existing algorithms, WNN-GIP and KBMF2K. Our approach is available at http://web.hku.hk/∼liym1018/projects/drug/drug.html or http://www.bmlnwpu.org/us/tools/PredictingDTI_S2/METHODS.html.

  8. Minimal predicted distance: a common metric for collision avoidance during pairwise interactions between walkers.

    PubMed

    Olivier, Anne-Hélène; Marin, Antoine; Crétual, Armel; Pettré, Julien

    2012-07-01

    This study investigated collision avoidance between two walkers by focusing on the conditions that lead to avoidance manoeuvres in locomotor trajectories. Following the hypothesis of a reciprocal interaction, we suggested a mutual variable as a continuous function of the two walkers' states, denoted minimum predicted distance (MPD). This function predicts the risk of collision, and its evolution over time captures the motion adaptations performed by the walkers. By groups of two, 30 walkers were assigned locomotion tasks which lead to potential collisions. Results showed that walkers adapted their motions only when required, i.e., when MPD is too low (<1 m). We concluded that walkers are able (i) to accurately estimate their reciprocal distance at the time the crossing will occur, and (ii) to mutually adapt this distance. Furthermore, the study of MPD evolution showed three successive phases in the avoidance interaction: observation where MPD(t) is constant, reaction where MPD(t) increases to acceptable values by adapting locomotion and regulation where MPD(t) reaches a plateau and slightly decreases. This final phase demonstrates that collision avoidance is actually performed with anticipation. Future work would consist in inspecting individual motion adaptations and relating them with the variations of MPD.

  9. 78 FR 48172 - Minimizing Risk for Children's Toy Laser Products; Draft Guidance for Industry and Food and Drug...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-08-07

    ...] [FR Doc No: 2013-19018] DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket... and Food and Drug Administration Staff; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) is announcing the availability of the...

  10. 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

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

    PubMed Central

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

    2015-01-01

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

  12. [Undesirable pharmacokinetic drug-to-drug interactions affecting the effectiveness and safety of anti-infectious pharmacotherapy].

    PubMed

    Dworacka, Marzena; Nowocień, Tamara

    2017-02-20

    The occurence of pharmacokinetic drug-to-drug interactions is the serious clinical problem in the course of pharmacotherapy of infections. Its essential part is the influence of such interactions on the effectiveness and safety of antimicrobial therapy. The aim of study was to present, the most significant on clinical hand, examples of interactions and their mechanisms between antimicrobial agents and other drugs on stages of absorption, distribution, biotransformation and elimination, leading to the decreased antimicrobial activity and ineffective pharmacotherapy or to the increased antimicrobial activity and to the increased risk of adverse effects due to agents used for anti-infectious pharmacotherapy.

  13. Possible drug–drug interaction in dogs and cats resulted from alteration in drug metabolism: A mini review

    PubMed Central

    Sasaki, Kazuaki; Shimoda, Minoru

    2015-01-01

    Pharmacokinetic drug–drug interactions (in particular at metabolism) may result in fatal adverse effects in some cases. This basic information, therefore, is needed for drug therapy even in veterinary medicine, as multidrug therapy is not rare in canines and felines. The aim of this review was focused on possible drug–drug interactions in dogs and cats. The interaction includes enzyme induction by phenobarbital, enzyme inhibition by ketoconazole and fluoroquinolones, and down-regulation of enzymes by dexamethasone. A final conclusion based upon the available literatures and author’s experience is given at the end of the review. PMID:26257936

  14. The Two Faces of Social Interaction Reward in Animal Models of Drug Dependence

    PubMed Central

    Rawas, Rana El

    2016-01-01

    Drug dependence is a serious health and social problem. Social factors can modify vulnerability to developing drug dependence, acting as risk factors or protective factors. Whereas stress and peer environment that encourage substance use may increase drug taking, strong attachments between family members and peer environment that do not experience drug use may protect against drug taking and, ultimately, drug dependence. The rewarding effects of drug abuse and social interaction can be evaluated using animal models. In this review we focus on evaluating social interaction reward in the conditioned place preference paradigm. We give an overview of how social interaction, if made available within the drug context, may facilitate, promote and interact with the drug’s effects. However, social interaction, if offered alternatively outside the drug context, may have pronounced protective effects against drug abuse and relapse. We also address the importance of the weight difference parameter between the social partners in determining the positive or “agonistic” versus the hostile or “antagonistic” social interaction. We conclude that understanding social interaction reward and its subsequent effects on drug reward is sorely needed for therapeutic interventions against drug dependence. PMID:26088685

  15. The new CMSS code for interactions with companies managing relationships to minimize conflicts.

    PubMed

    Kahn, Norman B; Lichter, Allen S

    2011-09-01

    Conflicts of interest in medicine have received significant attention in recent years, through the public and professional media, federal and state governments, and through a 2009 report of the Institute of Medicine on Conflict of Interest in Medical Research, Education and Practice. The Council of Medical Specialty Societies (CMSS) Code for Interactions with Companies was adopted by the CMSS in April 2010. The Code guides specialty societies in the profession of medicine in ethical relationships between societies and the pharmaceutical and medical device industries. The Code serves to protect and promote the independence of specialty societies and their leaders in corporate sponsorships, licensing, advertising, society meetings, exhibits, educational programs, journals, clinical practice guidelines, and research.

  16. Impact of excipient interactions on drug bioavailability from solid dosage forms.

    PubMed

    Panakanti, Ravikiran; Narang, Ajit S

    2012-10-01

    Excipients are generally pharmacologically inert, but can interact with drugs in the dosage form and the physiological factors at the site of absorption to affect the bioavailability of a drug product. A general mechanistic understanding of the basis of these interactions is essential to design robust drug products. This paper focuses on drug-excipient interactions in solid dosage forms that impact drug bioavailability, the drug substance and drug product properties affected by excipients, and the impact of excipients on physiologic processes. The extent to which drug bioavailability is affected by these interactions would vary on a case-by-case basis depending upon factors such as the potency and dose of the drug, therapeutic window, site of absorption, rate limiting factor in drug absorption (e.g., permeability or solubility limited), or whether drug metabolism, efflux, complexation, or degradation at the site of absorption play a role in determining its bioavailability. Nonetheless, a mechanistic understanding of drug-excipient interactions and their impact on drug release and absorption can help develop formulations that exhibit optimum drug bioavailability.

  17. Maraviroc: in vitro assessment of drug–drug interaction potential

    PubMed Central

    Hyland, Ruth; Dickins, Maurice; Collins, Claire; Jones, Hannah; Jones, Barry

    2008-01-01

    AIMS To characterize the cytochrome P450 enzyme(s) responsible for the N-dealkylation of maraviroc in vitro, and predict the extent of clinical drug–drug interactions (DDIs). METHODS Human liver and recombinant CYP microsomes were used to identify the CYP enzyme responsible for maraviroc N-dealkylation. Studies comprised enzyme kinetics and evaluation of the effects of specific CYP inhibitors. In vitro data were then used as inputs for simulation of DDIs with ketoconazole, ritonavir, saquinavir and atazanvir, using the Simcyp™ population-based absorption, distribution, metabolism and elimination (ADME) simulator. Study designs for simulations mirrored those actually used in the clinic. RESULTS Maraviroc was metabolized to its N-dealkylated product via a single CYP enzyme characterized by a Km of 21 µM and Vmax of 0.45 pmol pmol−1 min−1 in human liver microsomes and was inhibited by ketoconazole (CYP3A4 inhibitor). In a panel of recombinant CYP enzymes, CYP3A4 was identified as the major CYP responsible for maraviroc metabolism. Using recombinant CYP3A4, N-dealkylation was characterized by a Km of 13 µM and a Vmax of 3 pmol pmol−1 CYP min−1. Simulations therefore focused on the effect of CYP3A4 inhibitors on maraviroc pharmacokinetics. The simulated median AUC ratios were in good agreement with observed clinical changes (within twofold in all cases), although, in general, there was a trend for overprediction in the magnitude of the DDI. CONCLUSION Maraviroc is a substrate for CYP3A4, and exposure will therefore be modulated by CYP3A4 inhibitors. Simcyp™ has successfully simulated the extent of clinical interactions with CYP3A4 inhibitors, further validating this software as a good predictor of CYP-based DDIs. WHAT IS ALREADY KNOWN ABOUT THE SUBJECTMaraviroc is known to undergo oxidative metabolism in vivo and is a substrate for cytochrome P450 (CYP).Simcyp™ has recently become more widely used for the prediction of CYP-mediated drug–drug

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

    PubMed Central

    2011-01-01

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

  19. 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

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

    PubMed

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

    2017-02-01

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

  1. 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.

  2. Increasing the potency of an alhydrogel-formulated anthrax vaccine by minimizing antigen-adjuvant interactions.

    PubMed

    Watkinson, Allan; Soliakov, Andrei; Ganesan, Ashok; Hirst, Karie; Lebutt, Chris; Fleetwood, Kelly; Fusco, Peter C; Fuerst, Thomas R; Lakey, Jeremy H

    2013-11-01

    Aluminum salts are the most widely used vaccine adjuvants, and phosphate is known to modulate antigen-adjuvant interactions. Here we report an unexpected role for phosphate buffer in an anthrax vaccine (SparVax) containing recombinant protective antigen (rPA) and aluminum oxyhydroxide (AlOH) adjuvant (Alhydrogel). Phosphate ions bind to AlOH to produce an aluminum phosphate surface with a reduced rPA adsorption coefficient and binding capacity. However, these effects continued to increase as the free phosphate concentration increased, and the binding of rPA changed from endothermic to exothermic. Crucially, phosphate restored the thermostability of bound rPA so that it resembled the soluble form, even though it remained tightly bound to the surface. Batches of vaccine with either 0.25 mM (subsaturated) or 4 mM (saturated) phosphate were tested in a disease model at batch release, which showed that the latter was significantly more potent. Both formulations retained their potency for 3 years. The strongest aluminum adjuvant effects are thus likely to be via weakly attached or easily released native-state antigen proteins.

  3. Using minimal human-computer interfaces for studying the interactive development of social awareness

    PubMed Central

    Froese, Tom; Iizuka, Hiroyuki; Ikegami, Takashi

    2014-01-01

    According to the enactive approach to cognitive science, perception is essentially a skillful engagement with the world. Learning how to engage via a human-computer interface (HCI) can therefore be taken as an instance of developing a new mode of experiencing. Similarly, social perception is theorized to be primarily constituted by skillful engagement between people, which implies that it is possible to investigate the origins and development of social awareness using multi-user HCIs. We analyzed the trial-by-trial objective and subjective changes in sociality that took place during a perceptual crossing experiment in which embodied interaction between pairs of adults was mediated over a minimalist haptic HCI. Since that study required participants to implicitly relearn how to mutually engage so as to perceive each other's presence, we hypothesized that there would be indications that the initial developmental stages of social awareness were recapitulated. Preliminary results reveal that, despite the lack of explicit feedback about task performance, there was a trend for the clarity of social awareness to increase over time. We discuss the methodological challenges involved in evaluating whether this trend was characterized by distinct developmental stages of objective behavior and subjective experience. PMID:25309490

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

    PubMed Central

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

    2016-01-01

    Drug–drug interactions (DDIs) and associated toxicity from cardiovascular drugs represents a major problem for effective co-administration of cardiovascular therapeutics. A significant amount of drug toxicity from DDIs occurs because of drug interactions and multiple cardiovascular drug binding to the efflux transporter P-glycoprotein (Pgp), which is particularly problematic for cardiovascular drugs because of their relatively low therapeutic indexes. The calcium channel antagonist, verapamil and the cardiac glycoside, digoxin, exhibit DDIs with Pgp through non-competitive inhibition of digoxin transport, which leads to elevated digoxin plasma concentrations and digoxin toxicity. In the present study, verapamil-induced ATPase activation kinetics were biphasic implying at least two verapamil-binding sites on Pgp, whereas monophasic digoxin activation of Pgp-coupled ATPase kinetics suggested a single digoxin-binding site. Using intrinsic protein fluorescence and the saturation transfer double difference (STDD) NMR techniques to probe drug–Pgp interactions, verapamil was found to have little effect on digoxin–Pgp interactions at low concentrations of verapamil, which is consistent with simultaneous binding of the drugs and non-competitive inhibition. Higher concentrations of verapamil caused significant disruption of digoxin–Pgp interactions that suggested overlapping and competing drug-binding sites. These interactions correlated to drug-induced conformational changes deduced from acrylamide quenching of Pgp tryptophan fluorescence. Also, Pgp-coupled ATPase activity kinetics measured with a range of verapamil and digoxin concentrations fit well to a DDI model encompassing non-competitive and competitive inhibition of digoxin by verapamil. The results and previous transport studies were combined into a comprehensive model of verapamil–digoxin DDIs encompassing drug binding, ATP hydrolysis, transport and conformational changes. PMID:26823559

  5. Neighborhood Regularized Logistic Matrix Factorization for Drug-Target Interaction Prediction.

    PubMed

    Liu, Yong; Wu, Min; Miao, Chunyan; Zhao, Peilin; Li, Xiao-Li

    2016-02-01

    In pharmaceutical sciences, a crucial step of the drug discovery process is the identification of drug-target interactions. However, only a small portion of the drug-target interactions have been experimentally validated, as the experimental validation is laborious and costly. To improve the drug discovery efficiency, there is a great need for the development of accurate computational approaches that can predict potential drug-target interactions to direct the experimental verification. In this paper, we propose a novel drug-target interaction prediction algorithm, namely neighborhood regularized logistic matrix factorization (NRLMF). Specifically, the proposed NRLMF method focuses on modeling the probability that a drug would interact with a target by logistic matrix factorization, where the properties of drugs and targets are represented by drug-specific and target-specific latent vectors, respectively. Moreover, NRLMF assigns higher importance levels to positive observations (i.e., the observed interacting drug-target pairs) than negative observations (i.e., the unknown pairs). Because the positive observations are already experimentally verified, they are usually more trustworthy. Furthermore, the local structure of the drug-target interaction data has also been exploited via neighborhood regularization to achieve better prediction accuracy. We conducted extensive experiments over four benchmark datasets, and NRLMF demonstrated its effectiveness compared with five state-of-the-art approaches.

  6. Predicting drug pharmacokinetic properties using molecular interaction fields and SIMCA

    NASA Astrophysics Data System (ADS)

    Wolohan, Philippa R. N.; Clark, Robert D.

    2003-01-01

    We have developed a method that combines molecular interaction fields with soft independent modeling of class analogy (SIMCA) Wold:1977 to predict pharmacokinetic drug properties. Several additional considerations to those made in traditional QSAR are required in order to develop a successful QSPR strategy that is capable of accommodating the many complex factors that contribute to key pharmacokinetic properties such as ADME (absorption, distribution, metabolism, and excretion) and toxicology. An accurate prediction of oral bioavailability, for example, requires that absorption and first-pass hepatic elimination both be taken into consideration. To accomplish this, general properties of molecules must be related to their solubility and ability to penetrate biological membranes, and specific features must be related to their particular metabolic and toxicological profiles. Here we describe a method, which is applicable to structurally diverse data sets while utilizing as much detailed structural information as possible. We address the issue of the molecular alignment of a structurally diverse set of compounds using idiotropic field orientation (IFO), a generalization of inertial field orientation Clark:1998. We have developed a second flavor of this method, which directly incorporates electrostatics into the molecular alignment. Both variations of IFO produce a characteristic orientation for each structure and the corresponding molecular fields can then be analyzed using SIMCA. Models are presented for human intestinal absorption, blood-brain barrier penetration and bioavailability to demonstrate ways in which this tool can be used early in the drug development process to identify leads likely to exhibit poor pharmacokinetic behavior in pre-clinical studies, and we have explored the influence of conformation and molecular field type on the statistical properties of the models obtained.

  7. Definition of minimal domains of interaction within the recombination-activating genes 1 and 2 recombinase complex.

    PubMed

    Aidinis, V; Dias, D C; Gomez, C A; Bhattacharyya, D; Spanopoulou, E; Santagata, S

    2000-06-01

    During V(D)J recombination, recognition and cleavage of the recombination signal sequences (RSSs) requires the coordinated action of the recombination-activating genes 1 and 2 (RAG1/RAG2) recombinase complex. In this report, we use deletion mapping and site-directed mutagenesis to determine the minimal domains critical for interaction between RAG1 and RAG2. We define the active core of RAG2 required for RSS cleavage as aa 1-371 and demonstrate that the C-terminal 57 aa of this core provide a dominant surface for RAG1 interaction. This region corresponds to the last of six predicted kelch repeat motifs that have been proposed by sequence analysis to fold RAG2 into a six-bladed beta-propeller structure. Residue W317 within this sixth repeat is shown to be critical for mediating contact with RAG1 and concurrently for stabilizing binding and directing cleavage of the RSS. We also show that zinc finger B (aa 727-750) of RAG1 provides a dominant interaction domain for recruiting RAG2. In all, the data support a model of RAG2 as a multimodular protein that utilizes one of its six faces for establishing productive contacts with RAG1.

