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Sample records for minimizing drug interactions

  1. Drug Interactions

    PubMed Central

    Tong Logan, Angela; Silverman, Andrew

    2012-01-01

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

  2. Drug Interactions

    MedlinePlus

    ... not be taken at the same time as antacids. WHAT CAUSES THE MOST INTERACTIONS WITH HIV MEDICATIONS? ... azole” Some antibiotics (names end in “mycin”) The antacid cimetidine (Tagamet) Some drugs that prevent convulsions, including ...

  3. Food-Drug Interactions

    PubMed Central

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

    2011-01-01

    The effect of drug on a person may be different than expected because that drug interacts with another drug the person is taking (drug-drug interaction), food, beverages, dietary supplements the person is consuming (drug-nutrient/food interaction) or another disease the person has (drug-disease interaction). A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. These interactions may occur out of accidental misuse or due to lack of knowledge about the active ingredients involved in the relevant substances. Regarding food-drug interactions physicians and pharmacists recognize that some foods and drugs, when taken simultaneously, can alter the body's ability to utilize a particular food or drug, or cause serious side effects. Clinically significant drug interactions, which pose potential harm to the patient, may result from changes in pharmaceutical, pharmacokinetic, or pharmacodynamic properties. Some may be taken advantage of, to the benefit of patients, but more commonly drug interactions result in adverse drug events. Therefore it is advisable for patients to follow the physician and doctors instructions to obtain maximum benefits with least food-drug interactions. The literature survey was conducted by extracting data from different review and original articles on general or specific drug interactions with food. This review gives information about various interactions between different foods and drugs and will help physicians and pharmacists prescribe drugs cautiously with only suitable food supplement to get maximum benefit for the patient. PMID:22043389

  4. Drug Interactions and Antiretroviral Drug Monitoring

    PubMed Central

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

    2014-01-01

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

  5. Adverse Drug Interactions

    PubMed Central

    Becker, Daniel E.

    2011-01-01

    The potential for interactions with current medications should always be considered when administering or prescribing any drug. Considering the staggering number of drugs patients may be taking, this task can be daunting. Fortunately, drug classes employed in dental practice are relatively few in number and therapy is generally brief in duration. While this reduces the volume of potential interactions, there are still a significant number to be considered. This article will review basic principles of drug interactions and highlight those of greatest concern in dental practice. PMID:21410363

  6. Drug Interaction and Pharmacist

    PubMed Central

    Ansari, JA

    2010-01-01

    The topic of drug–drug interactions has received a great deal of recent attention from the regulatory, scientific, and health care communities worldwide. Nonsteroidal anti-inflammatory drugs, antibiotics and, in particular, rifampin are common precipitant drugs prescribed in primary care practice. Drugs with a narrow therapeutic range or low therapeutic index are more likely to be the objects for serious drug interactions. Object drugs in common use include warfarin, fluoroquinolones, antiepileptic drugs, oral contraceptives, cisapride, and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. The pharmacist, along with the prescriber has a duty to ensure that patients are aware of the risk of side effects and a suitable course of action should they occur. With their detailed knowledge of medicine, pharmacists have the ability to relate unexpected symptoms experienced by patients to possible adverse effects of their drug therapy. PMID:21042495

  7. 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

  8. Adverse antibiotic drug interactions.

    PubMed

    Bint, A J; Burtt, I

    1980-07-01

    There is enormous potential for drug interactions in patients who, today, often receive many drugs. Antibiotics are prominent amongst the groups of drugs commonly prescribed. Many interactions take place at the absorption stage. Antacids and antidiarrhoeal preparations, in particular, can delay and reduce the absorption of antibiotics such as tetracyclines and clindamycin, by combining with them in the gastrointestinal tract to form chelates or complexes. Other drugs can affect gastric motility, which in turn often controls the rate at which antibiotics are absorbed. Some broad spectrum antibiotics can alter the bacterial flora of the gut which may be related to malabsorption states. The potentiation of toxic side effects of one drug by another is a common type of interaction. Antibiotics which are implicated in this type of interaction are those which themselves possess some toxicity such as aminoglycosides, some cephalosporins, tetracyclines and colistin. Some of the most important adverse interactions with antibiotics are those which involve other drugs which have a low toxicity/efficacy ratio. These include anticoagulants such as warfarin, anticonvulsants such as phenytoin and phenobarbitone and oral antidiabetic drugs like tolbutamide. Risk of interaction arises when the metabolism of these drugs is inhibited by liver microsomal enzyme inhibitors such as some sulphonamides and chloramphenicol, or is enhanced by enzyme inducers such as rifampicin. PMID:6995091

  9. Serious drug interactions.

    PubMed

    Aronson, J

    1993-10-01

    Of the many varieties of drug interactions, which occur when the disposition or actions of one drug are changed by another, only a few are serious or potentially fatal. A representative outline of some of these illustrates the problem. Precipitant drugs are those which produce the interaction, and object drugs are those whose effects are changed. The interactions which are usually significant are those which alter the metabolism, involve renal excretion, or change the effects of the object drug, especially when the object drug has a low therapeutic index (cardiovascular drugs, anticoagulants, drugs acting on the brain, hypoglycemic drugs, hormones, and cytotoxic drugs). Warfarin toxicity, for example, is produced by aspirin, phenylbutazone, and azapropazone. The dosage requirements of warfarin are reduced by chloramphenicol, ciprofloxacin and other quinolones, erythromycin and some of the other macrolides, metronidazole and other imidazoles, tetracyclines, amiodarone, cimetidine (but not ranitidine), and fibrates. Potassium-depleting drugs can potentiate the action of digoxin, and the elimination of digoxin can be reduced by amiodarone, propafenone, quinidine, and verapamil. Combined oral contraceptives can lose effectiveness through the interaction of carbamazepine, griseofulvin, phenytoin, or rifampicin, which increase estrogen metabolism. In addition, broad-spectrum antibiotics such as ampicillin or tetracyclines also reduce contraceptive effectiveness by altering gut absorption. Even a single drink of an alcoholic beverage may be dangerous to people taking antidepressants, antihistamines, antipsychotic drugs, benzodiazepines, or lithium. Antihistamines suffer inhibited metabolism in the liver if taken in conjunction with the antifungal imidazoles and some of the macrolide antibiotics. Cardiotoxicity of antihistamines is also enhanced by drugs with similar cardiotoxic effects. Lithium potentiation is enhanced by the new serotonin-reuptake inhibitors, and lithium

  10. Antiplatelet drug interactions.

    PubMed

    Mackenzie, I S; Coughtrie, M W H; MacDonald, T M; Wei, L

    2010-12-01

    Both laboratory studies in healthy volunteers and clinical studies have suggested adverse interactions between antiplatelet drugs and other commonly used medications. Interactions described include those between aspirin and ibuprofen, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), and the thienopyridine, clopidogrel, and drugs inhibiting CYP2C19, notably the proton pump inhibitors (PPI) omeprazole and esomeprazole. Other interactions between thienopyridines and CYP3A4/5 have also been reported for statins and calcium channel blockers. The ibuprofen/aspirin interaction is thought to be caused by ibuprofen blocking the access of aspirin to platelet cyclo-oxygenase. The thienopyridine interactions are caused by inhibition of microsomal enzymes that metabolize these pro-drugs to their active metabolites. We review the evidence for these interactions, assess their clinical importance and suggest strategies of how to deal with them in clinical practice. We conclude that ibuprofen is likely to interact with aspirin and reduce its anti-platelet action particularly in those patients who take ibuprofen chronically. This interaction is of greater relevance to those patients at high cardiovascular risk. A sensible strategy is to advise users of aspirin to avoid chronic ibuprofen or to ingest aspirin at least 2 h prior to ibuprofen. Clearly the use of NSAIDs that do not interact in this way is preferred. For the clopidogrel CYP2C19 and CYP3A4/5 interactions, there is good evidence that these interactions occur. However, there is less good evidence to support the clinical importance of these interactions. Again, a reasonable strategy is to avoid the chronic use of drugs that inhibit CYP2C19, notably PPIs, in subjects taking clopidogrel and use high dose H2 antagonists instead. Finally, anti-platelet agents probably interact with other drugs that affect platelet function such as selective serotonin reuptake inhibitors, and clinicians should probably judge

  11. Oral contraceptive drug interactions.

    PubMed

    Baciewicz, A M

    1985-01-01

    Approximately 50 million women use oral contraceptives (OC). Studies and case reports demonstrate that OC failure may be caused by rifampin, anticonvulsant drugs, and possibly some antibiotics. Contraceptive steroids may interfere with the metabolism of the benzodiazepines, theophylline, and the glucocorticoids. Future investigation will document the clinical significance of other OC interactions as well as give rise to new interactions. PMID:2859674

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

    PubMed

    Krüger, K

    2012-04-01

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

  13. Drugging Membrane Protein Interactions.

    PubMed

    Yin, Hang; Flynn, Aaron D

    2016-07-11

    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 cells 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 of 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

  14. [Unexpected drug-interaction].

    PubMed

    Tajima, Yutaka

    2002-02-01

    The case of a male patient suffering from chronic normal pressure hydrocephalus is outlined. Antidepressant and pravastatin were administered because of the patient's abulia and hypercholesterolemia, but neuroleptic malignant syndrome-like conditions developed. All physicians should suppose the occurrence of such an "unexpected drug-interaction" in any case. The author considered that a good sense of careful discernment and rapid reference system of medical information are "essential tools" for clinical management. PMID:11925849

  15. Suppressive drug interactions between antifungals.

    PubMed

    de Vos, Marjon G J; Bollenbach, Tobias

    2014-04-24

    In this issue of Chemistry & Biology, Cokol and colleagues report a systematic study of drug interactions between antifungal compounds. Suppressive drug interactions occur more frequently than previously realized and come in different flavors with interesting implications. PMID:24766845

  16. 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

  17. Clinical nutrition and drug interactions

    PubMed Central

    Ekincioğlu, Aygin Bayraktar; Demirkan, Kutay

    2013-01-01

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

  18. Aprepitant: drug-drug interactions in perspective.

    PubMed

    Aapro, M S; Walko, C M

    2010-12-01

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

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

    PubMed

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

    1988-07-01

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

  20. 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

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

    PubMed

    Suzuki, Eiji

    2015-01-01

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

  2. 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. PMID:20566446

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

    PubMed

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

    2015-10-15

    The combination of aspirin and the thienopyridine clopidogrel is a cornerstone in the prevention of atherothrombotic events. These two agents act in concert to ameliorate the prothrombotic processes stimulated by plaque rupture and vessel injury complicating cardiovascular disease. Guidelines recommend the use of clopidogrel in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention, and the drug remains the most utilized P2Y12 receptor inhibitor despite the fact that newer antiplatelet agents are now available. In recent years, numerous studies have shown inconsistency in the efficacy of clopidogrel to prevent atherothrombotic events. Studies of platelet function testing have shown variability in the response to clopidogrel. One of the major reason for this phenomenon lies in the interaction between clopidogrel and other drugs that may affect clopidogrel absorption, metabolism, and ultimately its antiplatelet action. Importantly, these drug-drug interactions have prognostic implications, since patients with high on-treatment platelet reactivity associated with reduced clopidogrel metabolism have an increased risk of ischemia. Previous systematic reviews have focused on drug-drug interactions between clopidogrel and specific pharmacologic classes, such as proton pump inhibitors, calcium channel blockers, and statins. However, more recent pieces of scientific evidence show that clopidogrel may also interact with newer drugs that are now available for the treatment of cardiovascular patients. Accordingly, the aim of this review is to highlight and discuss recent data on drug-drug interactions between clopidogrel and third-generation proton pump inhibitors, pantoprazole and lansoprazole, statins, pitavastatin, and antianginal drug, ranolazine. PMID:26341013

  4. Drug interactions with grapefruit juice.

    PubMed

    Ameer, B; Weintraub, R A

    1997-08-01

    Some drugs demonstrate a significantly greater (up to 3-fold) mean oral bioavailability on coadministration with grapefruit juice. With some calcium antagonists, the benzodiazepines midazolam and triazolam and the antihistamine terfenadine, changes in bioavailability are accompanied by altered drug action. Study design factors possibly contribute to the magnitude of changes in drug bioavailability; they include the source of the citrus, its intake schedule, drug formulations and individual metabolising capacity. The components of citrus juice that are responsible for clinical drug interactions have yet to be fully determined. Based on the flavonoid naringin's unique distribution in the plant kingdom, abundance in grapefruit and ability to inhibit metabolic enzymes, naringin is likely to be one of the grapefruit components influencing drug metabolism. Other components present in citrus fruit, such as furanocoumarins, may be more potent inhibitors than flavonoids and are under investigation. Conclusions drawn from clinical drug interaction studies should be considered specific to the citrus fruit products evaluated because of the variation in their natural product content. The predominant mechanism for enhanced bioavailability is presumably the inhibition of oxidative drug metabolism in the small intestine. The consistent findings across studies of diverse cytochrome P450 (CYP) 3A substrates support the mechanistic hypothesis that 1 or more grapefruit juice components inhibit CYP3A enzymes in the gastrointestinal tract. The evaluation of the need to avoid the concomitant intake of grapefruit products with drugs is best done on an individual drug basis rather than collectively by drug class. Based on the narrow therapeutic range of cyclosporin and research experience in organ transplant recipients, its interaction with grapefruit juice is likely to be clinically significant. PMID:9260034

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

    PubMed

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

    2016-04-01

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

  6. Pharmacokinetic drug interactions of macrolides.

    PubMed

    Periti, P; Mazzei, T; Mini, E; Novelli, A

    1992-08-01

    The macrolide antibiotics include natural members, prodrugs and semisynthetic derivatives. These drugs are indicated in a variety of infections and are often combined with other drug therapies, thus creating the potential for pharmacokinetic interactions. Macrolides can both inhibit drug metabolism in the liver by complex formation and inactivation of microsomal drug oxidising enzymes and also interfere with microorganisms of the enteric flora through their antibiotic effects. Over the past 20 years, a number of reports have incriminated macrolides as a potential source of clinically severe drug interactions. However, differences have been found between the various macrolides in this regard and not all macrolides are responsible for drug interactions. With the recent advent of many semisynthetic macrolide antibiotics it is now evident that they may be classified into 3 different groups in causing drug interactions. The first group (e.g. troleandomycin, erythromycins) are those prone to forming nitrosoalkanes and the consequent formation of inactive cytochrome P450-metabolite complexes. The second group (e.g. josamycin, flurithromycin, roxithromycin, clarithromycin, miocamycin and midecamycin) form complexes to a lesser extent and rarely produce drug interactions. The last group (e.g. spiramycin, rokitamycin, dirithromycin and azithromycin) do not inactivate cytochrome P450 and are unable to modify the pharmacokinetics of other compounds. It appears that 2 structural factors are important for a macrolide antibiotic to lead to the induction of cytochrome P450 and the formation in vivo or in vitro of an inhibitory cytochrome P450-iron-nitrosoalkane metabolite complex: the presence in the macrolide molecules of a non-hindered readily accessible N-dimethylamino group and the hydrophobic character of the drug. Troleandomycin ranks first as a potent inhibitor of microsomal liver enzymes, causing a significant decrease of the metabolism of methylprednisolone, theophylline

  7. [Drug interactions with contraceptive methods].