  8. Heterogeneous side chain conformation highlights a network of interactions implicated in hysteresis of the knotted protein, minimal tied trefoil

    NASA Astrophysics Data System (ADS)

    Burban, David J.; Haglund, Ellinor; Capraro, Dominique T.; Jennings, Patricia A.

    2015-09-01

    Hysteresis is a signature for a bistability in the native landscape of a protein with significant transition state barriers for the interconversion of stable species. Large global stability, as in GFP, contributes to the observation of this rare hysteretic phenomenon in folding. The signature for such behavior is non-coincidence in the unfolding and refolding transitions, despite waiting significantly longer than the time necessary for complete denaturation. Our work indicates that hysteresis in the knotted protein, the minimal tied trefoil from Thermotoga maritma (MTTTm), is mediated by a network of side chain interactions within a tightly packed core. These initially identified interactions include proline 62 from a tight β-like turn, phenylalanine 65 at the beginning of the knotting loop, and histidine 114 that initiates the threading element. It is this tightly packed region and the knotting element that we propose is disrupted with prolonged incubation in the denatured state, and is involved in the observed hysteresis. Interestingly, the disruption is not linked to backbone interactions, but rather to the packing of side chains in this critical region.

  9. Edoxaban drug–drug interactions with ketoconazole, erythromycin, and cyclosporine

    PubMed Central

    Parasrampuria, Dolly A.; Mendell, Jeanne; Shi, Minggao; Matsushima, Nobuko; Zahir, Hamim

    2016-01-01

    Aims Edoxaban, a novel factor Xa inhibitor, is a substrate of cytochrome P450 3 A4 (CYP3A4) and the efflux transporter P‐glycoprotein (P‐gp). Three edoxaban drug–drug interaction studies examined the effects of P‐gp inhibitors with varying degrees of CYP3A4 inhibition. Methods In each study, healthy subjects received a single oral dose of 60 mg edoxaban with or without an oral dual P‐gp/CYP3A4 inhibitor as follows: ketoconazole 400 mg once daily for 7 days, edoxaban on day 4; erythromycin 500 mg four times daily for 8 days, edoxaban on day 7; or single dose of cyclosporine 500 mg with edoxaban. Serial plasma samples were obtained for pharmacokinetics and pharmacodynamics. Safety was assessed throughout the study. Results Coadministration of ketoconazole, erythromycin, or cyclosporine increased edoxaban total exposure by 87%, 85%, and 73%, respectively, and the peak concentration by 89%, 68%, and 74%, respectively, compared with edoxaban alone. The half‐life did not change appreciably. Exposure of M4, the major active edoxaban metabolite, was consistent when edoxaban was administered alone or with ketoconazole and erythromycin. With cyclosporine, M4 total exposure increased by 6.9‐fold and peak exposure by 8.7‐fold, suggesting an additional interaction. Pharmacodynamic effects were reflective of increased edoxaban exposure. No clinically significant adverse events were observed. Conclusions Administration of dual inhibitors of P‐gp and CYP3A4 increased edoxaban exposure by less than two‐fold. This effect appears to be primarily due to inhibition of P‐gp. The impact of CYP3A4 inhibition appears to be less pronounced, and its contribution to total clearance appears limited in healthy subjects. PMID:27530188

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

    PubMed Central

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

    2013-01-01

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

  11. 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.

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

    Armstrong, Scott C; Cozza, Kelly L

    2003-01-01

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

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

    PubMed

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

    2009-01-01

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

  15. Characterization of basic drug-human serum protein interactions by capillary electrophoresis.

    PubMed

    Martínez-Gómez, María A; Sagrado, Salvador; Villanueva-Camañas, Rosa M; Medina-Hernández, Maria J

    2006-09-01

    Drug-protein interactions are determining factors in the therapeutic, pharmacodynamic and toxicological drug properties. The affinity of drugs towards plasmatic proteins is apparently well established in bibliography. Albumin (HSA) especially binds neutral and negatively charged compounds; alpha(1)-acid glycoprotein (AGP) binds many cationic drugs, lipoproteins bind to nonionic and lipophilic drugs and some anionic drugs while globulins interact inappreciably with the majority of drugs. In this paper, the characterization of the interaction between cationic drugs, beta-blockers and phenotiazines towards HSA, AGP, and both HSA + AGP mixtures of proteins under physiological conditions by CE-frontal analysis is presented. Furthermore, the binding of these drugs to all plasmatic proteins is evaluated by using ultrafiltration and CE. The results indicate that the hydrophobic character of compounds seems to be the key factor on the interaction between cationic drugs towards proteins. In fact, hydrophobic basic drugs bind in great extension to HSA, while hydrophilic basic drugs present low interactions with proteins and bind especially to AGP.

  16. [Drug-food interactions in internal medicine: What physicians should know?].

    PubMed

    Mouly, S; Morgand, M; Lopes, A; Lloret-Linares, C; Bergmann, J-F

    2015-08-01

    Orally administered medications may interact with various fruits, vegetables, herbal medicines, functional foods or dietary supplements. Drug-food interactions, which are mostly unknown from prescribers, including internists, may be responsible for changes in drug plasma concentrations, which may decrease efficacy or led to sometimes life-threatening toxicity. Aging, concomitant medications, transplant recipients, patients with cancer, malnutrition, HIV infection and those receiving enteral or parenteral feeding are at increased risk of drug-food interactions. This review focused on the most clinically relevant drug-food interactions, including those with grapefruit juice, Saint-John's Wort, enteral or parenteral nutrition, their respective consequences in the clinical setting in order to provide thoughtful information for internists in their routine clinical practice. Specific clinical settings are also detailed, such as the Ramadan or multiple medications especially in elderly patients. Drug-food interactions are also presented with respect to the main therapeutic families, including the non-steroidal anti-inflammatory drugs, analgesics, cardiovascular medications, warfarin as well as new oral anticoagulants, anticancer drugs and immunosuppressant medications. Considerable effort has been achieved to a better understanding of food-drug interactions and increase clinicians' ability to anticipate their occurrence and consequences in clinical practice. Describing the frequency of relevant food-drug interactions in internal medicine is paramount in order to optimize patient care and drug dosing on an individual basis as well as to increase patients and doctors information.

  17. The RAS-Effector Interaction as a Drug Target.

    PubMed

    Keeton, Adam B; Salter, E Alan; Piazza, Gary A

    2017-01-15

    About a third of all human cancers harbor mutations in one of the K-, N-, or HRAS genes that encode an abnormal RAS protein locked in a constitutively activated state to drive malignant transformation and tumor growth. Despite more than three decades of intensive research aimed at the discovery of RAS-directed therapeutics, there are no FDA-approved drugs that are broadly effective against RAS-driven cancers. Although RAS proteins are often said to be "undruggable," there is mounting evidence suggesting it may be feasible to develop direct inhibitors of RAS proteins. Here, we review this evidence with a focus on compounds capable of inhibiting the interaction of RAS proteins with their effectors that transduce the signals of RAS and that drive and sustain malignant transformation and tumor growth. These reports of direct-acting RAS inhibitors provide valuable insight for further discovery and development of clinical candidates for RAS-driven cancers involving mutations in RAS genes or otherwise activated RAS proteins. Cancer Res; 77(2); 221-6. ©2017 AACR.

  18. In vivo study of drug interaction with brain benzodiazepine receptor

    SciTech Connect

    Inoue, O.; Shinotoh, H.; Ito, T.; Suzuki, K.; Hashimoto, K.; Yamasaki, T.

    1985-05-01

    The possibility of direct estimation of in vivo Bz receptor occupancy in brain was evaluated using C-11, or H-3-flumazepil (Ro15-1788). In animal experiments, 1 ..mu..Ci of H-3-Ro15-1788 was injected at 0.5 or 20 hr after i.v. injection of various dosage of clonazepam. Then radioactivity in cerebral cortex, cerebellum and blood at 5 min. after injection of the tracer was compared. Competitive inhibition of in vivo binding was clearly observed when clonazepam was pretreated at 0.5 hr before injection of the tracer. On the other hand, brain radioactivity was increased when clonazepam was administered at 20 hr before injection of the tracer. This increase in binding of H-3-Ro15-1788 might be caused by rebound of Bz receptor function by treatment with Bz agonist, and this rebound may have an important role in physiological function. Clinical investigation concerning drug interaction with brain Bz receptor was performed in normal volunteer and patients with neurological disorders. The distribution of C-11-Ro15-1788 in the brain of patients chronically treated with clonazepam were significantly heterogeneous. However, cerebral blood flow estimated with N-13 NH3 of these patients were normal.

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

    PubMed Central

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

    2015-01-01

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

  20. The Identity of the Nucleophile Substitution may Influence Metal Interactions with the Cleavage Site of the Minimal Hammerhead Ribozyme

    PubMed Central

    Osborne, Edith M.; Ward, W. Luke; Ruehle, Max Z.; DeRose, Victoria J.

    2010-01-01

    Potential metal interactions with the cleavage site of a minimal hammerhead ribozyme (mHHRz) were probed using 31P NMR-detected Cd2+ titration studies of HHRz constructs containing a phosphorothioate (PS) modification at the cleavage site. The mHHRz nucleophile position was replaced by either a 2′-F or a 2′-NH2 in order to block cleavage activity during the study. The 2′-F/PS cleavage site mHHRz construct, in which the 2′-F should closely imitate the atom size and electronegativity of a 2′OH, demonstrates low levels of metal ion association (<1 ppm 31P chemical shift changes). This observation indicates that having an atom size and electrostatic properties that are similar to the 2′-OH are not the governing factors in allowing metal interactions with the scissile phosphate of the mHHRz. With a 2′-NH2 substitution, a large upfield change in 31P NMR chemical shift of the phosphorothioate peak (Δ~3 ppm with 6 equivalents added Cd2+) indicates observable Cd2+ interactions with the substituted site. Since a 2′-NH2, but not a 2′-F, can serve as a metal ligand, these data suggest that a metal ion interaction with the HHRz cleavage site may include both the scissile phosphate and the 2′ nucleophile. Control samples in which the 2′-NH2/PS unit is placed either next to the mHHRz cleavage site (at U16.1), in a duplex, or in a amUPSU dinucleotide, show much weaker interactions with Cd2+. Results with these control samples indicate that simply the presence of a 2′-NH2/PS unit does not create a strong metal binding site, reinforcing the possibility that the 2′-NH2-moderated Cd-PS interaction is specific to the mHHRz cleavage site. Upfield chemical shifts of both 31P and H2′ 1H resonances in amUPSU are observed with addition of Cd2+, consistent with the predicted metal coordination to both 2′-NH2 and phosphorothioate ligands. These data suggest that metal ion association with the HHRz cleavage site may include an interaction with the 2

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

    PubMed

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

    2017-02-01

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

  2. Interaction between DNA and Drugs Having Protonable Basic Groups: Characterization through Affinity Constants, Drug Release Kinetics, and Conformational Changes.

    PubMed

    Alarcón, Liliana P; Baena, Yolima; Manzo, Rubén H

    2017-01-04

    This paper reports the in vitro characterization of the interaction between the phosphate groups of DNA and the protonated species of drugs with basic groups through the determination of the affinity constants, the reversibility of the interaction, and the effect on the secondary structure of the macromolecule. Affinity constants of the counterionic condensation DNA-drug were in the order of 10⁶. The negative electrokinetic potential of DNA decreased with the increase of the proportion of loading drugs. The drugs were slowly released from the DNA-drug complexes and had release kinetics consistent with the high degree of counterionic condensation. The circular dichroism profile of DNA was not modified by complexation with atenolol, lidocaine, or timolol, but was significantly altered by the more lipophilic drugs benzydamine and propranolol, revealing modifications in the secondary structure of the DNA. The in vitro characterization of such interactions provides a physicochemical basis that would contribute to identify the effects of this kind of drugs in cellular cultures, as well as side effects observed under their clinical use. Moreover, this methodology could also be projected to the fields of intracellular DNA transfection and the use of DNA as a carrier of active drugs.

  3. Co-drug strategy for promoting skin targeting and minimizing the transdermal diffusion of hydroquinone and tranexamic acid.

    PubMed

    Hsieh, Pei-Wen; Chen, Wei-Yu; Aljuffali, Ibrahim A; Chen, Chun-Che; Fang, Jia-You

    2013-01-01

    Hydroquinone and tranexamic acids (TXA) are skin-lightening agents with a hydrophilic nature and low skin absorption. A high dose is needed for clinical use, resulting in a high incidence of skin irritation. Co-drugs formed by conjugating hydroquinone and TXA were synthesized and their in vitro and in vivo skin absorption characteristics were evaluated. The two synthesized co-drugs were 4-hydroxyphenyl 4-(aminomethyl)cyclohexanecarboxylate (HAC) and 1,4- phenylene bis(aminomethyl)cyclohexanecarboxylate (BAC). The co-drugs were chemically stable in aqueous solution, but rapidly degraded to the respective parent drug in esterases and skin homogenates. Compared to hydroquinone application, 7.2- and 2.4-fold increments in the hydroquinone skin deposition were obtained with the in vitro application of HAC and BAC. HAC and BAC led to 3- and 2-fold enhancements of equivalent TXA deposition compared to TXA administration. The in vivo experiment showed a further enhancement of co-drugs compared to the in vitro setup. The transdermal penetration of co-drugs, especially BAC, was much lower than that of hydroquinone and TXA. This indicated high-level skin targeting by the co-drugs. HAC and BAC revealed strong affinities for the viable epidermis/dermis. Hair follicles are important reservoirs for co-drug delivery. Daily administration of co-drugs to the skin did not generate irritation for up to 7 days. Both co-drugs are superior candidates for treating skin hyperpigmentation.

  4. Interactions of dendrimers with biological drug targets: reality or mystery - a gap in drug delivery and development research.

    PubMed

    Ahmed, Shaimaa; Vepuri, Suresh B; Kalhapure, Rahul S; Govender, Thirumala

    2016-07-21

    Dendrimers have emerged as novel and efficient materials that can be used as therapeutic agents/drugs or as drug delivery carriers to enhance therapeutic outcomes. Molecular dendrimer interactions are central to their applications and realising their potential. The molecular interactions of dendrimers with drugs or other materials in drug delivery systems or drug conjugates have been extensively reported in the literature. However, despite the growing application of dendrimers as biologically active materials, research focusing on the mechanistic analysis of dendrimer interactions with therapeutic biological targets is currently lacking in the literature. This comprehensive review on dendrimers over the last 15 years therefore attempts to identify the reasons behind the apparent lack of dendrimer-receptor research and proposes approaches to address this issue. The structure, hierarchy and applications of dendrimers are briefly highlighted, followed by a review of their various applications, specifically as biologically active materials, with a focus on their interactions at the target site. It concludes with a technical guide to assist researchers on how to employ various molecular modelling and computational approaches for research on dendrimer interactions with biological targets at a molecular level. This review highlights the impact of a mechanistic analysis of dendrimer interactions on a molecular level, serves to guide and optimise their discovery as medicinal agents, and hopes to stimulate multidisciplinary research between scientific, experimental and molecular modelling research teams.

  5. Drug-target interaction prediction: databases, web servers and computational models.

    PubMed

    Chen, Xing; Yan, Chenggang Clarence; Zhang, Xiaotian; Zhang, Xu; Dai, Feng; Yin, Jian; Zhang, Yongdong

    2016-07-01

    Identification of drug-target interactions is an important process in drug discovery. Although high-throughput screening and other biological assays are becoming available, experimental methods for drug-target interaction identification remain to be extremely costly, time-consuming and challenging even nowadays. Therefore, various computational models have been developed to predict potential drug-target associations on a large scale. In this review, databases and web servers involved in drug-target identification and drug discovery are summarized. In addition, we mainly introduced some state-of-the-art computational models for drug-target interactions prediction, including network-based method, machine learning-based method and so on. Specially, for the machine learning-based method, much attention was paid to supervised and semi-supervised models, which have essential difference in the adoption of negative samples. Although significant improvements for drug-target interaction prediction have been obtained by many effective computational models, both network-based and machine learning-based methods have their disadvantages, respectively. Furthermore, we discuss the future directions of the network-based drug discovery and network approach for personalized drug discovery based on personalized medicine, genome sequencing, tumor clone-based network and cancer hallmark-based network. Finally, we discussed the new evaluation validation framework and the formulation of drug-target interactions prediction problem by more realistic regression formulation based on quantitative bioactivity data.

  6. Enzyme- and transporter-mediated drug interactions with small molecule tyrosine kinase inhibitors.

    PubMed

    Shao, Jie; Markowitz, John S; Bei, Di; An, Guohua

    2014-12-01

    Among the novel and target-specific classes of anticancer drugs, small molecule tyrosine kinase inhibitors (TKIs) represent an extremely promising and rapidly expanding group. TKIs attack cancer-specific targets and therefore have a favorable safety profile. However, as TKIs are taken orally along with other medications on a daily basis, there is an elevated risk of potentially significant drug-drug interactions. Most TKIs are metabolized primarily through CYP3A4. In addition, many TKIs are also CYP3A4 inhibitors at the same time. In addition to drug metabolizing enzymes (DMEs), another determinant of TKI disposition are drug transporters. There is accumulating evidence showing that the majority of currently marketed TKIs interact with ATP-binding cassette transporters, particularly P-glycoprotein as well as Breast Cancer Resistance Protein and serve as both substrates and inhibitors. Considering the dual roles of TKIs on both DMEs and drug transporters, and the importance of these enzyme and transporters in drug disposition, the potential for enzyme- and transporter-mediated TKI-drug interactions in patients with cancer is an important consideration. This review provides a comprehensive overview of drug interactions with small molecule TKIs mediated by DMEs and drug transporters. The TKI-drug interactions with TKIs being victims and/or perpetrators are summarized.

  7. Minimal Pairs: Minimal Importance?

    ERIC Educational Resources Information Center

    Brown, Adam

    1995-01-01

    This article argues that minimal pairs do not merit as much attention as they receive in pronunciation instruction. There are other aspects of pronunciation that are of greater importance, and there are other ways of teaching vowel and consonant pronunciation. (13 references) (VWL)

  8. Food-drug interactions via human cytochrome P450 3A (CYP3A).

    PubMed

    Fujita, Ken-ichi

    2004-01-01

    Food-drug interactions have been reported to occur in various systems in the body. The causes of these interactions are mainly divided into pharmacodynamic and pharmacokinetic processes. Among these processes, drug metabolism plays a crucial role in drug interactions. Metabolic food-drug interactions occur when a certain food alters the activity of a drug-metabolizing enzyme, leading to a modulation of the pharmacokinetics of drugs metabolized by the enzyme. A variety of interactions have been documented so far. Foods consisting of complex chemical mixtures, such as fruits, alcoholic beverages, teas, and herbs, possess the ability to inhibit or induce the activity of drug-metabolizing enzymes. According to results obtained thus far, cytochrome P450 3A4 (CYP3A4) appears to be a key enzyme in food-drug interactions. For example, interactions of grapefruit juice with felodipine and cyclosporine, red wine with cyclosporine, and St John's wort with various medicines including cyclosporine, have been demonstrated. The results indicate the requirement of dosage adjustment to maintain drug concentrations within their therapeutic windows. The CYP3A4-related interaction by food components may be related to the high level of expression of CYP3A4 in the small intestine, as well as its broad substrate specificity, as CYP3A4 is responsible for the metabolism of more than 50% of clinical pharmaceuticals. This review article summarizes the findings obtained to date concerning food-drug interactions and their clinical implications. It seems likely that more information regarding such interactions will accumulate in the future, and awareness is necessary for achieving optimal drug therapy.

  9. Potential of Drug Interactions among Hospitalized Cancer Patients in a Developing Country

    PubMed Central

    Tavakoli-Ardakani, Maria; Kazemian, Kaveh; Salamzadeh, Jamshid; Mehdizadeh, Mahshid

    2013-01-01

    Cancer patients are more susceptible to adverse drug-drug interactions (DDIs) due to receiving multiple medications especially chemotherapy medications, hormonal agents and supportive care drugs. The aim of this study is to describe the prevalence of potential DDIs and to identify risk factors for these potential interactions in hospitalized cancer patients in a developing country. A cross-sectional study conducted by reviewing charts of 224 consecutive in hospitalized patients in hematology-oncology ward of a teaching hospital in Tehran, during a 12 month period from July 2009 to July 2010. “Drug Interaction Facts 2008, 2009: The Authority on Drug Interactions” was used for screening the potential drug-drug interactions. Potential interactions were classified by levels of severity and documentation. The median age of patients was 50 years, the length of hospital stay for patient was 5 days and the number of drugs per patient was 8 drugs. Two hundred and twenty-eight potential interactions were detected. Nearly 14% of the interactions were major and 60% were moderate. Approximately 9% and 10% potential interactions were graded as established and probable. In multivariate analysis, being older than 61 years old, suffering from hematologic cancer, source of cancer in different specific organs (esophagus, testis and cervices more than other sources), and number of ordered drugs for patients were independent predictors of having at least one potential DDI in hospital order. Suffering from hematologic cancer, source of cancer in different organs, length of hospital stay and number of ordered drugs for patients were independent predictors for number of interactions per patients. Having a DDI seems to be more likely to occur in patients older than 61 years old. Hematologic cancers, having more medications in physician’s order, longer length of hospital stay, esophageal cancer, testicular cancer and cervical cancer have related to having a DDI and also having more

  10. The Interactive Seminar: An Educational Approach for Voluntary HIV Testing in a Drug Dependence Treatment Unit.

    ERIC Educational Resources Information Center

    Sedhom, Laila; And Others

    1994-01-01

    A survey of 118 male patients in a drug dependence treatment unit before and after an interactive seminar with a nonjudgmental professional showed that seminar participants, especially intravenous drug users, had higher rates of voluntary HIV testing than nonparticipants. Drug users who completed detoxification and attended the seminar also had…

  11. Alcohol, Tobacco and Other Drugs: College Student Satisfaction with an Interactive Educational Software Program

    ERIC Educational Resources Information Center

    Rotunda, Rob J.; West, Laura; Epstein, Joel

    2003-01-01

    Alcohol and drug use education and prevention continue to be core educational issues. In seeking to inform students at all levels about drug use, the present exploratory study highlights the potential educational use of interactive computer programs for this purpose. Seventy-three college students from two substance abuse classes interacted for at…

  12. Allotype specific interactions of drugs and HLA molecules in hypersensitivity reactions.

    PubMed

    Illing, Patricia T; Mifsud, Nicole A; Purcell, Anthony W

    2016-10-01

    It is hypothesised that associations between adverse drug reactions and specific alleles of the human leukocyte antigens arise due to specific interactions between the human leukocyte antigen molecules and the causative drug that stimulate immune responses targeting drug exposed tissues. To date this has only been definitively demonstrated for abacavir, an antiretroviral that causes a systemic adverse drug reaction, abacavir hypersensitivity syndrome, solely in HLA-B*57:01(+) individuals. Whilst this has informed the modification of abacavir to remove immunogenicity, there remains an imperative to define other interactions between drugs and specific HLA in order to understand the scope of interactions that can drive T cell mediated drug hypersensitivity. Here we review the current state of understanding of these interactions.

  13. SELF-BLM: Prediction of drug-target interactions via self-training SVM

    PubMed Central

    Keum, Jongsoo; Nam, Hojung

    2017-01-01

    Predicting drug-target interactions is important for the development of novel drugs and the repositioning of drugs. To predict such interactions, there are a number of methods based on drug and target protein similarity. Although these methods, such as the bipartite local model (BLM), show promise, they often categorize unknown interactions as negative interaction. Therefore, these methods are not ideal for finding potential drug-target interactions that have not yet been validated as positive interactions. Thus, here we propose a method that integrates machine learning techniques, such as self-training support vector machine (SVM) and BLM, to develop a self-training bipartite local model (SELF-BLM) that facilitates the identification of potential interactions. The method first categorizes unlabeled interactions and negative interactions among unknown interactions using a clustering method. Then, using the BLM method and self-training SVM, the unlabeled interactions are self-trained and final local classification models are constructed. When applied to four classes of proteins that include enzymes, G-protein coupled receptors (GPCRs), ion channels, and nuclear receptors, SELF-BLM showed the best performance for predicting not only known interactions but also potential interactions in three protein classes compare to other related studies. The implemented software and supporting data are available at https://github.com/GIST-CSBL/SELF-BLM. PMID:28192537

  14. [Clopidogrel--proton pump inhibitors drug interaction: implications to clinical practice].

    PubMed

    Fontes-Carvalho, Ricardo; Albuquerque, Aníbal

    2010-10-01

    Recent studies have raised the concern that proton pump inhibitors (PPIs) could potentially interfere with clopidogrel antiplatelet effect. This association is frequent in clinical practice and is recommended by recent consensus guidelines in patients taking dual antiplatelet therapy to prevent gastrointestinal (GI) bleeding. Clopidogrel is a pro-drug which needs to be metabolized into its active metabolite, by cytochrome P450, especially by CYP2C19 isoenzyme. Various PPIs can inhibit CYP2C19, which could possibly decrease clopidogrel bioactivation process and, therefore, its antiplatelet effect. Various platelet function studies have shown that omeprazol can significantly decrease clopidogrel inhibitory effect on platelet P2Y12 receptor, leading to an increase in the number of patients who are "nonresponders" to clopidogrel. These pharmacokinetic studies also shown that this is not probably a class effect of PPIs, because they are metabolized to varying degrees by CYP2C19. The clinical impact of these observations remains uncertain, because various observational studies have shown conflicting results, and remains to demonstrate if PPIs can really increase the risk of cardiovascular events in patients taking clopidogrel. In this review we will discuss the pharmacokinetic basis underlying this drug interaction, the effect of different PPIs on platelet function tests and we will analyze in detail the potential clinical implications of using this association, both on cardiovascular and gastrointestinal events. Until further data is available, some clinical strategies can be recommended: (1) individual gastrointestinal risk assessment, with PPIs administration only to patients on dual anti-platelet therapy with additional GI risk factors; (2) preferential use of PPIs that have shown less interference with clopidogrel efficacy; (3) wide separation of PPI and clopidogrel dosing to minimize the risk of interaction (PPI may be given before breakfast and clopidogrel at

  15. Machine learning-based prediction of drug–drug interactions by integrating drug phenotypic, therapeutic, chemical, and genomic properties

    PubMed Central

    Cheng, Feixiong; Zhao, Zhongming

    2014-01-01

    Objective Drug–drug interactions (DDIs) are an important consideration in both drug development and clinical application, especially for co-administered medications. While it is necessary to identify all possible DDIs during clinical trials, DDIs are frequently reported after the drugs are approved for clinical use, and they are a common cause of adverse drug reactions (ADR) and increasing healthcare costs. Computational prediction may assist in identifying potential DDIs during clinical trials. Methods Here we propose a heterogeneous network-assisted inference (HNAI) framework to assist with the prediction of DDIs. First, we constructed a comprehensive DDI network that contained 6946 unique DDI pairs connecting 721 approved drugs based on DrugBank data. Next, we calculated drug–drug pair similarities using four features: phenotypic similarity based on a comprehensive drug–ADR network, therapeutic similarity based on the drug Anatomical Therapeutic Chemical classification system, chemical structural similarity from SMILES data, and genomic similarity based on a large drug–target interaction network built using the DrugBank and Therapeutic Target Database. Finally, we applied five predictive models in the HNAI framework: naive Bayes, decision tree, k-nearest neighbor, logistic regression, and support vector machine, respectively. Results The area under the receiver operating characteristic curve of the HNAI models is 0.67 as evaluated using fivefold cross-validation. Using antipsychotic drugs as an example, several HNAI-predicted DDIs that involve weight gain and cytochrome P450 inhibition were supported by literature resources. Conclusions Through machine learning-based integration of drug phenotypic, therapeutic, structural, and genomic similarities, we demonstrated that HNAI is promising for uncovering DDIs in drug development and postmarketing surveillance. PMID:24644270

  16. Drug-nutrient interactions in the intensive care unit: literature review and current recommendations

    PubMed Central

    Heldt, Tatiane; Loss, Sergio Henrique

    2013-01-01

    Objective To describe the interactions between drugs and nutrients and their frequency in the intensive care unit and to assess the professional team's awareness regarding this subject. Methods The keywords "drug interactions" and "nutrition therapy" were searched in the PubMed (specifically MeSH) electronic database. The studies were systematically reviewed for descriptions of the types of interactions between drugs and nutrients, including their frequency and consequences. Results Sixty-seven articles were found. Among these, 20 articles were appropriate for the methodology adopted and accomplished the objectives of the study. Of these 20 articles, 14 articles described interactions between drugs and enteral nutrition, three described interactions between drugs and parenteral nutrition, and three described the importance and care required to avoid such interactions. Conclusions The literature about drug and nutrient interactions is limited and suggests the inability of health care teams to recognize the potential for these interactions. Possibly, the elaboration of a protocol to evaluate drug-nutrient interactions will increase the safety and efficacy of therapeutics. PMID:23917982

  17. [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.

  18. Interactions between Transporters and Herbal Medicines/Drugs: A Focus on Hepatoprotective Compounds.

    PubMed

    Zhang, Aijie; Li, Quansheng; He, Xin; Si, Duanyun; Liu, Changxiao

    2015-01-01

    Many herbal medicines and drugs are available in the clinic as potent hepatoprotective agents for the treatment of commonly occurring liver diseases. Recently, herbal medicines such as silymarin and curcumin have gained more attention and popularity for the treatment of various liver diseases because of their safety and efficacy profiles. Some of them are related to transporters for drug disposition processes, therapeutic efficacy and/or adverse drug reactions. Currently, herbal medicines and diet supplements made from natural products are widely used in patients who are being treated with conventional prescription medicines, which are related to an increasing risk of herbal-drug interactions (HDIs) and/or drug-drug interactions (DDIs). The purpose of present review is to summarize the contemporary knowledge of transporter-mediated HDIs or DDIs for herbal medicines/drugs focusing on hepatoprotective compounds. Several herbal medicines/drugs are discussed in detail in this review.

  19. Rational prescription of drugs within similar therapeutic or structural class for gastrointestinal disease treatment: Drug metabolism and its related interactions

    PubMed Central

    Zhou, Quan; Yan, Xiao-Feng; Zhang, Zhong-Miao; Pan, Wen-Sheng; Zeng, Su

    2007-01-01

    AIM: To review and summarize drug metabolism and its related interactions in prescribing drugs within the similar therapeutic or structural class for gastrointestinal disease treatment so as to promote rational use of medicines in clinical practice. METHODS: Relevant literature was identified by performing MEDLINE/Pubmed searches covering the period from 1988 to 2006. RESULTS: Seven classes of drugs were chosen, including gastric proton pump inhibitors, histamine H2-receptor antagonists, benzamide-type gastroprokinetic agents, selective 5-HT3 receptor antagonists, fluoroquinolones, macrolide antibiotics and azole antifungals. They showed significant differences in metabolic profile (i.e., the fraction of drug metabolized by cytochrome P450 (CYP), CYP reaction phenotype, impact of CYP genotype on interindividual pharmacokinetics variability and CYP-mediated drug-drug interaction potential). Many events of severe adverse drug reactions and treatment failures were closely related to the ignorance of the above issues. CONCLUSION: Clinicians should acquaint themselves with what kind of drug has less interpatient variability in clearance and whether to perform CYP genotyping prior to initiation of therapy. The relevant CYP knowledge helps clinicians to enhance the management of patients with gastrointestinal disease who may require treatment with polytherapeutic regimens. PMID:17948937

  20. 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.