    PubMed

    Simon, P; Hakkou, F; Warot, D

    1984-03-01

    3 possible types of drug interactions with contraceptives involve oral contraceptives (OCs), IUDs, and spermicides. The interaction of combined OCs with various drugs is frequently discussed in the literature, but the reported facts are sometimes contradictory. Case studies have indicated failure of OCs in patients taking ampicillin, but comparative studies using ampicillin and placebos have shown no difference in rates of estrogen, progestogens, follicle stimulating hormone, or luteinizing hormone in the 2 groups. Individual differences and predispositions among some women appear to play a role in drug interactions. The clinician should be wary of modifying accepted prescription practices too readily in the face of findings that may be explained by other as yet undisclosed factors. Interactions are difficult to establish, as are their mechanisms. They may perhaps be explained by the estrogen or progestogen components of the pills, the timing of the antibiotic dose, the duration of treatment and the dosage used, resistance of the intestinal flora, self-medication, or other factors. The drug troleandomycin is a special case; it appears to favor the already existing tendency of OCs to provoke cholestatic jaundice. A table of drug interactions with OCs can be divided into 2 parts, those that have been confirmed and whose mechanisms of action are known, including antiepileptics such as phenobarbital, butobarbital, phenytoin, and primidone, and the drug rifampicin, which are enzyme inductors; and those that are suspected but as yet unconfirmed and whose mechanism of action is not established. The unconfirmed interactions involve a variety of effects in addition to pregnancy. It is not yet established whether enzyme inductors are a greater problem for users of low-dose pills, but the probable existence of individual variations in sensitivity causes problems in setting recommendations applicable to all patients. Interactions between progestogen-only OCs and other drugs

  8. Potential drug interactions with melatonin.

    PubMed

    Papagiannidou, Eleni; Skene, Debra J; Ioannides, Costas

    2014-05-28

    Possible interactions of melatonin with concurrently administered drugs were investigated in in vitro studies utilising human hepatic post-mitochondrial preparations; similar studies were conducted with rat preparations to ascertain whether rat is a suitable surrogate for human. Drugs were selected based not only on the knowledge that the 6-hydroxylation of exogenous melatonin, its principal pathway of metabolism, is mainly mediated by hepatic CYP1A2, but also on the likelihood of the drug being concurrently administered with melatonin. Hepatic preparations were incubated with either melatonin or 6-hydroxymelatonin in the presence and absence of a range of concentrations of interacting drug, and the production of 6-sulphatoxymelatonin monitored using a radioimmunoassay procedure. Of the drugs screened, only the potent CYP1A2 inhibitor 5-methoxypsoralen impaired the 6-melatonin hydroxylation at pharmacologically relevant concentrations, and is likely to lead to clinical interactions; diazepam, tamoxifen and acetaminophen (paracetamol) did not impair the metabolic conversion of melatonin to 6-sulphatoxymelatonin at concentrations attained following therapeutic administration. 17-Ethinhyloestradiol appeared not to suppress the 6-hydroxylation of melatonin but inhibited the sulphation of 6-hydroxymelatonin, but this is unlikely to result in an interaction following therapeutic intake of the steroid. Species differences in the inhibition of melatonin metabolism in human and rat hepatic post-mitochondrial preparations were evident implying that the rat may not be an appropriate surrogate of human in such studies. PMID:24732412

  9. A new multiple-drug applicator with minimal drug cross-talk, leakage, and consumption.

    PubMed

    Fujita, Yosuke; Shimomura, Takeshi; Hosoguchi, Masafumi; Kano, Masanobu; Fukurotani, Kenkichi; Tabata, Toshihide

    2010-04-01

    The relative effects of multiple drugs give an important clue to dissect a neuronal mechanism and to seek for a candidate neurotherapeutical agent. Here we have devised a "flute" applicator which can deliver several drugs to a neural cell preparation. The applicator stands by, cleaning itself with bath perfusate and delivers drugs only during test applications. This minimizes drug cross-talk in and leakage from the applicator and drug consumption. Using the applicator, we successfully compared the relative effects of widely different doses of an agonist in single neurons. The flute applicator would be a useful tool for pharmacological analyses. PMID:20060427

  10. Comparative assessment of four drug interaction compendia

    PubMed Central

    Vitry, Agnes I

    2007-01-01

    Aims To assess the consistency of inclusion and grading of major drug interactions for 50 drugs in four leading international drug interaction compendia. Methods Four international drug interaction compendia were compared: the drug interactions appendix of the British National Formulary, the interaction supplement in the French drug compendium Vidal, and two US drug interaction compendia, Drug Interaction Facts and the Micromedex (Drug-Reax) program. Major interactions were defined as potentially hazardous in BNF or with the warning ‘contraindication’ or ‘avoid’ in Vidal or with the significance grading 1 or 2 in DIF. Major interactions for a list of 50 drugs were searched in all four compendia. Results A total of 1264 interactions meeting the inclusion criteria were identified for these 50 drugs. After deletion of 169 duplicates, 1095 interactions were included in the analysis. Of the drug interactions classified as major in any one compendium between 14% and 44% were not listed in the other compendia. The grading systems used for the severity and the quality of the supporting evidence in Micromedex and DIF were inconsistent. Conclusions There is a lack of consistency in the inclusion and grading of drug interactions of major significance for 50 drugs across the four drug compendia examined. This may reflect the lack of standardization of the terminology used to classify drug interactions and the lack of good epidemiological evidence on which to base the assessment of the clinical relevance of drug interactions. PMID:17166171

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

    PubMed

    Samardzic, I; Bacic-Vrca, V

    2015-06-01

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

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

    PubMed

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

    2016-09-01

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

  14. Grapefruit juice–drug interactions

    PubMed Central

    Bailey, David G; Malcolm, J; Arnold, O; David Spence, J

    1998-01-01

    The novel finding that grapefruit juice can markedly augment oral drug bioavailability was based on an unexpected observation from an interaction study between the dihydropyridine calcium channel antagonist, felodipine, and ethanol in which grapefruit juice was used to mask the taste of the ethanol. Subsequent investigations showed that grapefruit juice acted by reducing presystemic felodipine metabolism through selective post-translational down regulation of cytochrome P450 3A4 (CYP3A4) expression in the intestinal wall. Since the duration of effect of grapefruit juice can last 24 h, repeated juice consumption can result in a cumulative increase in felodipine AUC and Cmax. The high variability of the magnitude of effect among individuals appeared dependent upon inherent differences in enteric CYP3A4 protein expression such that individuals with highest baseline CYP3A4 had the highest proportional increase. At least 20 other drugs have been assessed for an interaction with grapefruit juice. Medications with innately low oral bioavailability because of substantial presystemic metabolism mediated by CYP3A4 appear affected by grapefruit juice. Clinically relevant interactions seem likely for most dihydropyridines, terfenadine, saquinavir, cyclosporin, midazolam, triazolam and verapamil and may also occur with lovastatin, cisapride and astemizole. The importance of the interaction appears to be influenced by individual patient susceptibility, type and amount of grapefruit juice and administration-related factors. Although in vitro findings support the flavonoid, naringin, or the furanocoumarin, 6′,7′-dihydroxybergamottin, as being active ingredients, a recent investigation indicated that neither of these substances made a major contribution to grapefruit juice-drug interactions in humans. PMID:9723817

  15. Drug Interactions: What You Should Know

    MedlinePlus

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

  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. Hazards and Benefits of Drug Interaction

    ERIC Educational Resources Information Center

    Labianca, Dominick A.

    1978-01-01

    Most cases of drug toxicity are direct consequences of drug misuse--either intentional or inadvertent. Discusses two types of drug interaction--synergistic and antagonistic. The former produces a combined effect greater than the sum of the effects of the individual drugs concerned; the latter is produced when the desired action of one drug is…

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

    PubMed

    Hennessy, S; Flockhart, D A

    2012-05-01

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

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

    PubMed

    Zavrsnik, Davorka; Spirtović, Selma; Becić, Fahir

    2006-01-01

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

  20. Drug-pyridoxal phosphate interactions.

    PubMed

    Ebadi, M; Gessert, C F; Al-Sayegh, A

    1982-01-01

    In this review it has been pointed out that vitamin B6 and its vitamers can be involved in many interactions with a number of drugs, as well as with the actions of various endocrines and neurotransmitters. Nutritional deficiencies, especially of vitamins and proteins, can affect the manner in which drugs undergo biotransformation, and thereby may also modify the therapeutic efficacy of certain drugs. The differences between nutritional vitamin B6 deficiency and the hereditary disorder producing pyridoxine dependency are discussed. In addition to a pyridoxine deficiency being able to adversely affect drug actions, the improper supplementation with vitamin B6 can in some instances also adversely affect drug efficacy. A decrease by pyridoxine in the efficacy of levodopa used in the treatment of Parkinsonism is an example. The interrelationships and enzymatic interconversions among pyridoxine vitamers, both phosphorylated and non-phosphorylated, are briefly discussed, particularly regarding their pharmacokinetic properties. The ways in which the normal biochemical functions of vitamin B6 may be interfered with by various drugs are reviewed. (1) The chronic administration of isoniazid for the prevention or treatment of tuberculosis can produce peripheral neuropathy which can be prevented by the concurrent administration of pyridoxine. An acute toxic overdose of isoniazid causes generalized convulsions, and the intravenous administration of pyridoxine hydrochloride will prevent or stop these seizures. (2) The acute ingestion of excessive monosodium glutamate will, in some individuals, cause a group of symptoms including among others headache, weakness, stiffness, and heartburn, collectively known as the 'Chinese Restaurant Syndrome.' These symptoms can be prevented by prior supplementation with vitamin B6. The beneficial effect is ascribed to the correction of a deficiency in the activity of glutamic oxaloacetic transaminase, an enzyme that is dependent on pyridoxal

  1. Psychotropics and drug interactions in the elderly patient.

    PubMed

    Katona, C L

    2001-12-01

    This short paper attempts to provide a framework to aid the old-age psychiatrist in choosing psychotropic drugs in a way that minimizes the risks of adverse drug reactions. It concentrates on the clinical problems most frequently encountered in old-age psychiatric practice. Older people are at risk of adverse drug interactions because of their higher rate of physical morbidity and increased likelihood of receiving polypharmacy, as well as due to age-related change in drug handling. The strongest evidence for relevant interactions in older people relates to changes in renal excretion (particularly relevant for lithium) and cytochrome P450 (relevant for a wide range of psychotropic and other drugs). Awareness of potential interactions is important in ensuring safe prescribing practice for older people with mental health problems. PMID:11748792

  2. [Drug interaction and estroprogestin efficacy].