  1. Puppet Play as Interactive Approach in Drug Abuse Prevention

    ERIC Educational Resources Information Center

    Nenadic-Bilan, Diana; Vigato, Teodora

    2010-01-01

    The national strategies of drug abuse prevention across Europe have come to recognise that the drug abuse problem presents a complex set of issues of which there is no simple solution. There is a considerable increase in investment in prevention, treatment and harm-reduction activities and increased focus on supply reduction. School settings are…

  2. Anticholinergic Accumulation: A Slumbering Interaction between Drugs and Food Supplements.

    PubMed

    Vrolijk, Misha F; Opperhuizen, Antoon; Jansen, Eugène H J M; Bast, Aalt; Haenen, Guido R M M

    2015-12-01

    Many compounds display anticholinergic effects which might give rise to cognitive impairment and even delirium. These side effects are caused by their ability to bind to muscarinic receptors in our brain. Especially with combination of compounds, these serious effects are seen. This phenomenon, known as anticholinergic accumulation, is especially seen in the elderly. A classification of drugs for anticholinergic side effects has been made based on clinical observations, the ACB score. Here, we aimed to substantiate this classification by comparing the affinity of numerous drugs for the muscarinic receptors to the ACB score. Additionally, a number of supplements were screened. The affinity of the compounds was determined by their ability to displace the radioligand [(3)H]pirenzepine of the muscarinic receptor induced by these compounds. Our results show that the affinity of a compound for the muscarinic receptors correlated with its ACB score. Also food supplements appeared to bind to these muscarinic receptors. Moreover, several drug-drug, supplement-supplement and supplement-drug combinations had an affinity that is higher than the affinity of single compounds. This explains the phenomenon of anticholinergic accumulation. In conclusion, care should be taken to drug-drug and supplement-drug combinations with respect to anticholinergic accumulation.

  3. Transporter-Mediated Disposition of Opioids: Implications for Clinical Drug Interactions.

    PubMed

    Gharavi, Robert; Hedrich, William; Wang, Hongbing; Hassan, Hazem E

    2015-08-01

    Opioid-related deaths, abuse, and drug interactions are growing epidemic problems that have medical, social, and economic implications. Drug transporters play a major role in the disposition of many drugs, including opioids; hence they can modulate their pharmacokinetics, pharmacodynamics and their associated drug-drug interactions (DDIs). Our understanding of the interaction of transporters with many therapeutic agents is improving; however, investigating such interactions with opioids is progressing relatively slowly despite the alarming number of opioids-mediated DDIs that may be related to transporters. This review presents a comprehensive report of the current literature relating to opioids and their drug transporter interactions. Additionally, it highlights the emergence of transporters that are yet to be fully identified but may play prominent roles in the disposition of opioids, the growing interest in transporter genomics for opioids, and the potential implications of opioid-drug transporter interactions for cancer treatments. A better understanding of drug transporters interactions with opioids will provide greater insight into potential clinical DDIs and could help improve opioids safety and efficacy.

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

    PubMed

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

    2016-03-07

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

  5. Herbal supplements and therapeutic drug monitoring: focus on digoxin immunoassays and interactions with St. John's wort.

    PubMed

    Dasgupta, Amitava

    2008-04-01

    Herbal supplements can affect concentrations of therapeutic drugs measured in biological fluids by different mechanisms. Herbal products can either directly interfere with the methodology used in the measurement of drugs or indirectly interfere by altering the pharmacokinetics of coadministered drugs. The active components of Chan Su, Lu-Shen-Wan, Dan Shen, Asian and Siberian ginseng, oleander containing supplements, and Ashwagandha interfere with digoxin measurements by immunoassays, especially the polyclonal antibody-based immunoassays. Herbal supplements are sometimes contaminated with Western drugs causing drug toxicity. A therapeutic drug monitoring (TDM) service is very helpful for diagnosis of drug toxicity in such patients. Herbal products such as St. John's wort, a popular herbal antidepressant, increase the clearance of certain drugs either by increasing the activity of liver or intestinal cytochrome P-450 mixed-function oxidase or through modulation of the P-glycoprotein efflux pump. Significantly reduced concentrations of various therapeutic drugs such as digoxin, theophylline, cyclosporine, tacrolimus, tricyclic antidepressants, warfarin, and protease inhibitors can be observed due to interaction of these drugs with St. John's wort, causing treatment failure. On the other hand, a few drugs such as carbamazepine, mycophenolic acid, and procainamide do not show any interaction with St. John's wort. Understanding the effect of herbal products on TDM methodologies and identification of interactions between herbal products and drugs by TDM are very important clinically.

  6. Cognitive enhancers (Nootropics). Part 3: drugs interacting with targets other than receptors or enzymes. Disease-modifying drugs. Update 2014.

    PubMed

    Froestl, Wolfgang; Pfeifer, Andrea; Muhs, Andreas

    2014-01-01

    Scientists working in the field of Alzheimer's disease and, in particular, cognitive enhancers, are very productive. The review "Drugs interacting with Targets other than Receptors or Enzymes. Disease-modifying Drugs" was accepted in October 2012. In the last 20 months, new targets for the potential treatment of Alzheimer's disease were identified. Enormous progress was realized in the pharmacological characterization of natural products with cognitive enhancing properties. This review covers the evolution of research in this field through May 2014.

  7. Effect of chirality on PVP/drug interaction within binary physical mixtures of ibuprofen, ketoprofen, and naproxen: a DSC study.

    PubMed

    Ivanov, Ivan T; Tsokeva, Zhivka

    2009-08-01

    We report on the thermal behavior of freshly prepared binary drug/polymer physical mixtures that contained ibuprofen, ketoprofen, or naproxen as a drug, and polyvinylpyrrolidone (PVP), hydroxyethylcellulose (HEC), or methylcellulose (MC) as excipient. At 6-10 degrees C/min heating rates the DSC detected a sharp, single endotherm that corresponds to the melting of drug. On heating physical mixtures of PVP and racemic ibuprofen or ketoprofen at lower heating rates, another endotherm was registered in front of the original one. To observe the additional endotherm, specific minimal values of the heating rate and of PVP weight fraction were needed; for ibuprofen and ketoprofen they were 1.5 and 2.0 degrees C/min, and 5 and 15% (w/w), respectively. At greater PVP weight fractions the top temperatures, T(mp), of both peaks were reduced almost linearly indicating strong solid-state interfacial reaction between the drug particles and PVP matrix. The additional endotherm was abolished at greater heating rates (2 degrees C/min for ibuprofen, 3 degrees C/min for ketoprofen), by replacing the racemate with respective S+-enantiomer and by replacing PVP with HEC and MC. Hence, the possible inclusion of enantioselective component within the PVP/drug interaction, responsible for the amorphization of physical mixture over storage, is assumed.

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

    PubMed

    Hochman, Jerome; Tang, Cuyue; Prueksaritanont, Thomayant

    2015-03-01

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

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

    PubMed

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

    2014-07-01

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

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

    PubMed

    Vilar, Santiago; Friedman, Carol; Hripcsak, George

    2017-02-17

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

  11. What Can Be Learned from Recent New Drug Applications? A Systematic Review of Drug Interaction Data for Drugs Approved by the US FDA in 2015.

    PubMed

    Yu, Jingjing; Zhou, Zhu; Owens, Katie H; Ritchie, Tasha K; Ragueneau-Majlessi, Isabelle

    2017-01-01

    As a follow up to previous reviews, the aim of the present analysis was to systematically examine all drug metabolism, transport, pharmacokinetics (PK), and drug-drug interaction (DDI) data available in the 33 new drug applications (NDAs) approved by the Food and Drug Administration (FDA) in 2015, using the University of Washington Drug Interaction Database, and to highlight the significant findings. In vitro, a majority of the new molecular entities (NMEs) were found to be substrates or inhibitors/inducers of at least one drug metabolizing enzyme or transporter. In vivo, 95 clinical DDI studies displayed positive PK interactions, with an area under the curve (AUC) ratio ≥ 1.25 for inhibition or ≤ 0.8 for induction. When NMEs were considered as victim drugs, 21 NMEs had at least one positive clinical DDI, with three NMEs shown to be sensitive substrates of CYP3A (AUC ratio ≥ 5 when coadministered with strong inhibitors): cobimetinib, isavuconazole (the active metabolite of prodrug isavuconazonium sulfate), and ivabradine. As perpetrators, nine NMEs showed positive inhibition and three NMEs showed positive induction, with some of these interactions involving both enzymes and transporters. The most significant changes for inhibition and induction were observed with rolapitant, a moderate inhibitor of CYP2D6 and lumacaftor, a strong inducer of CYP3A. Physiologically based pharmacokinetics simulations and pharmacogenetics studies were used for six and eight NMEs, respectively, to inform dosing recommendations. The effects of hepatic or renal impairment on the drugs' PK were also evaluated to support drug administration in these specific populations.

  12. Structure of Minimal Tetratricopeptide Repeat Domain Protein Tah1 Reveals Mechanism of Its Interaction with Pih1 and Hsp90*

    PubMed Central

    Jiménez, Beatriz; Ugwu, Francisca; Zhao, Rongmin; Ortí, Leticia; Makhnevych, Taras; Pineda-Lucena, Antonio; Houry, Walid A.

    2012-01-01

    Tah1 and Pih1 are novel Hsp90 interactors. Tah1 acts as a cofactor of Hsp90 to stabilize Pih1. In yeast, Hsp90, Tah1, and Pih1 were found to form a complex that is required for ribosomal RNA processing through their effect on box C/D small nucleolar ribonucleoprotein assembly. Tah1 is a minimal tetratricopeptide repeat protein of 111 amino acid residues that binds to the C terminus of the Hsp90 molecular chaperone, whereas Pih1 consists of 344 residues of unknown fold. The NMR structure of Tah1 has been solved, and this structure shows the presence of two tetratricopeptide repeat motifs followed by a C helix and an unstructured region. The binding of Tah1 to Hsp90 is mediated by the EEVD C-terminal residues of Hsp90, which bind to a positively charged channel formed by Tah1. Five highly conserved residues, which form a two-carboxylate clamp that tightly interacts with the ultimate Asp-0 residue of the bound peptide, are also present in Tah1. Tah1 was found to bind to the C terminus of Pih1 through the C helix and the unstructured region. The C terminus of Pih1 destabilizes the protein in vitro and in vivo, whereas the binding of Tah1 to Pih1 allows for the formation of a stable complex. Based on our data, a model for an Hsp90-Tah1-Pih1 ternary complex is proposed. PMID:22179618

  13. Chemotherapy drugs form ion pores in membranes due to physical interactions with lipids.

    PubMed

    Ashrafuzzaman, Mohammad; Tseng, Chih-Yuan; Duszyk, Marek; Tuszynski, Jack A

    2012-12-01

    We demonstrate the effects on membrane of the tubulin-binding chemotherapy drugs: thiocolchicoside and taxol. Electrophysiology recordings across lipid membranes in aqueous phases containing drugs were used to investigate the drug effects on membrane conductance. Molecular dynamics simulation of the chemotherapy drug-lipid complexes was used to elucidate the mechanism at an atomistic level. Both drugs are observed to induce stable ion-flowing pores across membranes. Discrete pore current-time plots exhibit triangular conductance events in contrast to rectangular ones found for ion channels. Molecular dynamics simulations indicate that drugs and lipids experience electrostatic and van der Waals interactions for short periods of time when found within each other's proximity. The energies from these two interactions are found to be similar to the energies derived theoretically using the screened Coulomb and the van der Waals interactions between peptides and lipids due to mainly their charge properties while forming peptide-induced ion channels in lipid bilayers. Experimental and in silico studies together suggest that the chemotherapy drugs induce ion pores inside lipid membranes due to drug-lipid physical interactions. The findings reveal cytotoxic effects of drugs on the cell membrane, which may aid in novel drug development for treatment of cancer and other diseases.

  14. 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

  15. 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.

  16. Drug development: how academia, industry and authorities interact.

    PubMed

    Garattini, Silvio; Perico, Norberto

    2014-10-01

    Unfortunately, abundant examples could be given of pitfalls in the current drug development paradigm-including in the design, conduct and evaluation of phase III clinical trials. This article discusses issues of particular relevance to clinical trials in nephrology, including the inappropriate use of placebo, publication of reports that emphasize potential treatment benefits over adverse reactions, the sometimes dubious impartiality of independent guidelines, and inadequate recruitment of elderly patients. This Perspectives article aims to highlight and summarize the flaws in the current drug development process, while suggesting a way forward that equally satisfies the requirements of academia, patients and the pharmaceutical industry. We suggest improvements to the drug development process and related legislation that intend to balance public needs with commercial aims and ensure effective drug evaluation by regulatory authorities.

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

    PubMed

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

    2014-09-01

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

  18. Organ Impairment—Drug–Drug Interaction Database: A Tool for Evaluating the Impact of Renal or Hepatic Impairment and Pharmacologic Inhibition on the Systemic Exposure of Drugs

    PubMed Central

    Yeung, CK; Yoshida, K; Kusama, M; Zhang, H; Ragueneau-Majlessi, I; Argon, S; Li, L; Chang, P; Le, CD; Zhao, P; Zhang, L; Sugiyama, Y; Huang, S-M

    2015-01-01

    The organ impairment and drug–drug interaction (OI-DDI) database is the first rigorously assembled database of pharmacokinetic drug exposure data from publicly available renal and hepatic impairment studies presented together with the maximum change in drug exposure from drug interaction inhibition studies. The database was used to conduct a systematic comparison of the effect of renal/hepatic impairment and pharmacologic inhibition on drug exposure. Additional applications are feasible with the public availability of this database. PMID:26380158

  19. Decellularized skeletal muscle as an in vitro model for studying drug-extracellular matrix interactions

    PubMed Central

    Wassenaar, Jean W.; Boss, Gerry R.; Christman, Karen L.

    2015-01-01

    Several factors can affect drug absorption after intramuscular (IM) injection: drug solubility, drug transport across cell membranes, and drug metabolism at the injection site. We found that potential interactions between the drug and the extracellular matrix (ECM) at the injection site can also affect the rate of absorption post-injection. Using decellularized skeletal muscle, we developed a simple method to model drug absorption after IM injection, and showed that the nature of the drug-ECM interaction could be investigated by adding compounds that alter binding. We validated the model using the vitamin B12 analog cobinamide with different bound ligands. Cobinamide is being developed as an IM injectable treatment for cyanide poisoning, and we found that the in vitro binding data correlated with previously published in vivo drug absorption in animals. Commercially available ECM products, such as collagen and GelTrex, did not recapitulate drug binding behavior. While decellularized ECM has been widely studied in fields such as tissue engineering, this work establishes a novel use of skeletal muscle ECM as a potential in vitro model to study drug-ECM interactions during drug development. PMID:26125502

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

    PubMed Central

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

    2016-01-01

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

  1. The role of mesocorticolimbic dopamine in regulating interactions between drugs of abuse and social behavior.

    PubMed

    Young, Kimberly A; Gobrogge, Kyle L; Wang, Zuoxin

    2011-01-01

    The use of addictive drugs can have profound short- and long-term consequences on social behaviors. Similarly, social experiences and the presence or absence of social attachments during early development and throughout life can greatly influence drug intake and the susceptibility to drug abuse. The following review details this reciprocal interaction, focusing on common drugs of abuse (e.g., psychostimulants, opiates, alcohol and nicotine) and social behaviors (e.g., maternal, sexual, play, aggressive and bonding behaviors). The neural mechanisms underlying this interaction are discussed, with a particular emphasis on the involvement of the mesocorticolimbic dopamine system.

  2. Pharmacogenomics and Herb-Drug Interactions: Merge of Future and Tradition

    PubMed Central

    Zhang, Yue-Li; Zeng, Mei-Zi; He, Fa-Zhong; Luo, Zhi-Ying; Luo, Jian-Quan; Wen, Jia-Gen; Chen, Xiao-Ping; Zhou, Hong-Hao; Zhang, Wei

    2015-01-01

    The worldwide using of herb products and the increasing potential herb-drug interaction issue has raised enthusiasm on discovering the underlying mechanisms. Previous review indicated that the interactions may be mediated by metabolism enzymes and transporters in pharmacokinetic pathways. On the other hand, an increasing number of studies found that genetic variations showed some influence on herb-drug interaction effects whereas these genetic factors did not draw much attention in history. We highlight that pharmacogenomics may involve the pharmacokinetic or pharmacodynamic pathways to affect herb-drug interaction. We are here to make an updated review focused on some common herb-drug interactions in association with genetic variations, with the aim to help safe use of herbal medicines in different individuals in the clinic. PMID:25821484

  3. Key Findings from Preclinical and Clinical Drug Interaction Studies Presented in New Drug and Biological License Applications Approved by the Food and Drug Administration in 2014.

    PubMed

    Yu, Jingjing; Ritchie, Tasha K; Zhou, Zhu; Ragueneau-Majlessi, Isabelle

    2016-01-01

    Regulatory approval documents contain valuable information, often not published, to assess the drug-drug interaction (DDI) profile of newly marketed drugs. This analysis aimed to systematically review all drug metabolism, transport, pharmacokinetics, and DDI data available in the new drug applications and biologic license applications approved by the U.S. Food and Drug Administration in 2014, using the University of Washington Drug Interaction Database, and to highlight the significant findings. Among the 30 new drug applications and 11 biologic license applications reviewed, 35 new molecular entities (NMEs) were well characterized with regard to drug metabolism, transport, and/or organ impairment and were fully analyzed in this review. In vitro, a majority of the NMEs were found to be substrates or inhibitors/inducers of at least one drug metabolizing enzyme or transporter. In vivo, when NMEs were considered as victim drugs, 16 NMEs had at least one in vivo DDI study with a clinically significant change in exposure (area under the time-plasma concentration curve or Cmax ratio ≥2 or ≤0.5), with 6 NMEs shown to be sensitive substrates of cytochrome P450 enzymes (area under the time-plasma concentration curve ratio ≥5 when coadministered with potent inhibitors): paritaprevir and naloxegol (CYP3A), eliglustat (CYP2D6), dasabuvir (CYP2C8), and tasimelteon and pirfenidone (CYP1A2). As perpetrators, seven NMEs showed clinically significant inhibition involving both enzymes and transporters, although no clinically significant induction was observed. Physiologically based pharmacokinetic modeling and pharmacogenetics studies were used for six and four NMEs, respectively, to optimize dosing recommendations in special populations and/or multiple impairment situations. In addition, the pharmacokinetic evaluations in patients with hepatic or renal impairment provided useful quantitative information to support drug administration in these fragile populations.

  4. Acute drug prescribing to children on chronic antiepilepsy therapy and the potential for adverse drug interactions in primary care

    PubMed Central

    Novak, Philipp H; Ekins-Daukes, Suzie; Simpson, Colin R; Milne, Robert M; Helms, Peter; McLay, James S

    2005-01-01

    Aims To investigate the extent of acute coprescribing in primary care to children on chronic antiepileptic therapy, which could give rise to potentially harmful drug–drug interactions. Design Acute coprescribing to children on chronic antiepileptic drug therapy in primary care was assessed in 178 324 children aged 0–17 years for the year 1 November 1999 to 31 October 2000. Computerized prescribing data were retrieved from 161 representative general practices in Scotland. Setting One hundred and sixty-one general practices throughout Scotland. Results During the study year 723 (0.41%) children chronically prescribed antiepileptic therapy were identified. Fourteen antiepileptic agents were prescribed, with carbamazepine, sodium valproate and lamotrigine accounting for 80% of the total. During the year children on chronic antiepileptic therapy were prescribed 4895 acute coprescriptions for 269 different medicines. The average number of acute coprescriptions for non-epileptic drug therapy were eight, 11, six, and six for the 0–1, 2–4, 5–11, and 12–17-year-olds, respectively. Of these acute coprescriptions 72 (1.5%) prescribed to 22 (3.0%) children were identified as a potential source of clinically serious interactions. The age-adjusted prevalence rates for potentially serious coprescribing were 86, 26, 22, and 33/1000 children chronically prescribed antiepileptic therapy in the 0–1, 2–4, 5–11, and 12–17-year-old age groups, respectively. The drugs most commonly coprescribed which could give rise to such interactions were antacids, erythromycin, ciprofloxacin, theophylline and the low-dose oral contraceptive. For 10 (45.5%0 of the 20 children identified at risk of a potentially clinically serious adverse drug interaction, the acute coprescription was prescribed off label because of age or specific contraindication/warning. Conclusions In primary care, 3.0% of children on chronic antiepileptic therapy are coprescribed therapeutic agents, which could

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

    PubMed Central

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

    2015-01-01

    The use of multi drug regimens among the elderly population has increased tremendously over the last decade although the benefits of medications are always accompanied by potential harm, even when prescribed at recommended doses. The elderly populations are particularly at an increased risk of adverse drug reactions considering comorbidity, poly-therapy, physiological changes affecting the pharmacokinetics and pharmacodynamics of many drugs and, in some cases, poor compliance due to cognitive impairment and/or depression. In this setting, drug–drug interaction may represent a serious and even life-threatening clinical condition. Moreover, the inability to distinguish drug-induced symptoms from a definitive medical diagnosis often results in addition of yet another drug to treat the symptoms, which in turn increases drug–drug interactions. Cognitive enhancers, including acetylcholinesterase inhibitors and memantine, are the most widely prescribed agents for Alzheimer’s disease (AD) patients. Behavioral and psychological symptoms of dementia, including psychotic symptoms and behavioral disorders, represent noncognitive disturbances frequently observed in AD patients. Antipsychotic drugs are at high risk of adverse events, even at modest doses, and may interfere with the progression of cognitive impairment and interact with several drugs including anti-arrhythmics and acetylcholinesterase inhibitors. Other medications often used in AD patients are represented by anxiolytic, like benzodiazepine, or antidepressant agents. These agents also might interfere with other concomitant drugs through both pharmacokinetic and pharmacodynamic mechanisms. In this review we focus on the most frequent drug–drug interactions, potentially harmful, in AD patients with behavioral symptoms considering both physiological and pathological changes in AD patients, and potential pharmacodynamic/pharmacokinetic drug interaction mechanisms. PMID:26392756

  6. A case of a probable drug interaction between lurasidone and atazanavir-based antiretroviral therapy.

    PubMed

    Naccarato, Mark; Hall, Elise; Wai, Alan; Ostrowski, Mario; Carvalhal, Adriana

    2016-01-01

    The cytochrome P450 isoform that is primarily involved in the metabolism of the antipsychotic lurasidone is CYP3A4. Drugs that inhibit or induce this enzyme would then be expected to increase or decrease serum concentrations of lurasidone, respectively. Atazanavir, an HIV-1 protease inhibitor, has demonstrated to be an inhibitor of CYP3A4 and would be expected to increase the exposure of any drug metabolized by this enzyme. We report a case of an atazanavir-precipitated drug-drug interaction that led to elevated serum concentrations of lurasidone and associated clinical symptoms of drug toxicity.

  7. Functional drug-gene interactions in lung cancer.

    PubMed

    Smida, Michal; Nijman, Sebastian M B

    2012-04-01

    Despite the dawn of the genomic information era, the challenges of cancer treatment remain formidable. Particularly for the most prevalent cancer types, including lung cancer, successful treatment of metastatic disease is rare and escalating costs for modern targeted drugs place an increasing strain on healthcare systems. Although powerful diagnostic tools to characterize individual tumor samples in great molecular detail are becoming rapidly available, the transformation of this information into therapy provides a major challenge. A fundamental difficulty is the molecular complexity of cancer cells that often causes drug resistance, but can also render tumors exquisitely sensitive to targeted agents. By using lung cancer as an example, we outline the principles that govern drug sensitivity and resistance from a genetic perspective and discuss how in vitro chemical-genetic screens can impact on patient stratification in the clinic.

  8. [Prevalence and clinical significance of interactions drug-enteral nutrition in Intensive Care Units].

    PubMed

    Reis, Adriano Max Moreira; de Carvalho, Rhanna Emanuela Fontenele Lima; de Faria, Leila Marcia Pereira; de Oliveira, Regina Célia; Zago, Karine Santana de Azevedo; Cavelagna, Milena Ferreira; Silva, Adriano Gomes; Neto, Manoel Luis; Cassiani, Silvia Helena de Bortoli

    2014-01-01

    This is a multicenter, cross-sectional retrospective study, which aimed to determine the prevalence of interactions drug-enteral nutrition (EN) in Intensive Care Units (ICU) of seven teaching hospitals in Brazil, and to analyze the clinical significance of them. Information on medications and EN administered with 24 hours and 120 hours of hospitalization were collected. For identification of drug-EN interaction was employed software Drug Reax®. It was investigated 1.124 records. Of these, 320 patients, with 24 hours of hospitalization, were on EN, and 20 (6.3%) had drug-EN interaction. Of the 504 patients with 120 hours of hospitalization, 39 (7.7%) had drug-EN interaction. The most frequent drug-EN interactions of clinical significance were phenytoin-EN, warfarin-EN and levothyroxine-EN. Drug-EN interactions may interfere with the quality and cost effectiveness of care in ICU, so it is essential that the health team has knowledge about them.

  9. Radiation Interaction with Therapeutic Drugs and Cell Membranes

    SciTech Connect

    Martin, Diana I.; Manaila, Elena N.; Matei, Constantin I.; Iacob, Nicusor I.; Ighigeanu, Daniel I.; Craciun, Gabriela D.; Moisescu, Mihaela I.; Savopol, Tudor D.; Kovacs, Eugenia A.; Cinca, Sabin A.; Margaritescu, Irina D.

    2007-04-23

    This transient permeabilized state of the cell membrane, named the 'cell electroporation' (CE) can be used to increase cells uptake of drugs that do not readily pass cell membrane, thus enabling their cytotoxicity. The anticancer drugs, such as bleomycin (BL) and cisplatin, are the most candidates for the combined use with ionizing and non-ionizing radiation fields. The methods and installations for the cell electroporation by electron beam (EB) and microwave (MW) irradiation are presented. The viability tests of the human leukocytes under EB and MW exposure with/without the BL in the cell cultures are discussed.

  10. Drug-nutrient interactions: a broad view with implications for practice.

    PubMed

    Boullata, Joseph I; Hudson, Lauren M

    2012-04-01

    The relevance of drug?nutrient interactions in daily practice continues to grow with the widespread use of medication. Interactions can involve a single nutrient, multiple nutrients, food in general, or nutrition status. Mechanistically, drug?nutrient interactions occur because of altered intestinal transport and metabolism, or systemic distribution, metabolism and excretion, as well as additive or antagonistic effects. Optimal patient care includes identifying, evaluating, and managing these interactions. This task can be supported by a systematic approach for categorizing interactions and rating their clinical significance. This review provides such a broad framework using recent examples, as well as some classic drug?nutrient interactions. Pertinent definitions are presented, as is a suggested approach for clinicians. This important and expanding subject will benefit tremendously from further clinician involvement.

  11. A nuclear magnetic resonance study of the interactions of antimalarial drugs with porphyrins.

    PubMed

    Moreau, S; Perly, B; Chachaty, C; Deleuze, C

    1985-05-29

    Haematins (hydroxyferriprotoporphyrin IX) constitute a possible receptor for antimalarial drugs such as chloroquine or quinine. This paper reports the study of the interactions of these two molecules with two tetrapyrrole (haematin and uroporphyrin I) by 1H-NMR spectroscopy. This method provided us with the geometry of the interactions in aqueous medium. The interaction consists of a close stacking of the porphyrin ring and the quinoleine moiety of the drugs. Using a porphyrin ring current model it was possible to reach the spatial relationships of the interacting species. It was concluded that hydrophobic forces play a key role in the interaction. The porphyrin plane can accommodate wide structural variations of the interacting species, leading to a weak specificity. The consequences on the mode of action of antimalarial drugs are discussed.

  12. Cognitive enhancers (nootropics). Part 3: drugs interacting with targets other than receptors or enzymes. disease-modifying drugs.

    PubMed

    Froestl, Wolfgang; Pfeifer, Andrea; Muhs, Andreas

    2013-01-01

    Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer's disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 19 categories according to their mechanism(s) of action, in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease modifying drugs, meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-β and tau. For drugs, whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. The review covers the evolution of research in this field over the last 25 years.

  13. Lack of in vitro interactions using human liver microsomes between rabeprazole and anticancer drugs.

    PubMed

    Tamaro, Ilaria; Genazzani, Armando; Canonico, Pierluigi; Grosa, Giorgio

    2009-01-01

    The potential interactions between rabeprazole, a widely used proton pump inhibitor, and anticancer drugs (5-fluorouracil, docetaxel, cyclophosphamide, gemcitabine, methotrexate, doxorubicin, etoposide) or drugs commonly present in the therapy of oncological patients (fluoxetine and ondansetron), were studied using in vitro human liver microsomes. The interactions between rabeprazole and the anticancer drugs were evaluated by measuring their concentrations in test and control incubations with HPLC-DAD-UV methods. To achieve this aim, nine HPLC-DAD-UV methods were developed using different stationary and mobile phases. The methods were then validated for the following parameters: selectivity, linearity, precision, and accuracy. As expected rabeprazole did not significantly inhibit the metabolism of the evaluated drugs in human liver microsomal preparations at the selected concentrations. These results shows that rabeprazole probably could be devoid of pharmacokinetic interactions with common drugs used during chemotherapy.

  14. Omics Approaches To Probe Microbiota and Drug Metabolism Interactions.

    PubMed

    Nichols, Robert G; Hume, Nicole E; Smith, Philip B; Peters, Jeffrey M; Patterson, Andrew D

    2016-12-19

    The drug metabolism field has long recognized the beneficial and sometimes deleterious influence of microbiota in the absorption, distribution, metabolism, and excretion of drugs. Early pioneering work with the sulfanilamide precursor prontosil pointed toward the necessity not only to better understand the metabolic capabilities of the microbiota but also, importantly, to identify the specific microbiota involved in the generation and metabolism of drugs. However, technological limitations important for cataloging the microbiota community as well as for understanding and/or predicting their metabolic capabilities hindered progress. Current advances including mass spectrometry-based metabolite profiling as well as culture-independent sequence-based identification and functional analysis of microbiota have begun to shed light on microbial metabolism. In this review, case studies will be presented to highlight key aspects (e.g., microbiota identification, metabolic function and prediction, metabolite identification, and profiling) that have helped to clarify how the microbiota might impact or be impacted by drug metabolism. Lastly, a perspective of the future of this field is presented that takes into account what important knowledge is lacking and how to tackle these problems.

  15. St John's wort (Hypericum perforatum): drug interactions and clinical outcomes

    PubMed Central

    Henderson, L; Yue, Q Y; Bergquist, C; Gerden, B; Arlett, P

    2002-01-01

    Aims The aim of this work is to identify the medicines which interact with the herbal remedy St John's wort (SJW), and the mechanisms responsible. Methods A systematic review of all the available evidence, including worldwide published literature and spontaneous case reports provided by healthcare professionals and regulatory authorities within Europe has been undertaken. Results A number of clinically significant interactions have been identified with prescribed medicines including warfarin, phenprocoumon, cyclosporin, HIV protease inhibitors, theophylline, digoxin and oral contraceptives resulting in a decrease in concentration or effect of the medicines. These interactions are probably due to the induction of cytochrome P450 isoenzymes CYP3A4, CYP2C9, CYP1A2 and the transport protein P-glycoprotein by constituent(s) in SJW. The degree of induction is unpredictable due to factors such as the variable quality and quantity of constituent(s) in SJW preparations. In addition, possible pharmacodynamic interactions with selective serotonin re-uptake inhibitors and serotonin (5-HT1d) receptor-agonists such as triptans used to treat migraine were identified. These interactions are associated with an increased risk of adverse reactions. Conclusions In Sweden and the UK the potential risks to patients were judged to be significant and therefore information about the interactions was provided to health care professionals and patients. The product information of the licensed medicines involved has been amended to reflect these newly identified interactions and SJW preparations have been voluntarily labelled with appropriate warnings. PMID:12392581

  16. Using compound similarity and functional domain composition for prediction of drug-target interaction networks.

    PubMed

    Chen, Lei; He, Zhi-Song; Huang, Tao; Cai, Yu-Dong

    2010-11-01

    Study of interactions between drugs and target proteins is an essential step in genomic drug discovery. It is very hard to determine the compound-protein interactions or drug-target interactions by experiment alone. As supplementary, effective prediction model using machine learning or data mining methods can provide much help. In this study, a prediction method based on Nearest Neighbor Algorithm and a novel metric, which was obtained by combining compound similarity and functional domain composition, was proposed. The target proteins were divided into the following groups: enzymes, ion channels, G protein-coupled receptors, and nuclear receptors. As a result, four predictors with the optimal parameters were established. The overall prediction accuracies, evaluated by jackknife cross-validation test, for four groups of target proteins are 90.23%, 94.74%, 97.80%, and 97.51%, respectively, indicating that compound similarity and functional domain composition are very effective to predict drug-target interaction networks.

  17. A linear scaling study of solvent-solute interaction energy of drug molecules in aqua solution.

    PubMed

    Bondesson, Laban; Rudberg, Elias; Luo, Yi; Sałek, Paweł

    2007-08-30

    Solvent-solute interaction energies for three well-known drug molecules in water solution are computed at the Hartree-Fock and B3LYP density functional theory levels using a linear scaling technique, which allows one to explicitly include in the model water molecules up to 14 A away from the solute molecule. The dependence of calculated interaction energies on the amount of included solvent has been examined. It is found that it is necessary to account for water molecules within an 8 A radius around the drug molecule to reach the saturated solvent interaction level. Effects of electron correlation and basis set on solvent-solute interaction energies are discussed.