    PubMed

    Rozenbaum, H

    1977-01-01

    Various mechanisms exist in female physiology which can impair the contraceptive action of estroprogestins. These hormones can be susceptivle to absorption by certain bacterial flora within the digestive tract. Some drugs, notably the cytochrome P 450, lead to the rapid deterioration of the sexual hormones. Estroprogestins and estrogens themselves are susceptible to modification by the action of protein plasma clearance. Through the inhibition of the excretion of hepatic enzymes, other hepatic metabolisms can be altered affecting the balance and metabolism of the sexual hormones. Certain phenomena of fixation competition exist at the receptor level, particularly in regard to corticoids. Estroprogestins are also noted to diminish the efficacy of anticoagulants dependent on Vitamin-K. The interaction of estroprogestins and certain medications, often used in conjunctive treatment, can reduce both the contraceptive efficacy of the hormone and of the other preparation. PMID:12260077

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

    PubMed

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

    2011-01-01

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

  4. 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)

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

    PubMed

    Berenguer Berenguer, Juan; González-García, Juan

    2013-07-01

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

  6. Minimal metabolic pathway structure is consistent with associated biomolecular interactions

    PubMed Central

    Bordbar, Aarash; Nagarajan, Harish; Lewis, Nathan E; Latif, Haythem; Ebrahim, Ali; Federowicz, Stephen; Schellenberger, Jan; Palsson, Bernhard O

    2014-01-01

    Pathways are a universal paradigm for functionally describing cellular processes. Even though advances in high-throughput data generation have transformed biology, the core of our biological understanding, and hence data interpretation, is still predicated on human-defined pathways. Here, we introduce an unbiased, pathway structure for genome-scale metabolic networks defined based on principles of parsimony that do not mimic canonical human-defined textbook pathways. Instead, these minimal pathways better describe multiple independent pathway-associated biomolecular interaction datasets suggesting a functional organization for metabolism based on parsimonious use of cellular components. We use the inherent predictive capability of these pathways to experimentally discover novel transcriptional regulatory interactions in Escherichia coli metabolism for three transcription factors, effectively doubling the known regulatory roles for Nac and MntR. This study suggests an underlying and fundamental principle in the evolutionary selection of pathway structures; namely, that pathways may be minimal, independent, and segregated. PMID:24987116

  7. Minimal metabolic pathway structure is consistent with associated biomolecular interactions.

    PubMed

    Bordbar, Aarash; Nagarajan, Harish; Lewis, Nathan E; Latif, Haythem; Ebrahim, Ali; Federowicz, Stephen; Schellenberger, Jan; Palsson, Bernhard O

    2014-01-01

    Pathways are a universal paradigm for functionally describing cellular processes. Even though advances in high-throughput data generation have transformed biology, the core of our biological understanding, and hence data interpretation, is still predicated on human-defined pathways. Here, we introduce an unbiased, pathway structure for genome-scale metabolic networks defined based on principles of parsimony that do not mimic canonical human-defined textbook pathways. Instead, these minimal pathways better describe multiple independent pathway-associated biomolecular interaction datasets suggesting a functional organization for metabolism based on parsimonious use of cellular components. We use the inherent predictive capability of these pathways to experimentally discover novel transcriptional regulatory interactions in Escherichia coli metabolism for three transcription factors, effectively doubling the known regulatory roles for Nac and MntR. This study suggests an underlying and fundamental principle in the evolutionary selection of pathway structures; namely, that pathways may be minimal, independent, and segregated. PMID:24987116

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

    PubMed

    Sørensen, Janina Maria

    2002-06-01

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

  9. Systematic discovery of drug interaction mechanisms

    PubMed Central

    Chevereau, Guillaume; Bollenbach, Tobias

    2015-01-01

    Drug combinations are increasingly important in disease treatments, for combating drug resistance, and for elucidating fundamental relationships in cell physiology. When drugs are combined, their individual effects on cells may be amplified or weakened. Such drug interactions are crucial for treatment efficacy, but their underlying mechanisms remain largely unknown. To uncover the causes of drug interactions, we developed a systematic approach based on precise quantification of the individual and joint effects of antibiotics on growth of genome-wide Escherichia coli gene deletion strains. We found that drug interactions between antibiotics representing the main modes of action are highly robust to genetic perturbation. This robustness is encapsulated in a general principle of bacterial growth, which enables the quantitative prediction of mutant growth rates under drug combinations. Rare violations of this principle exposed recurring cellular functions controlling drug interactions. In particular, we found that polysaccharide and ATP synthesis control multiple drug interactions with previously unexplained mechanisms, and small molecule adjuvants targeting these functions synthetically reshape drug interactions in predictable ways. These results provide a new conceptual framework for the design of multidrug combinations and suggest that there are universal mechanisms at the heart of most drug interactions. PMID:25924924

  10. Systematic discovery of drug interaction mechanisms.

    PubMed

    Chevereau, Guillaume; Bollenbach, Tobias

    2015-04-01

    Drug combinations are increasingly important in disease treatments, for combating drug resistance, and for elucidating fundamental relationships in cell physiology. When drugs are combined, their individual effects on cells may be amplified or weakened. Such drug interactions are crucial for treatment efficacy, but their underlying mechanisms remain largely unknown. To uncover the causes of drug interactions, we developed a systematic approach based on precise quantification of the individual and joint effects of antibiotics on growth of genome-wide Escherichia coli gene deletion strains. We found that drug interactions between antibiotics representing the main modes of action are highly robust to genetic perturbation. This robustness is encapsulated in a general principle of bacterial growth, which enables the quantitative prediction of mutant growth rates under drug combinations. Rare violations of this principle exposed recurring cellular functions controlling drug interactions. In particular, we found that polysaccharide and ATP synthesis control multiple drug interactions with previously unexplained mechanisms, and small molecule adjuvants targeting these functions synthetically reshape drug interactions in predictable ways. These results provide a new conceptual framework for the design of multidrug combinations and suggest that there are universal mechanisms at the heart of most drug interactions. PMID:25924924

  11. Drug interaction in the emergency service

    PubMed Central

    Okuno, Meiry Fernanda Pinto; Cintra, Raíssa Silveira; Vancini-Campanharo, Cássia Regina; Batista, Ruth Ester Assayag

    2013-01-01

    ABSTRACT Objective: To identify the occurrence of potential drug interactions in prescriptions for adult patients admitted to the Emergency Department of Hospital São Paulo. Methods: A cross-sectional and descriptive study. Its sample consisted of 200 medical prescriptions. The analysis of drug interactions was performed using the Drugs.com database, where they are classified according to severity of interaction as severe, moderate, mild and without interaction. Results: The number of drugs in prescriptions ranged from 2 to 19, and the average per prescription was 4.97 drugs. A total of 526 potential drug interactions were identified in 159 prescriptions (79.5%); in that, 109 were severe, 354 moderate, 63 mild interactions, and 41 showed no interaction. Conclusion: This study demonstrated potential drug interactions in 79.5% of prescriptions examined in the Emergency Department. Drug interactions can occur at any time when using medications and, during this working process, the nursing staff is involved in several steps. Therefore, training the nursing staff for the rational use of drugs can increase safety of care delivered to patients. PMID:24488385

  12. 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

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

    PubMed

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

    2015-06-01

    Ivacaftor is a novel cystic fibrosis (CF) transmembrane conductance regulator (CFTR) potentiator that improves the pulmonary function for patients with CF bearing a G551D CFTR-protein mutation. Because ivacaftor is highly bound (>97%) to plasma proteins, there is the strong possibility that co-administered CF drugs may compete for the same plasma protein binding sites and impact the free drug concentration. This, in turn, could lead to drastic changes in the in vivo efficacy of ivacaftor and therapeutic outcomes. This biochemical study compares the binding affinity of ivacaftor and co-administered CF drugs for human serum albumin (HSA) and α1 -acid glycoprotein (AGP) using surface plasmon resonance and fluorimetric binding assays that measure the displacement of site-selective probes. Because of their ability to strongly compete for the ivacaftor binding sites on HSA and AGP, drug-drug interactions between ivacaftor are to be expected with ducosate, montelukast, ibuprofen, dicloxacillin, omeprazole, and loratadine. The significance of these plasma protein drug-drug interactions is also interpreted in terms of molecular docking simulations. This in vitro study provides valuable insights into the plasma protein drug-drug interactions of ivacaftor with co-administered CF drugs. The data may prove useful in future clinical trials for a staggered treatment that aims to maximize the effective free drug concentration and clinical efficacy of ivacaftor. PMID:25707701

  14. Botanical-drug interactions: a scientific perspective.

    PubMed

    de Lima Toccafondo Vieira, Manuela; Huang, Shiew-Mei

    2012-09-01

    There is a continued predisposition of concurrent use of drugs and botanical products. A general lack of knowledge of the interaction potential together with an under-reporting of botanical use poses a challenge for the health care providers and a safety concern for patients. Botanical-drug interactions increase the patient risk, especially with regard to drugs with a narrow therapeutic index (e.g., warfarin, cyclosporine, and digoxin). Examples of case reports and clinical studies evaluating botanical-drug interactions of commonly used botanicals in the US are presented. The potential pharmacokinetic and pharmacodynamic bases of such interactions are discussed, as well as the challenges associated with the interpretation of the available data and prediction of botanical-drug interactions. Recent FDA experiences with botanical products and interactions including labeling implications as a risk management strategy are highlighted. PMID:22864989

  15. Medication Interactions: Food, Supplements and Other Drugs

    MedlinePlus

    ... Pressure High Blood Pressure Tools & Resources Stroke More Medication Interactions: Food, Supplements and Other Drugs Updated:Oct 15,2014 ... celebrations when eating habits tend to change. Common Medication Interactions Drugs with Food and Beverages Food and drinks don’t mix ...

  16. 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..

  17. Macrolide antibacterials. Drug interactions of clinical significance.

    PubMed

    von Rosensteil, N A; Adam, D

    1995-08-01

    Macrolide antibiotics can interact adversely with commonly used drugs, usually by altering metabolism due to complex formation and inhibition of cytochrome P-450 IIIA4 (CYP3A4) in the liver and enterocytes. In addition, pharmacokinetic drug interactions with macrolides can result from their antibiotic effect on microorganisms of the enteric flora, and through enhanced gastric emptying due to a motilin-like effect. Macrolides may be classified into 3 different groups according to their affinity for CYP3A4, and thus their propensity to cause pharmacokinetic drug interactions. Troleandomycin, erythromycin and its prodrugs decrease drug metabolism and may produce drug interactions (group 1). Others, including clarithromycin, flurithromycin, midecamycin, midecamycin acetate (miocamycin; ponsinomycin), josamycin and roxithromycin (group 2) rarely cause interactions. Azithromycin, dirithromycin, rikamycin and spiramycin (group 3) do not inactivate CYP3A4 and do not engender these adverse effects. Drug interactions with carbamazepine, cyclosporin, terfenadine, astemizole and theophylline represent the most frequently encountered interactions with macrolide antibiotics. If the combination of a macrolide and one of these compounds cannot be avoided, serum concentrations of concurrently administered drugs should be monitored and patients observed for signs of toxicity. Rare interactions and those of dubious clinical importance are those with alfentanil and sufentanil, antacids and cimetidine, oral anticoagulants, bromocriptine, clozapine, oral contraceptive steroids, digoxin, disopyramide, ergot alkaloids, felodipine, glibenclamide (glyburide), levodopa/carbidopa, lovastatin, methylprednisolone, phenazone (antipyrine), phenytoin, rifabutin and rifampicin (rifampin), triazolam and midazolam, valproic acid (sodium valproate) and zidovudine. PMID:7576262

  18. Exploring drug combinations in genetic interaction network

    PubMed Central

    2012-01-01

    Background Drug combination that consists of distinctive agents is an attractive strategy to combat complex diseases and has been widely used clinically with improved therapeutic effects. However, the identification of efficacious drug combinations remains a non-trivial and challenging task due to the huge number of possible combinations among the candidate drugs. As an important factor, the molecular context in which drugs exert their functions can provide crucial insights into the mechanism underlying drug combinations. Results In this work, we present a network biology approach to investigate drug combinations and their target proteins in the context of genetic interaction networks and the related human pathways, in order to better understand the underlying rules of effective drug combinations. Our results indicate that combinatorial drugs tend to have a smaller effect radius in the genetic interaction networks, which is an important parameter to describe the therapeutic effect of a drug combination from the network perspective. We also find that drug combinations are more likely to modulate functionally related pathways. Conclusions This study confirms that the molecular networks where drug combinations exert their functions can indeed provide important insights into the underlying rules of effective drug combinations. We hope that our findings can help shortcut the expedition of the future discovery of novel drug combinations. PMID:22595004

  19. Warfarin and Drug Interactions: Prescribing Vigilance.

    PubMed

    Hook, J; Millsopp, Lynne; Field, E Anne

    2016-01-01

    A patient taking warfarin presented to the Oral Medicine Clinic at Liverpool University Dental Hospital, having been prescribed metronidazole and miconazole by his general dental practitioner (GDP) for his oral mucosal problem. He subsequently developed bruising on his torso following mild trauma. Having read the drug information leaflet provided with his metronidazole and miconazole, he noted the potential drug interactions between these and warfarin. He therefore stopped his warfarin. The details of this case are outlined, and the potential for significant drug interactions with warfarin are highlighted. The need for dental practitioners to be vigilant concerning drug interactions is emphasized, together with the importance of CPD in relation to drug prescribing. CPD/CLINICAL RELEVANCE: This case report, which is of relevance to all dental practitioners, highlights the importance of up-to-date medical and drug histories and the continuing awareness of potential drug interactions. In this case, patient intervention after checking drug information leaflets prevented serious consequences. The importance and potentially serious consequences of significant drug interactions needs to be understood. PMID:27024900

  20. Antiepileptic Drug Interactions - Principles and Clinical Implications

    PubMed Central

    Johannessen, Svein I; Landmark, Cecilie Johannessen

    2010-01-01

    Antiepileptic drugs (AEDs) are widely used as long-term adjunctive therapy or as monotherapy in epilepsy and other indications and consist of a group of drugs that are highly susceptible to drug interactions. The purpose of the present review is to focus upon clinically relevant interactions where AEDs are involved and especially on pharmacokinetic interactions. The older AEDs are susceptible to cause induction (carbamazepine, phenobarbital, phenytoin, primidone) or inhibition (valproic acid), resulting in a decrease or increase, respectively, in the serum concentration of other AEDs, as well as other drug classes (anticoagulants, oral contraceptives, antidepressants, antipsychotics, antimicrobal drugs, antineoplastic drugs, and immunosupressants). Conversely, the serum concentrations of AEDs may be increased by enzyme inhibitors among antidepressants and antipsychotics, antimicrobal drugs (as macrolides or isoniazid) and decreased by other mechanisms as induction, reduced absorption or excretion (as oral contraceptives, cimetidine, probenicid and antacides). Pharmacokinetic interactions involving newer AEDs include the enzyme inhibitors felbamate, rufinamide, and stiripentol and the inducers oxcarbazepine and topiramate. Lamotrigine is affected by these drugs, older AEDs and other drug classes as oral contraceptives. Individual AED interactions may be divided into three levels depending on the clinical consequences of alterations in serum concentrations. This approach may point to interactions of specific importance, although it should be implemented with caution, as it is not meant to oversimplify fact matters. Level 1 involves serious clinical consequences, and the combination should be avoided. Level 2 usually implies cautiousness and possible dosage adjustments, as the combination may not be possible to avoid. Level 3 refers to interactions where dosage adjustments are usually not necessary. Updated knowledge regarding drug interactions is important to predict