  18. Physico-chemical characterization of liposomes and drug substance-liposome interactions in pharmaceutics using capillary electrophoresis and electrokinetic chromatography.

    PubMed

    Franzen, Ulrik; Østergaard, Jesper

    2012-12-07

    Liposomes are self-assembled phospholipid vesicles and have numerous research and therapeutic applications. In the pharmaceutical and biomedical sciences liposomes find use as models of biological membranes, partitioning medium and as drug carriers. The present review addresses the use of capillary electrophoresis and liposome electrokinetic chromatography for the characterization of liposomes in a pharmaceutical context. Capillary electrophoretic techniques have been used for the measurement of electrophoretic mobility, which provides information on liposome surface charge, size and membrane permeability of liposomes. The use of liposome electrokinetic chromatography and capillary electrophoresis for determination of liposome/water partitioning and characterization of drug-liposome interactions is reviewed. A number of studies indicate that capillary electrophoresis may have a role in the characterization of liposome drug delivery systems, e.g., for the investigation of encapsulation efficiency and drug leakage. The well-known characteristics of capillary electrophoresis, i.e., low sample volume requirement, high separation efficiency in aqueous media without a stationary phase, minimal sample preparation, and a high degree of automation, makes it an attractive approach in liposome research.

  19. Biomaterial-based regional chemotherapy: Local anticancer drug delivery to enhance chemotherapy and minimize its side-effects.

    PubMed

    Krukiewicz, Katarzyna; Zak, Jerzy K

    2016-05-01

    Since the majority of anticancer pharmacological agents affect not only cancer tissue but also normal cells, chemotherapy is usually accompanied with severe side effects. Regional chemotherapy, as the alternative version of conventional treatment, leads to the enhancement of the therapeutic efficiency of anticancer drugs and, simultaneously, reduction of toxic effects to healthy tissues. This paper provides an insight into different approaches of local delivery of chemotherapeutics, such as the injection of anticancer agents directly into tumor tissue, the use of injectable in situ forming drug carriers or injectable platforms in a form of implants. The wide range of biomaterials used as reservoirs of anticancer drugs is described, i.e. poly(ethylene glycol) and its copolymers, polyurethanes, poly(lactic acid) and its copolymers, poly(ɛ-caprolactone), polyanhydrides, chitosan, cellulose, cyclodextrins, silk, conducting polymers, modified titanium surfaces, calcium phosphate based biomaterials, silicone and silica implants, as well as carbon nanotubes and graphene. To emphasize the applicability of regional chemotherapy in cancer treatment, the commercially available products approved by the relevant health agencies are presented.

  20. Surface mediated cooperative interactions of drugs enhance mechanical forces for antibiotic action

    PubMed Central

    Ndieyira, Joseph W.; Bailey, Joe; Patil, Samadhan B.; Vögtli, Manuel; Cooper, Matthew A.; Abell, Chris; McKendry, Rachel A.; Aeppli, Gabriel

    2017-01-01

    The alarming increase of pathogenic bacteria that are resistant to multiple antibiotics is now recognized as a major health issue fuelling demand for new drugs. Bacterial resistance is often caused by molecular changes at the bacterial surface, which alter the nature of specific drug-target interactions. Here, we identify a novel mechanism by which drug-target interactions in resistant bacteria can be enhanced. We examined the surface forces generated by four antibiotics; vancomycin, ristomycin, chloroeremomycin and oritavancin against drug-susceptible and drug-resistant targets on a cantilever and demonstrated significant differences in mechanical response when drug-resistant targets are challenged with different antibiotics although no significant differences were observed when using susceptible targets. Remarkably, the binding affinity for oritavancin against drug-resistant targets (70 nM) was found to be 11,000 times stronger than for vancomycin (800 μM), a powerful antibiotic used as the last resort treatment for streptococcal and staphylococcal bacteria including methicillin-resistant Staphylococcus aureus (MRSA). Using an exactly solvable model, which takes into account the solvent and membrane effects, we demonstrate that drug-target interactions are strengthened by pronounced polyvalent interactions catalyzed by the surface itself. These findings further enhance our understanding of antibiotic mode of action and will enable development of more effective therapies. PMID:28155918

  1. Surface mediated cooperative interactions of drugs enhance mechanical forces for antibiotic action.

    PubMed

    Ndieyira, Joseph W; Bailey, Joe; Patil, Samadhan B; Vögtli, Manuel; Cooper, Matthew A; Abell, Chris; McKendry, Rachel A; Aeppli, Gabriel

    2017-02-03

    The alarming increase of pathogenic bacteria that are resistant to multiple antibiotics is now recognized as a major health issue fuelling demand for new drugs. Bacterial resistance is often caused by molecular changes at the bacterial surface, which alter the nature of specific drug-target interactions. Here, we identify a novel mechanism by which drug-target interactions in resistant bacteria can be enhanced. We examined the surface forces generated by four antibiotics; vancomycin, ristomycin, chloroeremomycin and oritavancin against drug-susceptible and drug-resistant targets on a cantilever and demonstrated significant differences in mechanical response when drug-resistant targets are challenged with different antibiotics although no significant differences were observed when using susceptible targets. Remarkably, the binding affinity for oritavancin against drug-resistant targets (70 nM) was found to be 11,000 times stronger than for vancomycin (800 μM), a powerful antibiotic used as the last resort treatment for streptococcal and staphylococcal bacteria including methicillin-resistant Staphylococcus aureus (MRSA). Using an exactly solvable model, which takes into account the solvent and membrane effects, we demonstrate that drug-target interactions are strengthened by pronounced polyvalent interactions catalyzed by the surface itself. These findings further enhance our understanding of antibiotic mode of action and will enable development of more effective therapies.

  2. Surface mediated cooperative interactions of drugs enhance mechanical forces for antibiotic action

    NASA Astrophysics Data System (ADS)

    Ndieyira, Joseph W.; Bailey, Joe; Patil, Samadhan B.; Vögtli, Manuel; Cooper, Matthew A.; Abell, Chris; McKendry, Rachel A.; Aeppli, Gabriel

    2017-02-01

    The alarming increase of pathogenic bacteria that are resistant to multiple antibiotics is now recognized as a major health issue fuelling demand for new drugs. Bacterial resistance is often caused by molecular changes at the bacterial surface, which alter the nature of specific drug-target interactions. Here, we identify a novel mechanism by which drug-target interactions in resistant bacteria can be enhanced. We examined the surface forces generated by four antibiotics; vancomycin, ristomycin, chloroeremomycin and oritavancin against drug-susceptible and drug-resistant targets on a cantilever and demonstrated significant differences in mechanical response when drug-resistant targets are challenged with different antibiotics although no significant differences were observed when using susceptible targets. Remarkably, the binding affinity for oritavancin against drug-resistant targets (70 nM) was found to be 11,000 times stronger than for vancomycin (800 μM), a powerful antibiotic used as the last resort treatment for streptococcal and staphylococcal bacteria including methicillin-resistant Staphylococcus aureus (MRSA). Using an exactly solvable model, which takes into account the solvent and membrane effects, we demonstrate that drug-target interactions are strengthened by pronounced polyvalent interactions catalyzed by the surface itself. These findings further enhance our understanding of antibiotic mode of action and will enable development of more effective therapies.

  3. Effects of Social Interaction and Warm Ambient Temperature on Brain Hyperthermia Induced by the Designer Drugs Methylone and MDPV

    PubMed Central

    Kiyatkin, Eugene A; Kim, Albert H; Wakabayashi, Ken T; Baumann, Michael H; Shaham, Yavin

    2015-01-01

    3,4-Methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV) are new drugs of abuse that have gained worldwide popularity. These drugs are structurally similar to 3,4-methylenedioxymethamphetamine (MDMA) and share many of its physiological and behavioral effects in humans, including the development of hyperthermia during acute intoxication. Here, we examined the effects of methylone (1–9 mg/kg, s.c.) or MDPV (0.1–1.0 mg/kg, s.c.) on brain temperature homeostasis in rats maintained in a standard laboratory environment (single-housed in a quiet rest at 22 °C) and under conditions that model human drug use (social interaction and 29 °C ambient temperature). By simultaneously monitoring temperatures in the nucleus accumbens, temporal muscle, and facial skin, we assessed the effects of methylone and MDPV on intra-brain heat production and cutaneous vascular tone, two critical factors that control brain temperature responses. Both methylone and MDPV dose-dependently increased brain temperature, but even at high doses that induced robust locomotor activation, hyperthermia was modest in magnitude (up to ∼2 °C). Both drugs also induced dose-dependent peripheral vasoconstriction, which appears to be a primary mechanism determining the brain hyperthermic responses. In contrast to the powerful potentiation of MDMA-induced hyperthermia by social interaction and warm ambient temperature, such potentiation was absent for methylone and minimal for MDPV. Taken together, despite structural similarities to MDMA, exposure to methylone or MDPV under conditions commonly associated with human drug use does not lead to profound elevations in brain temperature and sustained vasoconstriction, two critical factors associated with MDMA toxicity. PMID:25074640

  4. Effects of social interaction and warm ambient temperature on brain hyperthermia induced by the designer drugs methylone and MDPV.

    PubMed

    Kiyatkin, Eugene A; Kim, Albert H; Wakabayashi, Ken T; Baumann, Michael H; Shaham, Yavin

    2015-01-01

    3,4-Methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV) are new drugs of abuse that have gained worldwide popularity. These drugs are structurally similar to 3,4-methylenedioxymethamphetamine (MDMA) and share many of its physiological and behavioral effects in humans, including the development of hyperthermia during acute intoxication. Here, we examined the effects of methylone (1-9 mg/kg, s.c.) or MDPV (0.1-1.0 mg/kg, s.c.) on brain temperature homeostasis in rats maintained in a standard laboratory environment (single-housed in a quiet rest at 22 °C) and under conditions that model human drug use (social interaction and 29 °C ambient temperature). By simultaneously monitoring temperatures in the nucleus accumbens, temporal muscle, and facial skin, we assessed the effects of methylone and MDPV on intra-brain heat production and cutaneous vascular tone, two critical factors that control brain temperature responses. Both methylone and MDPV dose-dependently increased brain temperature, but even at high doses that induced robust locomotor activation, hyperthermia was modest in magnitude (up to ∼2 °C). Both drugs also induced dose-dependent peripheral vasoconstriction, which appears to be a primary mechanism determining the brain hyperthermic responses. In contrast to the powerful potentiation of MDMA-induced hyperthermia by social interaction and warm ambient temperature, such potentiation was absent for methylone and minimal for MDPV. Taken together, despite structural similarities to MDMA, exposure to methylone or MDPV under conditions commonly associated with human drug use does not lead to profound elevations in brain temperature and sustained vasoconstriction, two critical factors associated with MDMA toxicity.

  5. DGIdb 2.0: mining clinically relevant drug-gene interactions.

    PubMed

    Wagner, Alex H; Coffman, Adam C; Ainscough, Benjamin J; Spies, Nicholas C; Skidmore, Zachary L; Campbell, Katie M; Krysiak, Kilannin; Pan, Deng; McMichael, Joshua F; Eldred, James M; Walker, Jason R; Wilson, Richard K; Mardis, Elaine R; Griffith, Malachi; Griffith, Obi L

    2016-01-04

    The Drug-Gene Interaction Database (DGIdb, www.dgidb.org) is a web resource that consolidates disparate data sources describing drug-gene interactions and gene druggability. It provides an intuitive graphical user interface and a documented application programming interface (API) for querying these data. DGIdb was assembled through an extensive manual curation effort, reflecting the combined information of twenty-seven sources. For DGIdb 2.0, substantial updates have been made to increase content and improve its usefulness as a resource for mining clinically actionable drug targets. Specifically, nine new sources of drug-gene interactions have been added, including seven resources specifically focused on interactions linked to clinical trials. These additions have more than doubled the overall count of drug-gene interactions. The total number of druggable gene claims has also increased by 30%. Importantly, a majority of the unrestricted, publicly-accessible sources used in DGIdb are now automatically updated on a weekly basis, providing the most current information for these sources. Finally, a new web view and API have been developed to allow searching for interactions by drug identifiers to complement existing gene-based search functionality. With these updates, DGIdb represents a comprehensive and user friendly tool for mining the druggable genome for precision medicine hypothesis generation.

  6. ‘RE:fine drugs’: an interactive dashboard to access drug repurposing opportunities

    PubMed Central

    Moosavinasab, Soheil; Patterson, Jeremy; Strouse, Robert; Rastegar-Mojarad, Majid; Regan, Kelly; Payne, Philip R. O.; Huang, Yungui; Lin, Simon M.

    2016-01-01

    The process of discovering new drugs has been extremely costly and slow in the last decades despite enormous investment in pharmaceutical research. Drug repurposing enables researchers to speed up the process of discovering other conditions that existing drugs can effectively treat, with low cost and fast FDA approval. Here, we introduce ‘RE:fine Drugs’, a freely available interactive website for integrated search and discovery of drug repurposing candidates from GWAS and PheWAS repurposing datasets constructed using previously reported methods in Nature Biotechnology. ‘RE:fine Drugs’ demonstrates the possibilities to identify and prioritize novelty of candidates for drug repurposing based on the theory of transitive Drug–Gene–Disease triads. This public website provides a starting point for research, industry, clinical and regulatory communities to accelerate the investigation and validation of new therapeutic use of old drugs. Database URL: http://drug-repurposing.nationwidechildrens.org PMID:27189611

  7. Electrochemical investigation of interaction between mitomycin C and DNA in a novel drug-delivery system.

    PubMed

    Karadeniz, Hakan; Alparslan, Levent; Erdem, Arzum; Karasulu, Ercument

    2007-10-18

    A novel drug-delivery system was developed by loading the anticancer drug, mitomycin C (MC) into an oil/water system with the aim of investigation by electrochemical sensing the interaction between the drug and DNA in microemulsion phase. The physical and physicochemical properties (droplet size, pH, viscosity, conductivity and refractive index) of this microemulsion were examined. The electrochemical detection of the interaction between MC and double-stranded DNA (dsDNA) in microemulsion phase was performed by using differential pulse voltammetry (DPV) in combination with a disposable sensor, pencil graphite electrode (PGE). The magnitude of guanine oxidation signal was monitored before and after interaction between MC and dsDNA. The effect of different experimental parameters, such as MC concentration, MC interaction time with dsDNA, and dsDNA concentration were also studied to find the optimum analytical performance based on electrochemical detection of this interaction in microemulsion phase.

  8. A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design.

    PubMed

    Beno, Brett R; Yeung, Kap-Sun; Bartberger, Michael D; Pennington, Lewis D; Meanwell, Nicholas A

    2015-06-11

    Electron deficient, bivalent sulfur atoms have two areas of positive electrostatic potential, a consequence of the low-lying σ* orbitals of the C-S bond that are available for interaction with electron donors including oxygen and nitrogen atoms and, possibly, π-systems. Intramolecular interactions are by far the most common manifestation of this effect, which offers a means of modulating the conformational preferences of a molecule. Although a well-documented phenomenon, a priori applications in drug design are relatively sparse and this interaction, which is often isosteric with an intramolecular hydrogen-bonding interaction, appears to be underappreciated by the medicinal chemistry community. In this Perspective, we discuss the theoretical basis for sulfur σ* orbital interactions and illustrate their importance in the context of drug design and organic synthesis. The role of sulfur interactions in protein structure and function is discussed and although relatively rare, intermolecular interactions between ligand C-S σ* orbitals and proteins are illustrated.