  1. 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

  2. Sedative drug interactions of clinical importance.

    PubMed

    Cushman, P

    1986-01-01

    In an age of widespread availability of psychoactive drugs, use of multiple sedatives is very common. Why such multiple drug use prevails is poorly understood. Sequential drug use may leave sequential problems. Concomitant use of several drugs can produce a host of interactions. Increasingly, the metabolic basis of sedative interactions are becoming known. Cross-tolerance between sedatives permit substitution of one for another and reduced sedation when combined. Metabolic interactions at the hepatic oxidation enzyme level may greatly affect drug disposal rates. Recognition of polysubstance abuse can assist in management. Treatment ranges from urgent life support to abrupt or slow withdrawal, to substitution long-term treatment usually requiring specialized care, with abstinence the preferred goal. However, polysubstance abusers seem to have low probabilities of achieving lasting abstinence. PMID:2871595

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

    PubMed

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

    2012-10-17

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

  4. 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

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

    PubMed

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

    2016-01-01

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

  6. 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…

  7. Participatory design for drug-drug interaction alerts.

    PubMed

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

    2015-01-01

    The utilization of decision support systems, in the point of care, to alert drug-drug interactions has been shown to improve quality of care. Still, the use of these systems has not been as expected, it is believed, because of the difficulties in their knowledge databases; errors in the generation of the alerts and the lack of a suitable design. This study expands on the development of alerts using participatory design techniques based on user centered design process. This work was undertaken in three stages (inquiry, participatory design and usability testing) it showed that the use of these techniques improves satisfaction, effectiveness and efficiency in an alert system for drug-drug interactions, a fact that was evident in specific situations such as the decrease of errors to meet the specified task, the time, the workload optimization and users overall satisfaction in the system. PMID:25991099

  8. Advocating for a Harm-Minimization Approach to Drug Education in Australian Schools

    ERIC Educational Resources Information Center

    Guzys, Diana; Kendall, Sharon

    2006-01-01

    The concept of using a harm-minimization approach to drug education in Australian schools has existed in both national and state government policy documents for over two decades. However, this approach appears to be ineffectively and inconsistently incorporated within the curriculum. Harm minimization emphasizes strategies that reduce the harms…

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

    PubMed Central

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

    2016-01-01

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

  10. Minimally modified low density lipoprotein stimulates monocyte endothelial interactions.

    PubMed Central

    Berliner, J A; Territo, M C; Sevanian, A; Ramin, S; Kim, J A; Bamshad, B; Esterson, M; Fogelman, A M

    1990-01-01

    The effect of minimally modified LDL (MM-LDL) on the ability of large vessel endothelial cells (EC) to interact with monocytes and neutrophils was examined. These LDL preparations, obtained by storage or by mild iron oxidation, were indistinguishable from native LDL to the LDL receptor and were not recognized by the scavenger receptor. Treatment of EC with as little as 0.12 micrograms/ml MM-LDL caused a significant increase in the production of chemotactic factor for monocytes (sevenfold) and increased monocyte binding (three- to fivefold). Monocyte binding was maximal after 4 h of EC exposure to MM-LDL, persisted for 48 h, and was inhibited by cycloheximide. In contrast, neutrophil binding was not increased after 1-24 h of exposure. Activity in the MM-LDL preparations was found primarily in the polar lipid fraction. MM-LDL was toxic for EC from one rabbit but not toxic for the cells from another rabbit or any human umbilical vein EC. The resistant cells became sensitive when incubated with lipoprotein in the presence of cycloheximide, whereas the sensitive strain became resistant when preincubated with sublethal concentrations of MM-LDL. We conclude that exposure of EC to sublethal levels of MM-LDL enhances monocyte endothelial interactions and induces resistance to the toxic effects of MM-LDL. Images PMID:2318980

  11. Clinical drugs that interact with St. John's wort and implication in drug development.

    PubMed

    Di, Yuan Ming; Li, Chun Guang; Xue, Charlie Changli; Zhou, Shu-Feng

    2008-01-01

    St. John's wort (Hypericum perforatum, SJW) is one of the most commonly used herbal antidepressants for the treatment of minor to moderate depression. A major safety concern about SJW is its ability to alter the pharmacokinetics and/or clinical response of a variety of clinically important drugs that have distinctive chemical structure, mechanism of action and metabolic pathways. This review highlights and updates the knowledge on clinical interactions of prescribed drugs with SJW and the implication in drug development. A number of clinically significant interactions of SJW have been identified with conventional drugs, including anticancer agents (imatinib and irinotecan), anti-HIV agents (e.g. indinavir, lamivudine and nevirapine), anti-inflammatory agents (e.g. ibuprofen and fexofenadine), antimicrobial agents (e.g. erythromycin and voriconazole), cardiovascular drugs (e.g. digoxin, ivabradine, warfarin, verapamil, nifedipine and talinolol), central nervous system agents (e.g. amitriptyline, buspirone, phenytoin, methadone, midazolam, alprazolam, and sertraline), hypoglycaemic agents (e.g. tolbutamide and gliclazide), immuno-modulating agents (e.g. cyclosporine and tacrolimus), oral contraceptives, proton pump inhibitor (e.g. omeprazole), respiratory system agent (e.g. theophylline), statins (e.g. atorvastatin and pravastatin). Both pharmacokinetic and pharmacodynamic components may play a role in the interactions of drugs with SJW. For pharmacokinetic changes of drugs by SJW, induction of cytochrome P450s (e.g. CYP2C9 and 3A4) and P-glycoprotein (P-gp) are considered the major mechanism. Thus, it is not a surprise that many drugs that interact with SJW are substrates of CYP3A4, CYP2C9 and P-gp. A comprehensive understanding of clinical drugs that interact with SJW has important implications in drug development. New drugs may be designed to minimize interactions with SJW; and new SJW formulations may be designed to avoid drug interactions. Further clinical and

  12. 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

    ...The Food and Drug Administration (FDA) is announcing the availability of a draft document entitled ``Guidance for Industry and FDA Staff: Investigational New Drug Applications for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic and Immunologic Reconstitution in Patients with Disorders Affecting the Hematopoietic System'' dated June 2013.......

  13. 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

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

    PubMed

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

    2016-02-01

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

  15. 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

  16. Epistatic interactions and drug response.

    PubMed

    Weigelt, Britta; Reis-Filho, Jorge S

    2014-01-01

    The advent of massively parallel sequencing has allowed for an unprecedented genetic characterization of cancers, which has revealed not only the complexity of cancer genomes, but also the fact that tumours from the same anatomical site or even of the same histological and/or molecular subtype display distinct constellations of somatic genetic aberrations. Epistatic interactions (ie the interplay between genetic aberrations) are likely to play pivotal roles not only in terms of tumourigenesis and disease progression, but also in response to therapeutic interventions. In this review, we discuss the challenges posed by the complexity of tumour genomes and epistatic interactions, and approaches for harnessing the wealth of genetic information on human cancers for the implementation of precision medicine. PMID:24105606

  17. Interactions between antiepileptic and antipsychotic drugs.

    PubMed

    Besag, Frank M C; Berry, David

    2006-01-01

    Antiepileptic and antipsychotic drugs are often prescribed together. Interactions between the drugs may affect both efficacy and toxicity. This is a review of human clinical data on the interactions between the antiepileptic drugs carbamazepine, valproic acid (sodium valproate), vigabatrin, lamotrigine, gabapentin, topiramate, tiagabine, oxcarbazepine, levetiracetam, pregabalin, felbamate, zonisamide, phenobarbital and phenytoin with the antipsychotic drugs risperidone, olanzapine, quetiapine, clozapine, amisulpride, sulpiride, ziprasidone, aripiprazole, haloperidol and chlorpromazine; the limited information on interactions between antiepileptic drugs and zuclopenthixol, periciazine, fluphenazine, flupenthixol and pimozide is also presented. Many of the interactions depend on the induction or inhibition of the cytochrome P450 isoenzymes, but other important mechanisms involve the uridine diphosphate glucuronosyltransferase isoenzymes and protein binding. There is some evidence for the following effects. Carbamazepine decreases the plasma concentrations of both risperidone and its active metabolite. It also decreases concentrations of olanzapine, clozapine, ziprasidone, haloperidol, zuclopenthixol, flupenthixol and probably chlorpromazine and fluphenazine. Quetiapine increases the ratio of carbamazepine epoxide to carbamazepine and this may lead to toxicity. The data on valproic acid are conflicting; it may either increase or decrease clozapine concentrations, and it appears to decrease aripiprazole concentrations. Chlorpromazine possibly increases valproic acid concentrations. Lamotrigine possibly increases clozapine concentrations. Phenobarbital decreases clozapine, haloperidol and chlorpromazine concentrations. Phenytoin decreases quetiapine, clozapine, haloperidol and possibly chlorpromazine concentrations. There are major gaps in the data. In many cases there are no published clinical data on interactions that would be predicted on theoretical grounds. PMID

  18. A minimal model of predator–swarm interactions

    PubMed Central

    Chen, Yuxin; Kolokolnikov, Theodore

    2014-01-01

    We propose a minimal model of predator–swarm interactions which captures many of the essential dynamics observed in nature. Different outcomes are observed depending on the predator strength. For a ‘weak’ predator, the swarm is able to escape the predator completely. As the strength is increased, the predator is able to catch up with the swarm as a whole, but the individual prey is able to escape by ‘confusing’ the predator: the prey forms a ring with the predator at the centre. For higher predator strength, complex chasing dynamics are observed which can become chaotic. For even higher strength, the predator is able to successfully capture the prey. Our model is simple enough to be amenable to a full mathematical analysis, which is used to predict the shape of the swarm as well as the resulting predator–prey dynamics as a function of model parameters. We show that, as the predator strength is increased, there is a transition (owing to a Hopf bifurcation) from confusion state to chasing dynamics, and we compute the threshold analytically. Our analysis indicates that the swarming behaviour is not helpful in avoiding the predator, suggesting that there are other reasons why the species may swarm. The complex shape of the swarm in our model during the chasing dynamics is similar to the shape of a flock of sheep avoiding a shepherd. PMID:24598204

  19. Drug Interactions with New and Investigational Antiretrovirals

    PubMed Central

    Brown, Kevin C.; Paul, Sunita; Kashuba, Angela D.M.

    2010-01-01

    More than 20 individual and fixed-dose combinations of antiretrovirals are approved for the treatment of human immunodeficiency virus (HIV) infection. However, owing to the ongoing limitations of drug resistance and adverse effects, new treatment options are still required. A number of promising new agents in existing or new drug classes are in development or have recently been approved by the US FDA. Since these agents will be used in combination with other new and existing antiretrovirals, understanding the potential for drug interactions between these compounds is critical to their appropriate use. This article summarizes the drug interaction potential of new and investigational protease inhibitors (darunavir), non-nucleoside reverse transcriptase inhibitors (etravirine and rilpivirine), chemokine receptor antagonists (maraviroc, vicriviroc and INCB 9471), integrase inhibitors (raltegravir and elvitegravir) and maturation inhibitors (bevirimat). PMID:19492868

  20. Investigation of drug interactions with pinaverium bromide.

    PubMed

    Devred, C; Godeau, P; Guerot, C; Librez, P; Mougeot, G; Orsetti, A; Segrestaa, J M

    1986-01-01

    A series of studies was carried out at 6 centres to investigate possible drug interaction between the spasmolytic, pinaverium bromide, and cardiac glycosides, anticoagulants and hypoglycaemic agents given to patients as part of the long-term treatment of their condition. The results of clinical and laboratory investigations did not show any evidence of pinaverium bromide interfering with the action or activity of any of the drugs studied. PMID:3084176

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

    PubMed

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

    2012-12-01

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

  2. Potential drug interaction between paclitaxel and clopidogrel

    PubMed Central

    SHINODA, YASUTAKA; KIMURA, MICHIO; USAMI, EISEKI; ASANO, HIROKI; YOSHIMURA, TOMOAKI

    2016-01-01

    Paclitaxel is mainly inactivated in vivo by cytochrome P5402C8 (CYP2C8). In recent years, the clopidogrel metabolite has been reported to potently inhibit CYP2C8. However, clinical information regarding the interaction between these two drugs is limited. To the best of our knowledge, this is the first retrospective study investigating the potential for the drug interaction between paclitaxel and clopidogrel. A total of 8 cases in which clopidogrel and paclitaxel were used in combination were examined. The incidence of adverse events and discontinuation rate in these cases were assessed. Neutrophil counts were compared in patients prior and subsequent to the combined administration of clopidogrel and paclitaxel. Grade 3 neutropenia occurred in all cases of combination therapy and grade 4 occurred in 7 cases (88%). In addition, 4 cases (50%) showed febrile neutropenia. Four cases (50%) involved a severe adverse event requiring discontinuation of drug administration. In 1 case involving 6 courses of paclitaxel and nedaplatin therapy prior and subsequent to clopidogrel, there was a significant reduction in the average neutrophil count after 8 days of combination treatment (1,240±395 counts/mm3 without clopidogrel; 370±148 counts/mm3 with clopidogrel; mean ± standard deviation, P<0.01). Drug interactions during co-administration of clopidogrel and paclitaxel may cause severe neutropenia. To avoid these interactions, alternative medications should be considered. If these two drugs are used in combination, it may be necessary to monitor for adverse events more carefully. PMID:27347418

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

    PubMed

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

    2013-07-01

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

  4. Electrochemical approach of anticancer drugs--DNA interaction.

    PubMed

    Rauf, S; Gooding, J J; Akhtar, K; Ghauri, M A; Rahman, M; Anwar, M A; Khalid, A M

    2005-02-23

    The interaction of drugs with DNA is among the most important aspects of biological studies in drug discovery and pharmaceutical development processes. In recent years there has been a growing interest in the electrochemical investigation of interaction between anticancer drugs and DNA. Observing the pre and post electrochemical signals of DNA or drug interaction provides good evidence for the interaction mechanism to be elucidated. Also this interaction could be used for the quantification of these drugs and for the determination of new drugs targeting DNA. Electrochemical approach can provide new insight into rational drug design and would lead to further understanding of the interaction mechanism between anticancer drugs and DNA. PMID:15708659

  5. Pharmacokinetic drug interactions with phenytoin (Part I).

    PubMed

    Nation, R L; Evans, A M; Milne, R W

    1990-01-01

    Phenytoin, which is used primarily as an anticonvulsant agent, has a relatively low therapeutic index, and monitoring of plasma phenytoin concentration is often used to help guide therapy. It has properties which predispose it to an involvement in pharmacokinetic interactions, a large number of which have been reported. These properties include: low aqueous solubility and slow rate of gastrointestinal absorption; a relatively high degree of plasma protein binding; a clearance that is non-linear due to saturable oxidative biotransformation; and the ability to induce hepatic microsomal enzymes. Because of its narrow therapeutic range, drug interactions leading to alterations in plasma phenytoin concentration may be clinically important. Such interactions have often been reported initially as either cases of phenytoin intoxication or of decreased effectiveness. Drugs may modify the pharmacokinetics of phenytoin by altering its absorption, plasma protein binding, or hepatic biotransformation; alterations in the absorption and/or biotransformation may lead to changes in both the unbound plasma phenytoin concentration and, as a result, the clinical effect. Preparations which may decrease the gastrointestinal absorption of phenytoin include nutritional formulae and charcoal. There are many reports of drugs which may increase (e.g. folic acid, dexamethasone and rifampicin) or decrease (e.g. valproic acid, sulthiame, isoniazid, cimetidine, phenylbutazone, chloramphenicol and some sulphonamides) the metabolism of phenytoin. It is important to bear in mind that, as a result of its non-linear clearance, changes in phenytoin absorption and/or biotransformation will lead to more than proportionate changes in plasma drug concentration. Drugs which may displace phenytoin from plasma albumin include valproic acid, salicylic acid, phenylbutazone and some sulphonamides. Although an alteration in the unbound fraction of phenytoin in plasma would not, in itself, be expected to alter

  6. 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. PMID:26631222

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2015-10-01

    The past decade has seen increased numbers of studies publishing ligand-based computational models for drug transporters. Although they generally use small experimental data sets, these models can provide insights into structure-activity relationships for the transporter. In addition, such models have helped to identify new compounds as substrates or inhibitors of transporters of interest. We recently proposed that many transporters are promiscuous and may require profiling of new chemical entities against multiple substrates for a specific transporter. Furthermore, it should be noted that virtually all of the published ligand-based transporter models are only accessible to those involved in creating them and, consequently, are rarely shared effectively. One way to surmount this is to make models shareable or more accessible. The development of mobile apps that can access such models is highlighted here. These apps can be used to predict ligand interactions with transporters using Bayesian algorithms. We used recently published transporter data sets (MATE1, MATE2K, OCT2, OCTN2, ASBT, and NTCP) to build preliminary models in a commercial tool and in open software that can deliver the model in a mobile app. In addition, several transporter data sets extracted from the ChEMBL database were used to illustrate how such public data and models can be shared. Predicting drug-drug interactions for various transporters using computational models is potentially within reach of anyone with an iPhone or iPad. Such tools could help prioritize which substrates should be used for in vivo drug-drug interaction testing and enable open sharing of models. PMID:26199424

  9. Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs.

    PubMed

    Zaccara, Gaetano; Perucca, Emilio

    2014-12-01

    Interactions between antiepileptic drugs, or between antiepileptic drugs and other drugs, can be pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic interactions involve changes in absorption, distribution or elimination, whereas pharmacodynamic interactions involve synergism and antagonism at the site of action. Most clinically important interactions of antiepileptic drugs result from induction or inhibition of drug metabolism. Carbamazepine, phenytoin, phenobarbital and primidone are strong inducers of cytochrome P450 and glucuronizing enzymes (as well as P-glycoprotein) and can reduce the efficacy of co-administered medications such as oral anticoagulants, calcium antagonists, steroids, antimicrobial and antineoplastic drugs through this mechanism. Oxcarbazepine, eslicarbazepine acetate, felbamate, rufinamide, topiramate (at doses ≥ 200 mg/day) and perampanel (at doses ≥ 8 mg/day) have weaker inducing properties, and a lower propensity to cause interactions mediated by enzyme induction. Unlike enzyme induction, enzyme inhibition results in decreased metabolic clearance of the affected drug, the serum concentration of which may increase leading to toxic effects. Examples of important interactions mediated by enzyme inhibition include the increase in the serum concentration of phenobarbital and lamotrigine caused by valproic acid. There are also interactions whereby other drugs induce or inhibit the metabolism of antiepileptic drugs, examples being the increase in serum carbamazepine concentration by erythromycin, and the decrease in serum lamotrigine concentration by oestrogen-containing contraceptives. Pharmacodynamic interactions between antiepileptic drugs may also be clinically important. These interactions can have potentially beneficial effects, such as the therapeutic synergism of valproic acid combined with lamotrigine, or adverse effects, such as the reciprocal potentiation of neurotoxicity observed in patients treated with a combination of

  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. PMID:27474731

  11. Pharmacokinetic drug interactions with oral contraceptives.

    PubMed

    Back, D J; Orme, M L

    1990-06-01

    Oral contraceptive steroids are used by an estimated 60 to 70 million women world-wide. Over the past 20 years there have been both case reports and clinical studies on the topic of drug interactions with these agents. Some of the interactions are of definite therapeutic relevance, whereas others can be discounted as being of no clinical significance. Pharmacological interactions between oral contraceptive steroids and other compounds may be of 2 kinds: (a) drugs may impair the efficacy of oral contraceptive steroids, leading to breakthrough bleeding and pregnancy (in a few cases, the activity of the contraceptive is enhanced); (b) oral contraceptive steroids may interfere with the metabolism of other drugs. A number of anticonvulsants (phenobarbital, phenytoin, carbamazepine) are enzyme-inducing agents and thereby increase the clearance of the oral contraceptive steroids. Valproic acid has no enzyme-inducing properties, and thus women on this anticonvulsant can rely on their low dose oral contraceptive steroids for contraceptive protection. Researchers are now beginning to unravel the molecular basis of this interaction, with evidence of specific forms of cytochrome P450 (P450IIC and IIIA gene families) being induced by phenobarbital. Rifampicin, the antituberculous drug, also induces a cytochrome P450 which is a product of the P450IIIA gene subfamily. This isozyme is one of the major forms involved in 2-hydroxylation of ethinylestradiol. Broad spectrum antibiotics have been implicated in causing pill failure; case reports document the interaction, and general practitioners are convinced that it is real. The problem remains that there is still no firm clinical pharmacokinetic evidence which indicates that blood concentrations of oral contraceptive steroids are altered by antibiotics. However, perhaps this should not be a surprise, given that the incidence of the interaction may be very low. It is suggested that an individual at risk will have a low bioavailability

  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. PMID:24498827

  13. Protein-protein interactions as drug targets.

    PubMed

    Skwarczynska, Malgorzata; Ottmann, Christian

    2015-10-01

    Modulation of protein-protein interactions (PPIs) is becoming increasingly important in drug discovery and chemical biology. While a few years ago this 'target class' was deemed to be largely undruggable an impressing number of publications and success stories now show that targeting PPIs with small, drug-like molecules indeed is a feasible approach. Here, we summarize the current state of small-molecule inhibition and stabilization of PPIs and review the active molecules from a structural and medicinal chemistry angle, especially focusing on the key examples of iNOS, LFA-1 and 14-3-3. PMID:26510391

  14. Degradable Magnetic Composites for Minimally Invasive Interventions: Device Fabrication, Targeted Drug Delivery, and Cytotoxicity Tests.

    PubMed

    Peters, Christian; Hoop, Marcus; Pané, Salvador; Nelson, Bradley J; Hierold, Christofer

    2016-01-20

    Superparamagnetic nanoparticles and a functional, degradable polymer matrix based on poly(ethylene glycol) are combined to enable fully degradable magnetic microdevices for minimally invasive biomedical applications. A bioinspired helical microrobot platform mimicking Escherichia coli bacteria is fabricated and actuated using weak rotating magnetic fields. Locomotion based on corkscrew propulsion, targeted drug delivery, and low-degradation-product cytotoxicity are demonstrated. PMID:26603856

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

    PubMed

    Park, Young-Min

    2012-12-01

    I report here an elderly woman receiving perphenazine together with terbinafine. After 1 week of terbinafine treatment she experienced extrapyramidal symptoms and, in particular, akathisia. Her symptoms did not disappear for 6 weeks, and so at 2 weeks prior to this most recent admission she had stopped taking terbinafine. However, these symptoms persisted for 3 weeks after discontinuing terbinafine. It is well known that terbinafine inhibits CYP2D6 and that perphenazine is metabolized mainly by CYP2D6. Thus, when terbinafine and perphenazine are coadministrated, the subsequent increase in the concentration of perphenazine may induce extrapyramidal symptoms. Thus, terbinafine therapy may be associated with the induction and persistence of extrapyramidal symptoms, including akathisia. This case report emphasizes the importance of monitoring drug-drug interactions in patients undergoing terbinafine and perphenazine therapy. PMID:23251210

  16. Prolonged Drug-Drug Interaction between Terbinafine and Perphenazine

    PubMed Central

    2012-01-01

    I report here an elderly woman receiving perphenazine together with terbinafine. After 1 week of terbinafine treatment she experienced extrapyramidal symptoms and, in particular, akathisia. Her symptoms did not disappear for 6 weeks, and so at 2 weeks prior to this most recent admission she had stopped taking terbinafine. However, these symptoms persisted for 3 weeks after discontinuing terbinafine. It is well known that terbinafine inhibits CYP2D6 and that perphenazine is metabolized mainly by CYP2D6. Thus, when terbinafine and perphenazine are coadministrated, the subsequent increase in the concentration of perphenazine may induce extrapyramidal symptoms. Thus, terbinafine therapy may be associated with the induction and persistence of extrapyramidal symptoms, including akathisia. This case report emphasizes the importance of monitoring drug-drug interactions in patients undergoing terbinafine and perphenazine therapy. PMID:23251210

  17. 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

  18. Text Mining Driven Drug-Drug Interaction Detection

    PubMed Central

    Yan, Su; Jiang, Xiaoqian; Chen, Ying

    2014-01-01

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

  19. Text Mining Driven Drug-Drug Interaction Detection.

    PubMed

    Yan, Su; Jiang, Xiaoqian; Chen, Ying

    2013-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2014-04-24

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

  2. 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. PMID:24602259

  3. Gene-Drug Interaction in Stroke

    PubMed Central

    Amici, Serena; Paciaroni, Maurizio; Agnelli, Giancarlo; Caso, Valeria

    2011-01-01

    Stroke is the third cause of mortality and one of most frequent causes of long-term neurological disability, as well as a complex disease that results from the interaction of environmental and genetic factors. The focus on genetics has produced a large number of studies with the objective of revealing the genetic basis of cerebrovascular diseases. Furthermore, pharmacogenetic research has investigated the relation between genetic variability and drug effectiveness/toxicity. This review will examine the implications of pharmacogenetics of stroke; data on antihypertensives, statins, antiplatelets, anticoagulants, and recombinant tissue plasminogen activator will be illustrated. Several polymorphisms have been studied and some have been associated with positive drug-gene interaction on stroke, but the superiority of the genotype-guided approach over the clinical approach has not been proved yet; for this reason, it is not routinely recommended. PMID:22135769

  4. 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

  5. Evaluation of drug interactions with nanofibrillar cellulose.

    PubMed

    Kolakovic, Ruzica; Peltonen, Leena; Laukkanen, Antti; Hellman, Maarit; Laaksonen, Päivi; Linder, Markus B; Hirvonen, Jouni; Laaksonen, Timo

    2013-11-01

    Nanofibrillar cellulose (NFC) (also referred to as cellulose nanofibers, nanocellulose, microfibrillated, or nanofibrillated cellulose) has recently gotten wide attention in various research areas and it has also been studied as excipient in formulation of the pharmaceutical dosage forms. Here, we have evaluated the interactions between NFC and the model drugs of different structural characteristics (size, charge, etc.). The series of permeation studies were utilized to evaluate the ability of the drugs in solution to diffuse through the thin, porous, dry NFC films. An incubation method was used to determine capacity of binding of chosen model drugs to NFC as well as isothermal titration calorimetry (ITC) to study thermodynamics of the binding process. A genetically engineered fusion protein carrying double cellulose binding domain was used as a positive control since its affinity and capacity of binding for NFC have already been reported. The permeation studies revealed the size dependent diffusion rate of the model drugs through the NFC films. The results of both binding and ITC studies showed that the studied drugs bind to the NFC material and indicated the pH dependence of the binding and electrostatic forces as the main mechanism. PMID:23774185

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

    PubMed

    Coondoo, Arijit; Chattopadhyay, Chandan

    2013-07-01

    A drug interaction is a process by which a drug or any other substance interacts with another drug and affects its activity by increasing or decreasing its effect, causing a side effect or producing a new effect unrelated to the effect of either. Interactions may be of various types-drug-drug interactions, drug-food interactions, drug-medical condition interactions, or drug-herb interactions. Interactions may occur by single or multiple mechanisms. They may occur in vivo or in vitro (pharmaceutical reactions). In vivo interactions may be further subdivided into pharmacodynamic or pharmacokinetic reactions. Topical drug interactions which may be agonistic or antagonistic may occur between two drugs applied topically or between a topical and a systemic drug. Topical drug-food interaction (for example, grape fruit juice and cyclosporine) and drug-disease interactions (for example, topical corticosteroid and aloe vera) may also occur. It is important for the dermatologist to be aware of such interactions to avoid complications of therapy in day-to-day practice. PMID:23918993