  9. Prediction of Drug Indications Based on Chemical Interactions and Chemical Similarities

    PubMed Central

    Huang, Guohua; Lu, Yin; Lu, Changhong; Cai, Yu-Dong

    2015-01-01

    Discovering potential indications of novel or approved drugs is a key step in drug development. Previous computational approaches could be categorized into disease-centric and drug-centric based on the starting point of the issues or small-scaled application and large-scale application according to the diversity of the datasets. Here, a classifier has been constructed to predict the indications of a drug based on the assumption that interactive/associated drugs or drugs with similar structures are more likely to target the same diseases using a large drug indication dataset. To examine the classifier, it was conducted on a dataset with 1,573 drugs retrieved from Comprehensive Medicinal Chemistry database for five times, evaluated by 5-fold cross-validation, yielding five 1st order prediction accuracies that were all approximately 51.48%. Meanwhile, the model yielded an accuracy rate of 50.00% for the 1st order prediction by independent test on a dataset with 32 other drugs in which drug repositioning has been confirmed. Interestingly, some clinically repurposed drug indications that were not included in the datasets are successfully identified by our method. These results suggest that our method may become a useful tool to associate novel molecules with new indications or alternative indications with existing drugs. PMID:25821813

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

    PubMed

    Ismail, Mohammad; Khan, Farmanullah; Noor, Sidra; Haider, Iqbal; Haq, Inam-Ul; Ali, Zahid; Shah, Zahir; Hassam, Mohsin

    2016-10-01

    Background Patients admitted to intensive care unit (ICU) present with severe and life-threatening illnesses. Most of them suffer from various comorbidities. They usually receive complex pharmacotherapy with large number of medicines which increase the risk of drug-drug interactions (DDIs). Objective The present report aimed to investigate prevalence and levels of potential DDIs (pDDIs) in medical ICU. Methods Medications profiles of 416 patients were checked for pDDIs using Micromedex Drug-Reax(®). Prevalence, levels of severity and levels of documentation were reported. Results Of total 416 patients, 310 were exposed to pDDIs (overall prevalence = 74.5 %). Likewise, a prevalence rate of 13.9 % was recorded for contraindicated pDDIs, 52.2 % for major pDDI and 58.4 % for moderate pDDI. This study reported 740 interacting drug pairs that were presented in total 1686 pDDIs. Of 1686 pDDIs, 4.3 % were of contraindicated severity, 33.8 % of major severity and 49.6 % of moderate severity, whereas 45.5 % were of fair scientific evidence and 41.4 % of good scientific evidence. Conclusion In this study, pDDIs were found highly prevalent in ICU patients at a rate of 74.5 %. Most of the pDDIs had moderate severity; however, substantial number of interactions (38.1 %) had major and contraindicated severity.

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

    PubMed

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

    2012-10-01

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

  12. Research on drug-receptor interactions and prediction of drug activity via oriented immobilized receptor capillary electrophoresis.

    PubMed

    Liu, Chunye; Zhang, Xuejiao; Jing, Hui; Miao, Yanqing; Zhao, Lingzhi; Han, Yan; Cui, Cuixia

    2015-10-01

    Oriented covalent immobilized β2 -adrenergic receptor (β2 -AR) CE (OIRCE) was developed to determine the interactions between a set of natural extracts of Radix Paeoniae Rubra (NERPR) and β2 -AR, and to predict the activity of NERPR. The inner capillary surface is chemically bonded with stable β2 -AR coating via microwave-assisted technical synthesis. The modified capillaries were characterized via infrared spectroscopy and fluorescence microscopy. Furthermore, the bonding amounts of β2 -AR were first obtained via fluorescence spectroscopy method. In determining the amount of bonded β2 -AR, the regression equation A  =  576 707C + 35.449 and the correlation coefficient 0.9995 were obtained. This result revealed an excellent linear relationship in the range of 2 × 10(-4)  mg/mL to 1 × 10(-3)  mg/mL. The normalized capacity factor (KRCE ) was obtained using OIRCE in evaluating drug-receptor interactions. Related theories and equations were used to calculate KRCE values from apparent migration times of a solute and EOF. The order of KRCE and the binding constant (Kb ) values between drugs and β2 -AR was well consistent. The results confirmed that the OIRCE and KRCE values can be effectually used to investigate drug-receptor interactions, and OIRCE has the potential to predict drug activity and to select leading compounds from natural chemicals.

  13. Accumulating Evidence for a Drug–Drug Interaction Between Methotrexate and Proton Pump Inhibitors

    PubMed Central

    Mackey, Ann Corken; Kluetz, Paul; Jappar, Dilara; Korvick, Joyce

    2012-01-01

    Background. A number of medications are known to interact with methotrexate through various mechanisms. The aim of this article is to apprise practitioners of a new labeling change based on the accumulating evidence for a possible drug–drug interaction between methotrexate (primarily at high doses) and proton pump inhibitors (PPIs). Methods. The U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database of spontaneous adverse event reports and the published literature were searched for cases reporting an interaction between methotrexate and PPIs. Results. A search of the AERS database and existing literature found several individual case reports of drug–drug interactions and three additional supportive studies that suggest potential underlying mechanisms for the interaction. Conclusion. There is evidence to suggest that concomitant use of methotrexate (primarily at high doses) with PPIs such as omeprazole, esomeprazole, and pantoprazole may decrease methotrexate clearance, leading to elevated serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. In several case reports, no methotrexate toxicity was found when a histamine H2 blocker was substituted for a PPI. Based on the reviewed data, the FDA updated the methotrexate label to include the possible drug–drug interaction between high-dose methotrexate and PPIs. Physicians should be alerted to this potential drug–drug interaction in patients receiving concomitant high-dose methotrexate and PPIs. PMID:22477728

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

    PubMed

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

    2017-04-05

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

  15. Potentially significant versus clinically significant drug interactions: pomegranate juice as a case in point.

    PubMed

    Andrade, Chittaranjan

    2014-04-01

    In vitro and in vivo laboratory data show that pomegranate juice consistently inhibits intestinal CYP2C9 and CYP3A4 enzymes. Pomegranate juice may therefore increase the bioavailability of drugs that are metabolized by these enzymes. However, studies in humans find that pomegranate juice does not increase exposure to either CYP2C9 or CYP3A4 substrates. These contradictory findings suggest that potential drug interactions identified in the laboratory may not necessarily translate into clinically significant drug interactions in humans, and hence that laboratory data are insufficient grounds upon which clinical decisions may be based.

  16. Evaluation of crystal violet decolorization assay for minimal inhibitory concentration detection of primary antituberculosis drugs against Mycobacterium tuberculosis isolates*

    PubMed Central

    Coban, Ahmet Yilmaz; Akbal, Ahmet Ugur; Uzun, Meltem; Cayci, Yeliz Tanriverdi; Birinci, Asuman; Durupinar, Belma

    2016-01-01

    In this study we evaluated the crystal violet decolorization assay (CVDA) for detection of minimum inhibitory concentration (MIC) of antituberculosis drugs. 53 isolates were tested in this study and 13 of them were multidrug resistant (MDR) isolates. The antibiotics concentrations were 2-0.06 mg/L for isoniazid (INH) and rifampicin (RIF) and were 16-0.25 mg/L for streptomycin (STM) and ethambutol (EMB). Crystal violet (CV-25 mg/L) was added into the microwells on the seventh day of incubation and incubation was continued until decolorization. Decolorization of CV was the predictor of bacterial growth. Overall agreements for four drugs were detected as 98.1%, and the average time was detected as 9.5 ± 0.89 day after inoculation. One isolate for INH and two isolates for STM were determined resistant in the reference method, but susceptible by the CVDA. One isolate was susceptible to EMB by the reference method, but resistant by the CVDA. All results were concordant for RIF. This study shows that CVDA is a rapid, reliable and suitable for determination of MIC values of Mycobacterium tuberculosis. And it can be used easily especially in countries with limited-sources. PMID:27304025

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

    PubMed

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

    2015-04-01

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

  18. The interaction of drug use, sex work, and HIV among transgender women.

    PubMed

    Hoffman, Beth R

    2014-06-01

    Transgender women have a higher prevalence of drug use, HIV, drug use, and sex work than the general population. This article explores the interaction of these variables and discusses how sex work and drug use behaviors contribute to the high rates of HIV. A model predicting HIV rates with sex work and drug use as well as these behaviors in the transgender woman's social network is presented. Challenges to intervening with transgender women, as well as suggestions and criteria for successful interventions, are discussed.

  19. 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

  20. Protein-Protein Interactions as New Targets for Ion Channel Drug Discovery

    PubMed Central

    Stoilova-McPhie, Svetla; Ali, Syed; Laezza, Fernanda

    2014-01-01

    Protein-protein interactions (PPI) are key molecular elements that provide the basis of signaling in virtually all cellular processes. The precision and specificity of these molecular interactions have ignited a strong interest in pursuing PPI surfaces as new targets for drug discovery, especially against ion channels in the central nervous system (CNS) where selectivity and specificity are vital for developing drugs with limited side effects. Ion channels are large transmembrane domain proteins assembled with multiple regulatory proteins binding to the intracellular portion of channels. These macromolecular complexes are difficult to isolate, purify and reconstitute, posing a significant barrier in targeting these PPI for drug discovery purposes. Here, we will provide a short overview of salient features of PPI and discuss successful studies focusing on protein-channel interactions that could inspire new drug discovery campaigns targeting ion channel complexes. PMID:25485305

  1. Lipid-lipid and lipid-drug interactions in biological membranes

    NASA Astrophysics Data System (ADS)

    Martynowycz, Michael W.

    Interactions between lipids and drug molecules in biological membranes help govern proper biological function in organisms. The mechanisms responsible for hydrophobic drug permeation remain elusive. Many small molecule drugs are hydrophobic. These drugs inhibit proteins in the cellular interior. The rise of antibiotic resistance in bacteria is thought to be caused by mutations in protein structure, changing drug kinetics to favor growth. However, small molecule drugs have been shown to have different mechanisms depending in the structure of the lipid membrane of the target cell. Biological membranes are investigated using Langmuir monolayers at the air-liquid interface. These offer the highest level of control in the mimetic system and allow them to be investigated using complementary techniques. Langmuir isotherms and insertion assays are used to determine the area occupied by each lipid in the membrane and the change in area caused by the introduction of a drug molecule, respectively. Specular X-ray reflectivity is used to determine the electron density of the monolayer, and grazing incidence X-ray diffraction is used to determine the in-plane order of the monolayer. These methods determine the affinity of the drug and the mechanism of action. Studies are presented on hydrophobic drugs with mammalian membrane mimics using warfarin along with modified analogues, called superwarfarins. Data shows that toxicity of these modified drugs are modulated by the membrane cholesterol content in cells; explaining several previously unexplained effects of the drugs. Membrane mimics of bacteria are investigated along with their interactions with a hydrophobic antibiotic, novobiocin. Data suggests that permeation of the drug is mediated by modifications to the membrane lipids, and completely ceases translocation under certain circumstances. Circumventing deficiencies in small, hydrophobic drugs is approached by using biologically mimetic oligomers. Peptoids, mimetic of host

  2. Pharmacologic counter measures minimizing post-space flight orthostatic intolerance. [bed rest, drug disposition, and physiological function

    NASA Technical Reports Server (NTRS)

    Harrison, D. C.; Kates, R.

    1982-01-01

    The effect of bed rest on drug disposition and physiological function was investigated as part of a project to determine the cardiovascular effects of space flight. One group of subjects was given doses of lidocane, penicillin-G, and ICG during a control period and following seven days of bed rest. Cardiac function was evaluated by echo-cardiography. Renal function was evaluated in a second group before and after several days of bed rest. Inulin, para-aminohippurate, and dextran clearances were studied. In the first group, the post-bed rest parameters were not statistically different from the pre-bed rest valves. In the second study, renal function did not change significantly after seven days of bed rest. Plans for future research are reviewed.

  3. Simulation and Prediction of the Drug‐Drug Interaction Potential of Naloxegol by Physiologically Based Pharmacokinetic Modeling

    PubMed Central

    Bui, K; Sostek, M; Al‐Huniti, N

    2016-01-01

    Naloxegol, a peripherally acting μ‐opioid receptor antagonist for the treatment of opioid‐induced constipation, is a substrate for cytochrome P450 (CYP) 3A4/3A5 and the P‐glycoprotein (P‐gp) transporter. By integrating in silico, preclinical, and clinical pharmacokinetic (PK) findings, minimal and full physiologically based pharmacokinetic (PBPK) models were developed to predict the drug‐drug interaction (DDI) potential for naloxegol. The models reasonably predicted the observed changes in naloxegol exposure with ketoconazole (increase of 13.1‐fold predicted vs. 12.9‐fold observed), diltiazem (increase of 2.8‐fold predicted vs. 3.4‐fold observed), rifampin (reduction of 76% predicted vs. 89% observed), and quinidine (increase of 1.2‐fold predicted vs. 1.4‐fold observed). The moderate CYP3A4 inducer efavirenz was predicted to reduce naloxegol exposure by ∼50%, whereas weak CYP3A inhibitors were predicted to minimally affect exposure. In summary, the PBPK models reasonably estimated interactions with various CYP3A modulators and can be used to guide dosing in clinical practice when naloxegol is coadministered with such agents. PMID:27299937

  4. Drug-polymer-water interaction and its implication for the dissolution performance of amorphous solid dispersions.

    PubMed

    Chen, Yuejie; Liu, Chengyu; Chen, Zhen; Su, Ching; Hageman, Michael; Hussain, Munir; Haskell, Roy; Stefanski, Kevin; Qian, Feng

    2015-02-02

    The in vitro dissolution mechanism of an amorphous solid dispersion (ASD) remains elusive and highly individualized, yet rational design of ASDs with optimal performance and prediction of their in vitro/in vivo performance are very much desirable in the pharmaceutical industry. To this end, we carried out comprehensive investigation of various ASD systems of griseofulvin, felodipine, and ketoconazole, in PVP-VA or HPMC-AS at different drug loading. Physiochemical properties and processes related to drug-polymer-water interaction, including the drug crystallization tendency in aqueous medium, drug-polymer interaction before and after moisture exposure, supersaturation of drug in the presence of polymer, polymer dissolution kinetics, etc., were characterized and correlated with the dissolution performance of ASDs at different dose and different drug/polymer ratio. It was observed that ketoconazole/HPMC-AS ASD outperformed all other ASDs in various dissolution conditions, which was attributed to the drug's low crystallization tendency, the strong ketoconazole/HPMC-AS interaction and the robustness of this interaction against water disruption, the dissolution rate and the availability of HPMC-AS in solution, and the ability of HPMC-AS in maintaining ketoconazole supersaturation. It was demonstrated that all these properties have implications for the dissolution performance of various ASD systems, and further quantification of them could be used as potential predictors for in vitro dissolution of ASDs. For all ASDs investigated, HPMC-AS systems performed better than, or at least comparably with, their PVP-VA counterparts, regardless of the drug loading or dose. This observation cannot be solely attributed to the ability of HPMC-AS in maintaining drug supersaturation. We also conclude that, for fast crystallizers without strong drug-polymer interaction, the only feasible option to improve dissolution might be to lower the dose and the drug loading in the ASD. In this

  5. Synergistic interactions in two-drug and three-drug combinations (thymol, EDTA and vancomycin) against multi drug resistant bacteria including E. coli.

    PubMed

    Hamoud, Razan; Zimmermann, Stefan; Reichling, Jürgen; Wink, Michael

    2014-03-15

    Combinations of two or more drugs, which affect different targets, have frequently been used as a new approach against resistant bacteria. In our work we studied the antimicrobial activity (MIC, MBC) of individual drugs (the phenolic monoterpene thymol, EDTA and vancomycin), of two-drug interactions between thymol and EDTA in comparison with three-drug interactions with vancomycin against sensitive and resistant bacteria. Thymol demonstrated moderate bactericidal activity (MBC between 60 and 4000μg/ml) while EDTA only exhibited bacteriostatic activity over a range of 60-4000μg/ml. MICs of vancomycin were between 0.125 and 16μg/ml against Gram-positive and between 32 and 128μg/ml against Gram-negative bacteria. Checkerboard dilution and time-kill curve assays were performed to evaluate the mode of interaction of several combinations against Methicillin-resistant Staphylococcus aureus (MRSA NCTC 10442) and Escherichia coli (ATCC 25922). Checkerboard data indicate indifferent interaction against Gram-positive (FICI=1-1.3) and synergy against Gram-negative bacteria (FICI≈0.4), while time kill analyses suggest synergistic effect in different combinations against both types of bacteria. It is remarkable that the combinations could enhance the sensitivity of E. coli to vancomycin 16-fold to which it is normally insensitive. We have provided proof for the concept, that combinations of known antibiotics with modern phytotherapeutics can expand the spectrum of useful therapeutics.

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

    PubMed Central

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

    2016-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2016-11-01

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

  8. Profile of the intermolecular forces governing the interaction of drugs with mucin.

    PubMed

    Caron, Giulia; Visentin, Sonja; Pontremoli, Carlotta; Ermondi, Giuseppe

    2015-07-05

    The study highlights the balance of the intermolecular forces governing the interaction between drugs and mucin. The interaction strength is expressed as a retention factor k (data retrieved from the literature (Gargano et al., 2014)) obtained by a new bio-affinity chromatographic method in which the stationary phase is based on covalently immobilized mucin (porcine gastric mucin, PGM). A quantitative structure-property relationship (QSPR) between logk and 82 VolSurf+ descriptors was established and mechanistically interpreted. Results evidence that all blocks contribute similarly to the model; moreover, hydrogen bonding donor (HBD) properties of solutes favor the interaction with mucin; and thus, support their detrimental role on drug permeability.