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

    PubMed Central

    Coondoo, Arijit; Chattopadhyay, Chandan

    2013-01-01

    A drug interaction is a process by which a drug or any other substance interacts with another drug and affects its activity by increasing or decreasing its effect, causing a side effect or producing a new effect unrelated to the effect of either. Interactions may be of various types-drug-drug interactions, drug-food interactions, drug-medical condition interactions, or drug-herb interactions. Interactions may occur by single or multiple mechanisms. They may occur in vivo or in vitro (pharmaceutical reactions). In vivo interactions may be further subdivided into pharmacodynamic or pharmacokinetic reactions. Topical drug interactions which may be agonistic or antagonistic may occur between two drugs applied topically or between a topical and a systemic drug. Topical drug-food interaction (for example, grape fruit juice and cyclosporine) and drug-disease interactions (for example, topical corticosteroid and aloe vera) may also occur. It is important for the dermatologist to be aware of such interactions to avoid complications of therapy in day-to-day practice. PMID:23918993

  8. 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

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

    PubMed Central

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

    2013-01-01

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

  10. 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

  11. 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

  12. Minimizing DILI risk in drug discovery - A screening tool for drug candidates.

    PubMed

    Schadt, S; Simon, S; Kustermann, S; Boess, F; McGinnis, C; Brink, A; Lieven, R; Fowler, S; Youdim, K; Ullah, M; Marschmann, M; Zihlmann, C; Siegrist, Y M; Cascais, A C; Di Lenarda, E; Durr, E; Schaub, N; Ang, X; Starke, V; Singer, T; Alvarez-Sanchez, R; Roth, A B; Schuler, F; Funk, C

    2015-12-25

    Drug-induced liver injury (DILI) is a leading cause of acute hepatic failure and a major reason for market withdrawal of drugs. Idiosyncratic DILI is multifactorial, with unclear dose-dependency and poor predictability since the underlying patient-related susceptibilities are not sufficiently understood. Because of these limitations, a pharmaceutical research option would be to reduce the compound-related risk factors in the drug-discovery process. Here we describe the development and validation of a methodology for the assessment of DILI risk of drug candidates. As a training set, 81 marketed or withdrawn compounds with differing DILI rates - according to the FDA categorization - were tested in a combination of assays covering different mechanisms and endpoints contributing to human DILI. These include the generation of reactive metabolites (CYP3A4 time-dependent inhibition and glutathione adduct formation), inhibition of the human bile salt export pump (BSEP), mitochondrial toxicity and cytotoxicity (fibroblasts and human hepatocytes). Different approaches for dose- and exposure-based calibrations were assessed and the same parameters applied to a test set of 39 different compounds. We achieved a similar performance to the training set with an overall accuracy of 79% correctly predicted, a sensitivity of 76% and a specificity of 82%. This test system may be applied in a prospective manner to reduce the risk of idiosyncratic DILI of drug candidates. PMID:26407524

  13. 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

  14. Drug Interactions with Lithium: An Update.

    PubMed

    Finley, Patrick R

    2016-08-01

    Lithium has been used for the management of psychiatric illnesses for over 50 years and it continues to be regarded as a first-line agent for the treatment and prevention of bipolar disorder. Lithium possesses a narrow therapeutic index and comparatively minor alterations in plasma concentrations can have significant clinical sequelae. Several drug classes have been implicated in the development of lithium toxicity over the years, including diuretics and non-steroidal anti-inflammatory compounds, but much of the anecdotal and experimental evidence supporting these interactions is dated, and many newer medications and medication classes have been introduced during the intervening years. This review is intended to provide an update on the accumulated evidence documenting potential interactions with lithium, with a focus on pharmacokinetic insights gained within the last two decades. The clinical relevance and ramifications of these interactions are discussed. PMID:26936045

  15. 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

  16. A pocket aide-memoire on drug interactions.

    PubMed

    Stockley, I H

    1975-04-01

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

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

    PubMed Central

    Nikolić, Božana S.; Ilić, Maja S.

    2013-01-01

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

  18. 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

  19. Inferring Cuisine - Drug Interactions Using the Linked Data Approach

    PubMed Central

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

    2015-01-01

    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. PMID:25792182

  20. Drug interactions with the newer antiepileptic drugs (AEDs)--part 1: pharmacokinetic and pharmacodynamic interactions between AEDs.

    PubMed

    Patsalos, Philip N

    2013-11-01

    Since 1989 there has been an exponential introduction of new antiepileptic drugs (AEDs) into clinical practice and these include eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, pregabalin, retigabine (ezogabine), rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide; 16 in total. Because often the treatment of epilepsy is lifelong, and because patients are commonly prescribed polytherapy with other AEDs, AED interactions are an important consideration in the treatment of epilepsy and indeed can be a major therapeutic challenge. For new AEDs, their propensity to interact is particularly important because inevitably they can only be prescribed, at least in the first instance, as adjunctive polytherapy. The present review details the pharmacokinetic and pharmacodynamic interactions that have been reported to occur with the new AEDs. Interaction study details are described, as necessary, so as to allow the reader to take a view as to the possible clinical significance of particular interactions. The principal pharmacokinetic interaction relates to hepatic enzyme induction or inhibition whilst pharmacodynamic interactions principally entail adverse effect synergism, although examples of anticonvulsant synergism also exist. Overall, the new AEDs are less interacting primarily because many are renally excreted or not hepatically metabolised (e.g. gabapentin, lacosamide, levetiracetam, topiramate, vigabatrin) and most do not (or minimally) induce or inhibit hepatic metabolism. A total of 139 pharmacokinetic interactions between concurrent AEDs have been described. The least pharmacokinetic interactions (n ≤ 5) are associated with gabapentin, lacosamide, tiagabine, vigabatrin and zonisamide, whilst lamotrigine (n = 17), felbamate (n = 15), oxcarbazepine (n = 14) and rufinamide (n = 13) are associated with the most. To date, felbamate, gabapentin, oxcarbazepine, perampanel, pregabalin

  1. Pharmacogenomic study using bio- and nanobioelectrochemistry: Drug-DNA interaction.

    PubMed

    Hasanzadeh, Mohammad; Shadjou, Nasrin

    2016-04-01

    Small molecules that bind genomic DNA have proven that they can be effective anticancer, antibiotic and antiviral therapeutic agents that affect the well-being of millions of people worldwide. Drug-DNA interaction affects DNA replication and division; causes strand breaks, and mutations. Therefore, the investigation of drug-DNA interaction is needed to understand the mechanism of drug action as well as in designing DNA-targeted drugs. On the other hand, the interaction between DNA and drugs can cause chemical and conformational modifications and, thus, variation of the electrochemical properties of nucleobases. For this purpose, electrochemical methods/biosensors can be used toward detection of drug-DNA interactions. The present paper reviews the drug-DNA interactions, their types and applications of electrochemical techniques used to study interactions between DNA and drugs or small ligand molecules that are potentially of pharmaceutical interest. The results are used to determine drug binding sites and sequence preference, as well as conformational changes due to drug-DNA interactions. Also, the intention of this review is to give an overview of the present state of the drug-DNA interaction cognition. The applications of electrochemical techniques for investigation of drug-DNA interaction were reviewed and we have discussed the type of qualitative or quantitative information that can be obtained from the use of each technique. PMID:26838928

  2. Drug-Nutrient Interactions and Drug-Supplement Interactions: What You Need to Know

    MedlinePlus

    ... a healthy diet that includes foods high in vitamins and minerals, such as fruits, vegetables, lean meats, and fish. What is a drug-supplement interaction? Almost half of all Americans say they have taken a ... supplement is a vitamin, mineral, or herb that you take to improve ...

  3. Duloxetine: clinical pharmacokinetics and drug interactions.

    PubMed

    Knadler, Mary Pat; Lobo, Evelyn; Chappell, Jill; Bergstrom, Richard

    2011-05-01

    Duloxetine, a potent reuptake inhibitor of serotonin (5-HT) and norepinephrine, is effective for the treatment of major depressive disorder, diabetic neuropathic pain, stress urinary incontinence, generalized anxiety disorder and fibromyalgia. Duloxetine achieves a maximum plasma concentration (C(max)) of approximately 47 ng/mL (40 mg twice-daily dosing) to 110 ng/mL (80 mg twice-daily dosing) approximately 6 hours after dosing. The elimination half-life of duloxetine is approximately 10-12 hours and the volume of distribution is approximately 1640 L. The goal of this paper is to provide a review of the literature on intrinsic and extrinsic factors that may impact the pharmacokinetics of duloxetine with a focus on concomitant medications and their clinical implications. Patient demographic characteristics found to influence the pharmacokinetics of duloxetine include sex, smoking status, age, ethnicity, cytochrome P450 (CYP) 2D6 genotype, hepatic function and renal function. Of these, only impaired hepatic function or severely impaired renal function warrant specific warnings or dose recommendations. Pharmacokinetic results from drug interaction studies show that activated charcoal decreases duloxetine exposure, and that CYP1A2 inhibition increases duloxetine exposure to a clinically significant degree. Specifically, following oral administration in the presence of fluvoxamine, the area under the plasma concentration-time curve and C(max) of duloxetine significantly increased by 460% (90% CI 359, 584) and 141% (90% CI 93, 200), respectively. In addition, smoking is associated with a 30% decrease in duloxetine concentration. The exposure of duloxetine with CYP2D6 inhibitors or in CYP2D6 poor metabolizers is increased to a lesser extent than that observed with CYP1A2 inhibition and does not require a dose adjustment. In addition, duloxetine increases the exposure of drugs that are metabolized by CYP2D6, but not CYP1A2. Pharmacodynamic study results indicate

  4. 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

  5. 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. PMID:25937320

  6. Pharmacokinetics and drug interactions of eslicarbazepine acetate.

    PubMed

    Bialer, Meir; Soares-da-Silva, Patricio

    2012-06-01

    Eslicarbazepine acetate (ESL) is a novel once-daily antiepileptic drug (AED) approved in Europe since 2009 that was found to be efficacious and well tolerated in a phase III clinical program in adult patients with partial onset seizures previously not controlled with treatment with one to three AEDs, including carbamazepine (CBZ). ESL shares with CBZ and oxcarbazepine (OXC) the dibenzazepine nucleus bearing the 5-carboxamide substitute, but is structurally different at the 10,11 position. This molecular variation results in differences in metabolism, preventing the formation of toxic epoxide metabolites such as carbamazepine-10,11-epoxide. Unlike OXC, which is metabolized to both eslicarbazepine and (R)-licarbazepine, ESL is extensively converted to eslicarbazepine. The systemic exposure to eslicarbazepine after ESL oral administration is approximately 94% of the parent dose, with minimal exposure to (R)-licarbazepine and OXC. After ESL oral administration, the effective half-life (t(1/2,eff) ) of eslicarbazepine was 20-24 h, which is approximately two times longer than its terminal half-life (t(1/2)). At clinically relevant doses (400-1,600 mg/day) ESL has linear pharmacokinetics (PK) with no effects of gender or moderate liver impairment. However, because eslicarbazepine is eliminated primarily (66%) by renal excretion, dose adjustment is recommended for patients with renal impairment. Eslicarbazepine clearance is induced by phenobarbital, phenytoin, and CBZ and it dose-dependently decreases plasma exposure of oral contraceptive and simvastatin. PMID:22612290

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

    PubMed

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

    2005-01-01

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

  8. Stochastic gating and drug-ribosome interactions.

    PubMed

    Vaiana, Andrea C; Sanbonmatsu, Kevin Y

    2009-02-27

    Gentamicin is a potent antibiotic that is used in combination therapy for inhalation anthrax disease. The drug is also often used in therapy for methicillin-resistant Staphylococcusaureus. Gentamicin works by flipping a conformational switch on the ribosome, disrupting the reading head (i.e., 16S ribosomal decoding bases 1492-1493) used for decoding messenger RNA. We use explicit solvent all-atom molecular simulation to study the thermodynamics of the ribosomal decoding site and its interaction with gentamicin. The replica exchange molecular dynamics simulations used an aggregate sampling of 15 mus when summed over all replicas, allowing us to explicitly calculate the free-energy landscape, including a rigorous treatment of enthalpic and entropic effects. Here, we show that the decoding bases flip on a timescale faster than that of gentamicin binding, supporting a stochastic gating mechanism for antibiotic binding, rather than an induced-fit model where the bases only flip in the presence of a ligand. The study also allows us to explore the nonspecific binding landscape near the binding site and reveals that, rather than a two-state bound/unbound scenario, drug dissociation entails shuttling between many metastable local minima in the free-energy landscape. Special care is dedicated to validation of the obtained results, both by direct comparison to experiment and by estimation of simulation convergence. PMID:19146858

  9. 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

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

    PubMed

    Kremers, Pierre

    2002-03-19

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

  11. Drug interactions and the evolution of antibiotic resistance

    PubMed Central

    Yeh, Pamela J.; Hegreness, Matthew J.; Aiden, Aviva Presser; Kishony, Roy

    2010-01-01

    Large-scale, systems biology approaches now allow us to systematically map synergistic and antagonistic interactions between drugs. Consequently, drug antagonism is emerging as a powerful tool to study biological function and relatedness between cellular components as well as to uncover mechanisms of drug action. Furthermore, theoretical models and new experiments suggest that antagonistic interactions between antibiotics can counteract the evolution of drug resistance. PMID:19444248

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

    PubMed

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

    2014-08-01

    Absorption of an orally administered drug with pH-dependent solubility may be altered when it is coadministered with a gastric acid-reducing agent (ARA). Assessing a drug's potential for pH-dependent drug-drug interactions (DDIs), considering study design elements for such DDI studies, and interpreting and communicating study results in the drug labeling to guide drug dosing are important for drug development. We collected pertinent information related to new molecular entities approved from January 2003 to May 2013 by the US Food and Drug Administration for which clinical DDI studies with ARAs were performed. On the basis of assessments of data on pH solubility and in vivo DDIs with ARAs, we proposed a conceptual framework for assessing the need for clinical pH-dependent DDI studies for weak base drugs (WBDs). Important study design considerations include selection of ARAs and timing of dosing of an ARA relative to the WBD in a DDI study. Labeling implications for drugs having DDIs with ARAs are also illustrated. PMID:24733008

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

    PubMed

    Moore, Nicholas; Pollack, Charles; Butkerait, Paul

    2015-01-01

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

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

    PubMed

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

    2013-01-01

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

  15. Kinetics of drug interactions in the treatment of epilepsy.

    PubMed

    van der Kleijn, E; Vree, T; Guelen, P; Schobten, F; Westenberg, H; Knop, H

    1978-10-01

    The interactions of antiepileptic drugs in multiple drug treatment have been discussed. Although some combinations may lead to predictable increase or decrease of clearance of the respective drugs, most combinations will individually lead to a reduced predictability. Monitoring plasma concentrations may lead to adaptations of the choice of the drug and of the dosage regimen. Also physiological conditions control the individual clearance of antiepileptic drugs. PMID:700910

  16. 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

  17. 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

    ... specifically address children's toy laser products. FDA recently issued a proposed rule (78 FR 37723) that... HUMAN SERVICES Food and Drug Administration Minimizing Risk for Children's Toy Laser Products; Draft... availability of the draft guidance entitled ``Minimizing Risk for Children's Toy Laser Products.'' This...

  18. 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

  19. Regularity of Local Minimizers of the Interaction Energy Via Obstacle Problems

    NASA Astrophysics Data System (ADS)

    Carrillo, J. A.; Delgadino, M. G.; Mellet, A.

    2016-05-01

    The repulsion strength at the origin for repulsive/attractive potentials determines the regularity of local minimizers of the interaction energy. In this paper, we show that if this repulsion is like Newtonian or more singular than Newtonian (but still locally integrable), then the local minimizers must be locally bounded densities (and even continuous for more singular than Newtonian repulsion). We prove this (and some other regularity results) by first showing that the potential function associated to a local minimizer solves an obstacle problem and then by using classical regularity results for such problems.

  20. 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…

  1. 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.

  2. 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. PMID:25771206

  3. 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

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

    PubMed Central

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

    2014-01-01

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

  5. MDMA: interactions with other psychoactive drugs.

    PubMed

    Mohamed, Wael M Y; Ben Hamida, Sami; Cassel, Jean-Christophe; de Vasconcelos, Anne Pereira; Jones, Byron C

    2011-10-01

    3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is one of the most widely abused illegal drugs. Some users self-report euphoria and an increased perception and feeling of closeness to others. When taken in warm environments, MDMA users may develop acute complications with potential fatal consequences. In rodents, MDMA increases locomotor activity and, depending on ambient temperature, may produce a dose-dependent, potentially lethal hyperthermia. Like most other recreational drugs, MDMA is frequently taken in combination with other substances including tobacco, EtOH, marijuana, amphetamines, cocaine and, caffeine. Although polydrug use is very common, the understanding of the effects of this multiple substance use, as well as the analysis of consequences of different drug-drug associations, received rather little attention. The purpose of this review is to summarize our current knowledge about the changes on MDMA-related behavior, pharmacology, and neurotoxicity associated with co-consumption of other drugs of abuse and psychoactive agents. PMID:21756931

  6. 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

  7. Overview of green tea interaction with cardiovascular drugs.

    PubMed

    Werba, José P; Misaka, Shingen; Giroli, Monica G; Yamada, Shizuo; Cavalca, Viviana; Kawabe, Keisuke; Squellerio, Isabella; Laguzzi, Federica; Onoue, Satomi; Veglia, Fabrizio; Myasoedova, Veronika; Takeuchi, Kazuhiko; Adachi, Eisuke; Inui, Naoki; Tremoli, Elena; Watanabe, Hiroshi

    2015-01-01

    Sensitive to the massive diffusion of purported metabolic and cardiovascular positive effects of green tea and catechincontaining extracts, many consumers of cardiovascular drugs assume these products as a "natural" and presumably innocuous adjunctive way to increase their overall health. However, green tea may interfere with the oral bioavailability or activity of cardiovascular drugs by various mechanisms, potentially leading to reduced drug efficacy or increased drug toxicity. Available data about interactions between green tea and cardiovascular drugs in humans, updated in this review, are limited so far to warfarin, simvastatin and nadolol, and suggest that the average effects are mild to modest. Nevertheless, in cases of unexpected drug response or intolerance, it is warranted to consider a possible green tea-drug interaction, especially in people who assume large volumes of green tea and/or catechin-enriched products with the conviction that "more-is-better". PMID:25312732

  8. 'RE:fine drugs': an interactive dashboard to access drug repurposing opportunities.

    PubMed

    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

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

    PubMed

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

    2013-01-01

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

  10. 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

  11. 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

  12. 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

  13. Clinically and pharmacologically relevant interactions of antidiabetic drugs.

    PubMed

    May, Marcus; Schindler, Christoph

    2016-04-01

    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

  14. Kinetics membrane disruption due to drug interactions of chlorpromazine hydrochloride.

    PubMed

    Nussio, Matthew R; Sykes, Matthew J; Miners, John O; Shapter, Joseph G

    2009-01-20

    Drug-membrane interactions assume considerable importance in pharmacokinetics and drug metabolism. Here, we present the interaction of chlorpromazine hydrochloride (CPZ) with supported phospholipid bilayers. It was demonstrated that CPZ binds rapidly to phospholipid bilayers, disturbing the molecular ordering of the phospholipids. These interactions were observed to follow first order kinetics, with an activation energy of approximately 420 kJ mol(-1). Time-dependent membrane disruption was also observed for the interaction with CPZ, such that holes appeared in the phospholipid bilayer after the interaction of CPZ. For this process of membrane disruption, "lag-burst" kinetics was demonstrated. PMID:19093750

  15. Drug interactions: inhibition of acetaminophen glucuronidation by drugs.

    PubMed

    Bolanowska, W; Gessner, T

    1978-07-01

    Glucuronidation of [3H]acetaminophen (APAP) was studied in rat liver preparations. Both Triton X-100 and UDP-N acetylglucosamine (UDPAG) activated 3- to 4-fold the glucuronidation of APAP by liver homogenates or microsomes. Prednisolone inhibited microsomal glucuronidation of APAP, yielding apparent noncompetitive kinetics in native and in UDPAG-activated microsomes. Studies with UDPAG-activated microsomal preparations show that many drugs can inhibit glucuronidation of APAP markedly; among the most poten inhibitors are: morphine, dicumarol, hydroxyzine, phenolphthalein, chloramphenicol and tetracycline. PMID:660554

  16. 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

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

    PubMed Central

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

    2014-01-01

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

  19. Adaptive Landscape by Environment Interactions Dictate Evolutionary Dynamics in Models of Drug Resistance.

    PubMed

    Ogbunugafor, C Brandon; Wylie, C Scott; Diakite, Ibrahim; Weinreich, Daniel M; Hartl, Daniel L

    2016-01-01

    The adaptive landscape analogy has found practical use in recent years, as many have explored how their understanding can inform therapeutic strategies that subvert the evolution of drug resistance. A major barrier to applications of these concepts is a lack of detail concerning how the environment affects adaptive landscape topography, and consequently, the outcome of drug treatment. Here we combine empirical data, evolutionary theory, and computer simulations towards dissecting adaptive landscape by environment interactions for the evolution of drug resistance in two dimensions-drug concentration and drug type. We do so by studying the resistance mediated by Plasmodium falciparum dihydrofolate reductase (DHFR) to two related inhibitors-pyrimethamine and cycloguanil-across a breadth of drug concentrations. We first examine whether the adaptive landscapes for the two drugs are consistent with common definitions of cross-resistance. We then reconstruct all accessible pathways across the landscape, observing how their structure changes with drug environment. We offer a mechanism for non-linearity in the topography of accessible pathways by calculating of the interaction between mutation effects and drug environment, which reveals rampant patterns of epistasis. We then simulate evolution in several different drug environments to observe how these individual mutation effects (and patterns of epistasis) influence paths taken at evolutionary "forks in the road" that dictate adaptive dynamics in silico. In doing so, we reveal how classic metrics like the IC50 and minimal inhibitory concentration (MIC) are dubious proxies for understanding how evolution will occur across drug environments. We also consider how the findings reveal ambiguities in the cross-resistance concept, as subtle differences in adaptive landscape topography between otherwise equivalent drugs can drive drastically different evolutionary outcomes. Summarizing, we discuss the results with regards to their

  20. Adaptive Landscape by Environment Interactions Dictate Evolutionary Dynamics in Models of Drug Resistance

    PubMed Central

    Ogbunugafor, C. Brandon; Wylie, C. Scott; Diakite, Ibrahim; Weinreich, Daniel M.; Hartl, Daniel L.

    2016-01-01

    The adaptive landscape analogy has found practical use in recent years, as many have explored how their understanding can inform therapeutic strategies that subvert the evolution of drug resistance. A major barrier to applications of these concepts is a lack of detail concerning how the environment affects adaptive landscape topography, and consequently, the outcome of drug treatment. Here we combine empirical data, evolutionary theory, and computer simulations towards dissecting adaptive landscape by environment interactions for the evolution of drug resistance in two dimensions—drug concentration and drug type. We do so by studying the resistance mediated by Plasmodium falciparum dihydrofolate reductase (DHFR) to two related inhibitors—pyrimethamine and cycloguanil—across a breadth of drug concentrations. We first examine whether the adaptive landscapes for the two drugs are consistent with common definitions of cross-resistance. We then reconstruct all accessible pathways across the landscape, observing how their structure changes with drug environment. We offer a mechanism for non-linearity in the topography of accessible pathways by calculating of the interaction between mutation effects and drug environment, which reveals rampant patterns of epistasis. We then simulate evolution in several different drug environments to observe how these individual mutation effects (and patterns of epistasis) influence paths taken at evolutionary “forks in the road” that dictate adaptive dynamics in silico. In doing so, we reveal how classic metrics like the IC50 and minimal inhibitory concentration (MIC) are dubious proxies for understanding how evolution will occur across drug environments. We also consider how the findings reveal ambiguities in the cross-resistance concept, as subtle differences in adaptive landscape topography between otherwise equivalent drugs can drive drastically different evolutionary outcomes. Summarizing, we discuss the results with

  1. 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

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

    PubMed Central

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

    2011-01-01

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

  3. 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

  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. PMID:27220203

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

    PubMed

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

    2016-07-01

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

  6. Adverse drug interactions with nonsteroidal anti-inflammatory drugs (NSAIDs). Recognition, management and avoidance.

    PubMed

    Johnson, A G; Seideman, P; Day, R O

    1993-02-01

    The prevalence and incidence of adverse drug interactions involving nonsteroidal anti-inflammatory drugs (NSAIDs) remains unknown. To identify those proposed drug interactions of greatest clinical significance, it is appropriate to focus on interactions between commonly used and/or commonly coprescribed drugs, interactions for which there are numerous well documented case reports in reputable journals, interactions validated by well designed in vivo human studies and those affecting high-risk drugs and/or high-risk patients. While most interactions between NSAIDs and other drugs are pharmacokinetic, NSAID-related pharmacodynamic interactions may be considerably more important in the clinical context, and prescriber ignorance is likely to be a major determinant of many adverse drug interactions. Prescribing NSAIDs is relatively contraindicated for patients on oral anticoagulants due to the risk of haemorrhage, and for patients taking high-dose methotrexate due to the dangers of bone marrow toxicity, renal failure and hepatic dysfunction. Combination NSAID therapy cannot be justified as toxicity may be increased without any improvement in efficacy. Where lithium or anti-hypertensives are coprescribed with NSAIDs, close monitoring is mandatory for lithium toxicity and hypertension, respectively, and aspirin (acetylsalicylic acid) or sulindac are preferred. Phenytoin or oral hypoglycaemic agents may be administered with NSAIDs other than pyrazoles and salicylates provided that patients are monitored carefully at the initiation and cessation of NSAID treatment. Digoxin, aminoglycosides and probenecid may be coprescribed with NSAIDs, but close monitoring is required, particularly for high-risk patients such as the elderly. Indomethacin and triamterene should be avoided due to the risk of renal failure. High dose aspirin should be replaced by naproxen in patients on valproic acid (sodium valproate) and care is required when corticosteroids are administered to patients

  7. 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

  8. On-chip investigation of cell-drug interactions.

    PubMed

    Zheng, Xin Ting; Yu, Ling; Li, Peiwu; Dong, Hua; Wang, Yingjun; Liu, Yun; Li, Chang Ming

    2013-11-01

    Investigation of cell-drug interaction is of great importance in drug discovery but continues to pose significant challenges to develop robust, fast and high-throughput methods for pharmacologically profiling of potential drugs. Recently, cell chips have emerged as a promising technology for drug discovery/delivery, and their miniaturization and flow-through operation significantly reduce sample consumption while dramatically improving the throughput, reliability, resolution and sensitivity. Herein we review various types of miniaturized cell chips used in investigation of cell-drug interactions. The design and fabrication of cell chips including material selection, surface modification, cell trapping/patterning, concentration gradient generation and mimicking of in vivo environment are presented. Recent advances of on-chip investigations of cell-drug interactions, in particular the high-throughput screening, cell sorting, cytotoxicity testing, drug resistance analysis and pharmacological profiling are examined and discussed. It is expected that this survey can provide thoughtful basics and important applications of on-chip investigations of cell-drug interactions, thus greatly promoting research and development interests in this area. PMID:23428898

  9. Drug interactions and long-term antidiabetic therapy

    PubMed Central

    Logie, A. W.; Galloway, D. B.; Petrie, J. C.