  9. Role of Molecular Interactions for Synergistic Precipitation Inhibition of Poorly Soluble Drug in Supersaturated Drug-Polymer-Polymer Ternary Solution.

    PubMed

    Prasad, Dev; Chauhan, Harsh; Atef, Eman

    2016-03-07

    We are reporting a synergistic effect of combined Eudragit E100 and PVP K90 in precipitation inhibition of indomethacin (IND) in solutions at low polymer concentration, a phenomenon that has significant implications on the usefulness of developing novel ternary solid dispersion of poorly soluble drugs. The IND supersaturation was created by cosolvent technique, and the precipitation studies were performed in the absence and the presence of individual and combined PVP K90 and Eudragit E100. The studies were also done with PEG 8000 as a noninteracting control polymer. A continuous UV recording of the IND absorption was used to observe changes in the drug concentration over time. The polymorphic form and morphology of precipitated IND were characterized by Raman spectroscopy and scanning electron microscopy. The change in the chemical shift in solution (1)H NMR was used as novel approach to probe IND-polymer interactions. Molecular modeling was used for calculating binding energy between IND-polymer as another indication of IND-polymer interaction. Spontaneous IND precipitation was observed in the absence of polymers. Eudragit E100 showed significant inhibitory effect on nuclei formation due to stronger interaction as reflected in higher binding energy and greater change in chemical shift by NMR. PVP K90 led to significant crystal growth inhibition due to adsorption on growing IND crystals as confirmed by modified crystal habit of precipitate in the presence of PVP K90. Combination of polymers resulted in a synergistic precipitation inhibition and extended supersaturation. The NMR confirmed interaction between IND-Eudragit E100 and IND-PVP K90 in solution. The combination of polymers showed similar peak shift albeit using lower polymer concentration indicating stronger interactions. The results established the significant synergistic precipitation inhibition effect upon combining Eudragit E100 and PVP K90 due to drug-polymer interaction.

  10. Drug carrier interaction with blood: a critical aspect for high-efficient vascular-targeted drug delivery systems

    PubMed Central

    Sobczynski, Daniel J; Fish, Margaret B; Fromen, Catherine A; Carasco-Teja, Mariana; Coleman, Rhima M; Eniola-Adefeso, Omolola

    2015-01-01

    Vascular wall endothelial cells control several physiological processes and are implicated in many diseases, making them an attractive candidate for drug targeting. Vascular-targeted drug carriers (VTCs) offer potential for reduced side effects and improved therapeutic efficacy, however, only limited therapeutic success has been achieved to date. This is perhaps due to complex interactions of VTCs with blood components, which dictate VTC transport and adhesion to endothelial cells. This review focuses on VTC interaction with blood as well as novel ‘bio-inspired’ designs to mimic and exploit features of blood in VTC development. Advanced approaches for enhancing VTCs are discussed along with applications in regenerative medicine, an area of massive potential growth and expansion of VTC utility in the near future. PMID:26272334

  11. Lack of a Significant Drug Interaction between Raltegravir and Tenofovir▿

    PubMed Central

    Wenning, Larissa A.; Friedman, Evan J.; Kost, James T.; Breidinger, Sheila A.; Stek, Jon E.; Lasseter, Kenneth C.; Gottesdiener, Keith M.; Chen, Joshua; Teppler, Hedy; Wagner, John A.; Stone, Julie A.; Iwamoto, Marian

    2008-01-01

    Raltegravir is a novel human immunodeficiency virus type 1 (HIV-1) integrase inhibitor with potent in vitro activity (95% inhibitory concentration of 31 nM in 50% human serum). This article reports the results of an open-label, sequential, three-period study of healthy subjects. Period 1 involved raltegravir at 400 mg twice daily for 4 days, period 2 involved tenofovir disoproxil fumarate (TDF) at 300 mg once daily for 7 days, and period 3 involved raltegravir at 400 mg twice daily plus TDF at 300 mg once daily for 4 days. Pharmacokinetic profiles were also determined in HIV-1-infected patients dosed with raltegravir monotherapy versus raltegravir in combination with TDF and lamivudine. There was no clinically significant effect of TDF on raltegravir. The raltegravir area under the concentration time curve from 0 to 12 h (AUC0-12) and peak plasma drug concentration (Cmax) were modestly increased in healthy subjects (geometric mean ratios [GMRs], 1.49 and 1.64, respectively). There was no substantial effect of TDF on raltegravir concentration at 12 h postdose (C12) in healthy subjects (GMR [TDF plus raltegravir-raltegravir alone], 1.03; 90% confidence interval [CI], 0.73 to 1.45), while a modest increase (GMR, 1.42; 90% CI, 0.89 to 2.28) was seen in HIV-1-infected patients. Raltegravir had no substantial effect on tenofovir pharmacokinetics: C24, AUC, and Cmax GMRs were 0.87, 0.90, and 0.77, respectively. Coadministration of raltegravir and TDF does not change the pharmacokinetics of either drug to a clinically meaningful degree. Raltegravir and TDF may be coadministered without dose adjustments. PMID:18625763

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

    PubMed

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

    2014-09-01

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

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

    PubMed

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

    2010-03-01

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

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

    PubMed

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

    2013-09-01

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

  15. Lack of clinically relevant drug–drug interactions when dalcetrapib is co-administered with ezetimibe

    PubMed Central

    Derks, Michael; Abt, Markus; Phelan, Mary

    2010-01-01

    AIMS Dalcetrapib, which targets cholesteryl ester transfer protein activity, is in development for prevention of cardiovascular events. Because dalcetrapib will likely be prescribed with other lipid-modifying therapies such as ezetimibe, a study was performed to investigate potential pharmacokinetic interactions between dalcetrapib and ezetimibe. Lipids changes and tolerability were secondary endpoints. METHODS Co-administration of dalcetrapib 900 mg (higher than the phase III dose) with ezetimibe was investigated in a three period, three treatment crossover study in healthy males: 7 days of dalcetrapib, 7 days of dalcetrapib plus ezetimibe, 7 days of ezetimibe alone. A full pharmacokinetic profile was performed on day 7 of each treatment. RESULTS Co-administration of dalcetrapib with ezetimibe was associated with minimal changes in dalcetrapib exposure compared with dalcetrapib alone. Least squares mean ratio (LSMR) (90% confidence interval) was 93.6 (87.1, 100.7) for AUC(0,24 h) and 99.0 (85.2, 115.0) for Cmax. Ezetimibe exposure was reduced with co-administration of ezetimibe with dalcetrapib compared with ezetimibe alone: LSMR 80.3 (74.6, 86.4) for AUC(0,24 h) and 88.9 (80.9, 99.9) for Cmax for total ezetimibe. High-density lipoprotein cholesterol increases associated with co-administration of dalcetrapib with ezetimibe (+29.8%) were comparable with those with dalcetrapib alone (+25.6%), while the reduction in low-density lipoprotein cholesterol with co-administration (−35.9%) was greater than with ezetimibe alone (−20.9%). Dalcetrapib was generally well tolerated when administered alone and when co-administered with ezetimibe. CONCLUSION Co-administration of dalcetrapib with ezetimibe was not associated with clinically significant changes in pharmacokinetic parameters or tolerability and did not diminish the lipid effects of either drug. PMID:21175438

  16. Approved drug mimics of short peptide ligands from protein interaction motifs.

    PubMed

    Parthasarathi, Laavanya; Casey, Fergal; Stein, Amelie; Aloy, Patrick; Shields, Denis C

    2008-10-01

    Most biological functions are regulated through complex networks of transient protein interactions, and, thus, finding effective ways to modulate them would represent an important step towards defining the next generation of drugs. In this study, we set out to determine if existing approved drugs may represent a good source of compounds from which initial lead inhibitors of protein-protein interactions mediated by short peptide regions may be drawn. Peptide structures were defined in terms of pharmacophores and searched against U.S. Food and Drug Administration (FDA)-approved drugs to identify similar compounds. The top ranking matches (using a score that corrects root-mean-square deviation (rmsd) for the number of matched pharmacophores and for the number of drug rotatable bonds) included a number of nuclear receptor ligands that matched allosterically to the corepressor binding site of peroxisome proliferator-activated receptor alpha (PPARalpha). The top ranking drug matches were docked to the peptide-binding site using AUTODOCK. The majority of the top-ranking matches showed a negative estimated free energy change upon binding that is comparable to, or greater than, that of the original peptide. We conclude that the usage of certain approved drugs may represent a useful strategy in inhibiting specific protein-protein interactions. Such a strategy may benefit from the increased likelihood that developed compounds might have favorable bioactivity and safety profiles in clinical use.

  17. CHARACTERIZATION OF DRUG INTERACTIONS WITH SERUM PROTEINS BY USING HIGH-PERFORMANCE AFFINITY CHROMATOGRAPHY

    PubMed Central

    Hage, David S.; Anguizola, Jeanethe; Barnaby, Omar; Jackson, Abby; Yoo, Michelle J.; Papastavros, Efthimia; Pfaunmiller, Erika; Sobansky, Matt; Tong, Zenghan

    2011-01-01

    The binding of drugs with serum proteins can affect the activity, distribution, rate of excretion, and toxicity of pharmaceutical agents in the body. One tool that can be used to quickly analyze and characterize these interactions is high-performance affinity chromatography (HPAC). This review shows how HPAC can be used to study drug-protein binding and describes the various applications of this approach when examining drug interactions with serum proteins. Methods for determining binding constants, characterizing binding sites, examining drug-drug interactions, and studying drug-protein dissociation rates will be discussed. Applications that illustrate the use of HPAC with serum binding agents such as human serum albumin, α1-acid glycoprotein, and lipoproteins will be presented. Recent developments will also be examined, such as new methods for immobilizing serum proteins in HPAC columns, the utilization of HPAC as a tool in personalized medicine, and HPAC methods for the high-throughput screening and characterization of drug-protein binding. PMID:21395530

  18. Efflux transporters- and cytochrome P-450-mediated interactions between drugs of abuse and antiretrovirals☆

    PubMed Central

    Pal, Dhananjay; Kwatra, Deep; Minocha, Mukul; Paturi, Durga K.; Budda, Balasubrahmanyam; Mitra, Ashim K.

    2010-01-01

    Multidrug regimens and corresponding drug interactions cause many adverse reactions and treatment failures. Drug efflux transporters: P-gp, MRP, BCRP in conjunction with metabolizing enzymes (CYPs) are major factors in such interactions. Most effective combination antiretrovirals (ARV) therapy includes a PI or a NNRTI or two NRTI. Coadministration of such ARV may induce efflux transporters and/or CYP3A4 resulting in sub-therapeutic blood levels and therapeutic failure due to reduced absorption and/or increased metabolism. A similar prognosis is true for ARV-compounds and drugs of abuse combinations. Morphine and nicotine enhance CYP3A4 and MDR1 expression in vitro. A 2.5 fold rise of cortisol metabolite was evident in smokers relative to nonsmokers. Altered functions of efflux transporters and CYPs in response to ARV and drugs of abuse may result in altered drug absorption and metabolism. Appropriate in vitro models can be employed to predict such interactions. Influence of genetic polymorphism, SNP and inter-individual variation in drug response has been discussed. Complexity underlying the relationship between efflux transporters and CYP makes it difficult to predict the outcome of HAART as such, particularly when HIV patients taking drugs of abuse do not adhere to HAART regimens. HIV+ pregnant women on HAART medications, indulging in drugs of abuse, may develop higher viral load due to such interactions and lead to increase in mother to child transmission of HIV. A multidisciplinary approach with clear understanding of mechanism of interactions may allow proper selection of regimens so that desired therapeutic outcome of HAART can be reached without any side effects. PMID:20932495

  19. Drug-Alcohol Interactions Among Older Adults in the United States

    PubMed Central

    Qato, Dima M.; Manzoor, Beenish S.; Lee, Todd

    2015-01-01

    Objectives The older adult population in the United States (U.S.) uses multiple medications and more than half of older adults drink alcohol regularly. In addition, older adults are more likely to experience adverse effects of medications and alcohol consumption may put them at higher risk. Our primary objective is to characterize the extent and nature of drug-alcohol interactions among older adults in the U.S. Design, Setting, Participants, Measurements We used a nationally-representative population-based sample of community-dwelling older adults in the U.S. Regular drinkers were defined as respondents that consumed alcohol at least weekly. Medication use was defined as the use of a prescription or non-prescription medication or dietary supplement at least daily or weekly. Micromedex was used to determine drug interactions with alcohol and their corresponding severity. Results Among the 2,975 older adults in the sample, more than 41% (N=1106) consume alcohol regularly and more than 20% (N=567) are at-risk for a drug-alcohol interaction because they are regular drinkers and concurrently using alcohol interacting medications. More than 90% of these interactions were of moderate or major severity. Antidepressants and analgesics were the most commonly used alcohol-interacting medications among regular drinkers. Older adult men with multiple chronic conditions had the highest prevalence of potential drug-alcohol interactions. Conclusion The potential for drug-alcohol interactions among the older adult population in the U.S. may have important clinical implications. Efforts to better understand and prevent the use of alcohol-interacting medications among regular drinkers, particularly heavy drinkers, are warranted in this population. PMID:26503899

  20. Inhibition of cytochrome P450 3A: relevant drug interactions in gastroenterology.

    PubMed

    Sagir, A; Schmitt, M; Dilger, K; Häussinger, D

    2003-01-01

    Cytochrome P450 3A (CYP3A) is involved in biotransformation of more than half of all drugs currently available. Drug interactions by inhibition of CYP3A are of major interest in patients receiving combinations of drugs. Some interactions with CYP3A inhibitors also involve inhibition of the multidrug export pump, P-glycoprotein. An increasing number of adverse drug reactions might be avoided on the basis of knowledge about CYP3A substrates and inhibitors. This article summarizes some examples of such interactions relevant to gastroenterologists. Serious cases by coadministration of CYP3A inhibitors resulting in acute hepatitis, hypotension, rhabdomyolyis, torsade de pointes, sedation, or ergotism are presented: interactions with azole antifungals (ketoconazole, itraconazole, fluconazole), HIV protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir), macrolide antibiotics (clarithromycin, erythromycin), and grapefruit juice. In addition, 1 case is reported who presented the highest trough levels of the CYP3A substrate budesonide in serum ever measured. Practitioners have to be aware of the high potential of metabolic drug interactions when they prescribe a CYP3A inhibitor. It is wise to check carefully comedication in patients complaining of side effects with substrates of CYP3A.

  1. Adherence to Guidelines for Avoiding Drug Interactions Associated with Warfarin - A Nationwide Swedish Register Study

    PubMed Central

    Lindh, Jonatan D.; Andersson, Marine L.; Mannheimer, Buster

    2014-01-01

    Purpose To investigate the extent to which clinicians avoid well-established drug-drug interactions associated with warfarin. We hypothesised that clinicians would avoid combining non-steroidal anti-inflammatory drugs (NSAIDs), tramadol and sulfamethoxazole with warfarin. Methods A cross-sectional analysis of nationwide dispensing data was performed in Swedish individuals 18 years or older (n =  7 563 649). Odds ratios of interacting NSAIDs, tramadol and sulfamethoxazole versus respective prevalence of comparator drugs codeine, and ciprofloxacin in patients co-dispensed interacting warfarin versus patients unexposed was calculated. Results The odds of receiving an interacting NSAID versus the comparator codeine was markedly lower in patients with warfarin than in the remaining population (adjusted OR 0.21; 95% CI 0.20 – 0.22). Also, the interacting drugs tramadol and sulfamethoxazole were less common among patients dispensed warfarin as compared to the remaining population, although the decrease was much more modest (adjusted OR 0.83; CI 0.80–0.87 and 0.81; CI 0.73 – 0.90). Conclusions In conclusion, Swedish doctors in the vast majority of cases refrain from prescribing NSAIDs to patients already on warfarin. Tramadol and sulfamethoxazole are however rarely avoided. PMID:24830709

  2. Nonlinear response surface in the study of interaction analysis of three combination drugs

    PubMed Central

    Wan, Wen; Pei, Xin-Yan; Grant, Steven; Birch, Jeffrey B.; Felthousen, Jessica; Dai, Yun; Fang, Hong-Bin; Tan, Ming; Sun, Shumei

    2016-01-01

    Few articles have been written on analyzing three-way interactions between drugs. It may seem to be quite straightforward to extend a statistical method from two-drugs to three-drugs. However, there may exist more complex nonlinear response surface of the interaction index