    1976-01-01

    1 A study has been carried out on a representative sample (709 patients) of the Aberdeen Diabetic Clinic. The aims were to measure the occurrence and attempt to assess the clinical significance of drug interactions involving antidiabetic agents. 2 In the month before interview, 63% of the patients were taking between one and nine additional prescribed medicines. Fifty-one per cent of the patients had been exposed to one to five drugs with a potential to interact with their anti-diabetic therapy. Only 22% of the patients had taken no drugs other than their anti-diabetic medication. 3 The degree of control of diabetes, based on arbitrary criteria on data from seven consecutive out-patient visits, was significantly worse for sulphonylurea-treated patients exposed to drugs with the potential to interact compared to patients not taking such drugs. In particular, control was adversely affected in older patients taking concurrent barbiturate or diuretic therapy. No such influence of interacting drugs on control was evident in patients on insulin or biguanide therapy. 4 A system designed to prevent the unintentional initiation of drug interactions in patients on hypoglycaemic agents is described. PMID:22216525

  10. 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. PMID:22417366

  11. Potential drug interactions in an ambulatory geriatric population.

    PubMed

    Costa, A J

    1991-09-01

    Drug interactions are a common cause of iatrogenic disease in geriatric patients. Computer programs now exist which allow one to analyse groups of drugs for potential interactions. In an audit of charts of 100 geriatric patients seen in the Family Practice Center at Barberton Citizens Hospital, a computer printout was obtained, listing all patients aged 60 years and over who were seen at the Center during 1989. Names were selected randomly from this list by the head nurse and their charts were obtained for review, generating information on patient identification number, age, sex, diagnoses, medications, and allergies. The medications were analysed using the Hansten Drug Interaction Knowledge Base Program, which identified 27 patients as being on a combination of medications which had one or more potential drug interactions. A total of 37 potential drug interactions were identified in this group of 27 patients. Relative risk ratios were determined using the computer program, 'Epi Info,' for sex (female versus male), age (greater than or equal to 75 vs. 60-75 years), number of diagnoses greater than or equal to 3 vs. 0-2), and number of medications (greater than or equal to 4 vs. 0-3). The five medications, or groups of medications, which were most likely to be involved in potential drug interactions were digoxin, beta-blockers, oestrogen, oral hypoglycaemic agents, and diuretics. PMID:1822974

  12. 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

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

    PubMed Central

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

    2016-01-01

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

  14. Interactions between antiepileptic drugs and hormones.

    PubMed

    Svalheim, Sigrid; Sveberg, Line; Mochol, Monika; Taubøll, Erik

    2015-05-01

    Antiepileptic drugs (AEDs) are known to have endocrine side effects in both men and women. These can affect fertility, sexuality, thyroid function, and bone health, all functions of major importance for well-being and quality of life. The liver enzyme inducing antiepileptic drugs (EIAEDs), like phenobarbital, phenytoin, and carbamazepine, and also valproate (VPA), a non-EIAED, are most likely to cause such side effects. AED treatment can alter the levels of different sex hormones. EIAEDs increase sex hormone binding globulin (SHBG) concentrations in both men and women. Over time, this elevation can lead to lower levels of bioactive testosterone and estradiol, which may cause menstrual disturbances, sexual problems, and eventually reduced fertility. VPA can cause weight gain in both men and women. In women, VPA can also lead to androgenization with increased serum testosterone concentrations, menstrual disturbances, and polycystic ovaries. Lamotrigine has not been shown to result in endocrine side effects. The newer AEDs have not yet been thoroughly studied, but case reports indicate that some of these drugs could also be suspected to cause such effects if endocrine changes commence after treatment initiation. It is important to be aware of possible endocrine side effects of AEDs as they can have a major impact on quality of life, and are, at least partly, reversible after AED discontinuation. PMID:25797888

  15. The origin of ferromagnetic interaction between bound magnetic polarons in diluted magnetic semiconductors: A minimal model

    NASA Astrophysics Data System (ADS)

    Bednarski, Henryk

    2014-01-01

    We present a detailed analysis of the role of various interaction mechanisms contributing to the bound magnetic polaron (BMP) molecule Hamiltonian with the purpose of gaining an insight into the origin of the ferromagnetic interaction between BMPs. Explicitly, it appears that the BMP molecule Hamiltonian without interatomic direct exchange interaction does not lead to appearance of the parallel alignment of polaronic clouds in the lowest energy state even for large magnitudes of the polaronic exchange fields (up to ~65 meV in Cd0.95Mn0.05Se). Also, it appears that for the range of moderate values of polaronic exchange fields (16-25 meV in Cd0.95Mn0.05Se), the regular Hubbard BMP pair Hamiltonian must be supplemented with the direct interatomic (Heisenberg) exchange interaction to form a minimal model Hamiltonian of BMP molecule with the parallel alignment of the polaronic clouds in the lowest energy state.

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

    PubMed

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

    2015-02-01

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

  17. Truly “Rational” Polytherapy: Maximizing Efficacy and Minimizing Drug Interactions, Drug Load, and Adverse Effects

    PubMed Central

    St. Louis, Erik K

    2009-01-01

    While several newer AEDs have study data that support monotherapy usage, most possess FDA indications for adjunctive treatment of partial onset seizures, leading to their initial (and often persistent) clinical use as adjunctive polytherapy for patients with refractory epilepsy. This review considers a practical approach to the appropriate role for polytherapy in epilepsy, presents the evidence for AED polytherapy, reviews the mythic but practically reasonable concept of “rational polytherapy,” and concludes with practical strategies for avoiding and employing polytherapy in clinical practice. The appropriate indications for AED polytherapy include transitional polytherapy during titration of a new adjunctive AED toward monotherapy or long-term maintenance AED polytherapy in medically refractory epilepsy. PMID:19949567

  18. 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

  19. Kinetic analysis of drug-protein interactions by affinity chromatography.

    PubMed

    Bi, Cong; Beeram, Sandya; Li, Zhao; Zheng, Xiwei; Hage, David S

    2015-10-01

    Information on the kinetics of drug-protein interactions is of crucial importance in drug discovery and development. Several methods based on affinity chromatography have been developed in recent years to examine the association and dissociation rates of these processes. These techniques include band-broadening measurements, the peak decay method, peak fitting methods, the split-peak method, and free fraction analysis. This review will examine the general principles and applications of these approaches and discuss their use in the characterization, screening and analysis of drug-protein interactions in the body. PMID:26724332

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

    PubMed

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

    2012-01-01

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

  1. 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

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

    PubMed Central

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

    2013-01-01

    Background: Potential drug–drug interactions (PDDIs) in patients with cancer are common, but have not previously been quantified for oral anticancer treatment. We assessed the prevalence and seriousness of potential PDDIs among ambulatory cancer patients on oral anticancer treatment. Methods: A search was conducted in a computer-based medication prescription system for dispensing oral anticancer drugs to outpatients in three Dutch centres. Potential drug–drug interactions were identified using electronic (Drug Interaction Fact software) and manual screening methods (peer-reviewed reports). Results: In the 898 patients included in the study, 1359 PDDIs were identified in 426 patients (46%, 95% confidence interval (CI)=42–50%). In 143 patients (16%), a major PDDI was identified. The drug classes most frequently involved in a major PDDI were coumarins and opioids. The majority of cases concerned central nervous system interactions, PDDIs that can cause gastrointestinal toxicity and prolongation of QT intervals. In multivariate analysis, concomitant use of more drugs (odds ratio (OR)=1.66, 95% CI=1.54–1.78, P<0001) and genito-urinary cancer (OR=0.25, 95% CI=0.12–0.52, P<0001) were risk factors. Conclusion: Potential drug–drug interactions are very common among cancer patients on oral cancer therapy. Physicians and pharmacists should be more aware of these potential interactions. PMID:23412102

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed

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

    2009-12-01

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

  6. 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. PMID:26795834

  7. 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...

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

    PubMed

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

    2016-01-01

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

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

    PubMed

    Camilleri, M

    2016-08-01

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

  10. VNP: Interactive Visual Network Pharmacology of Diseases, Targets, and Drugs

    PubMed Central

    Hu, Q-N; Deng, Z; Tu, W; Yang, X; Meng, Z-B; Deng, Z-X; Liu, J

    2014-01-01

    In drug discovery, promiscuous targets, multifactorial diseases, and “dirty” drugs construct complex network relationships. Network pharmacology description and analysis not only give a systems-level understanding of drug action and disease complexity but can also help to improve the efficiency of target selection and drug design. Visual network pharmacology (VNP) is developed to visualize network pharmacology of targets, diseases, and drugs with a graph network by using disease, target or drug names, chemical structures, or protein sequence. To our knowledge, VNP is the first free interactive VNP server that should be very helpful for systems pharmacology research. VNP is freely available at http://cadd.whu.edu.cn/ditad/vnpsearch. PMID:24622768

  11. Drug interaction of levothyroxine with infant colic drops.

    PubMed

    Balapatabendi, Mihirani; Harris, David; Shenoy, Savitha D

    2011-09-01

    Infacol (Forest Laboratories UK, Kent, UK) is a widely available over-the-counter preparation used to relieve colic symptoms in neonates and infants. The active ingredient is simeticone. No drug interactions with simeticone are documented in the current summary of product characteristics. The authors report the case of an infant with confirmed congenital hypothyroidism on levothyroxine who experienced a possible drug interaction with simeticone. Despite adequate levothyroxine dosage, thyroid stimulating hormone (TSH) was high, suggesting undertreatment. Questioning revealed the child was taking Infacol drops before feeds while on levothyroxine. The colic drops were immediately discontinued and TSH promptly normalised with a reduction in thyroxine requirement to an age appropriate dosage. Drug interaction of thyroxine with simeticone has not been reported previously and is not listed in the British National Formulary for Children. Clinicians and parents need to be aware of this interaction to avoid unnecessary undertreatment and prevent potential long-term neurological sequelae. PMID:21785118

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

    PubMed

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

    2014-09-01

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

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

    PubMed

    Ereshefsky, Larry

    2009-08-01

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

  14. [Interactions between oral contraceptives and other drugs].

    PubMed

    Hansen, T H; Jensen, S B

    1991-10-28

    Failures of oral contraceptives are possible when combined with rifampicin or antiepileptics, especially phenobarbitone and phenytoin. The mode of action is shown by clinical trials to be due to induction of hepatic enzymes thus increasing the steroid metabolism. Failure or oral contraceptives has occurred with the concomitant use of antibiotics, i.e. ampicillin and sulfonamides. Clinical trials have focused upon the changes in the intestinal flora induced by antibiotics. This might influence the enterohepatic circulation of estrogen and thereby decrease reabsorption of estrogen, but this has not been definitely proved. The failures may be caused by individual pharmacokinetics of oral contraceptives. Oral contraceptives are able to influence the pharmacodynamics of various other drugs metabolized by oxidation or conjugation but besides an increased pharmacological effect of prednisolone and increased toxicity of imipramine the clinical importance is uncertain. PMID:1949335

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

    PubMed

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

    2015-12-25

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

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

    PubMed

    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

  17. 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

  18. Computational drug design targeting protein-protein interactions.

    PubMed

    Bienstock, Rachelle J

    2012-01-01

    Novel discoveries in molecular disease pathways within the cell, combined with increasing information regarding protein binding partners has lead to a new approach in drug discovery. There is interest in designing drugs to modulate protein-protein interactions as opposed to solely targeting the catalytic active site within a single enzyme or protein. There are many challenges in this new approach to drug discovery, particularly since the protein-protein interface has a larger surface area, can comprise a discontinuous epitope, and is more amorphous and less well defined than the typical drug design target, a small contained enzyme-binding pocket. Computational methods to predict modes of protein-protein interaction, as well as protein interface hot spots, have garnered significant interest, in order to facilitate the development of drugs to successfully disrupt and inhibit protein-protein interactions. This review summarizes some current methods available for computational protein-protein docking, as well as tabulating some examples of the successful design of antagonists and small molecule inhibitors for protein-protein interactions. Several of these drugs are now beginning to appear in the clinic. PMID:22316151

  19. [Drug interactions in the elderly with diabetes mellitus].

    PubMed

    Hendrychová, T; Vlček, J

    2012-04-01

    The elderly with diabetes mellitus are usually treated with many types of drugs. This, together with pharmacokinetic and pharmacodynamic changes connected with aging, can lead to an occurrence of drug interactions. They are often manifested as hypoglycaemia, decompensation of diabetes or an increase of frequency of adverse effects of drugs used together. It is important to pay an attention especially to hypoglycaemia, which brings many risks in the elderly. An article is focused on probable drug interactions when combination of various antidiabetics, antidiabetics with antihypertensives or hypolipidemics is used. Despite ACE-inhibitors and beta-blockers can influence the compensation of diabetics, their use is not contraindicated in these patients, because of their huge benefit in the prevention of cardiovascular events. An article brings an overview of antidiabetics metabolised by means of the system of cytochrome P 450 and resulting drug interactions with inhibitors and inductors of these enzymes. These drug interactions are not usually important in clinical practice and it is possible to prevent them with careful monitoring of glycaemia, instruction of patients and alternatively modification of the doses of hypoglycaemic medication after a termination of the treatment of responsible inductor or inhibitor. PMID:22559804

  20. The incidence and clinical relevance of drug interactions in pediatrics

    PubMed Central

    Qorraj-Bytyqi, Hasime; Hoxha, Rexhep; Krasniqi, Shaip; Bahtiri, Elton; Kransiqi, Valon

    2012-01-01

    Objective: To investigate the prevalence of the major drug interactions in children and verify the rate and profile of drug interactions in hospitalized pediatric patients. Materials and Methods: A retrospective study was designed and data collected from the files of hospitalized children in Pulmonology, Nephrology, and Gastroenterology wards of a Pediatric Clinic, from July 1999 to 2004. Results: From the analyzed material, we detected 34 cases of interactions, of which 1 was pharmacodynamics interaction, 13 were pharmacokinetic interactions, and 20 of unknown mechanisms. According to the rate of significance, 4 cases were categorized in the first significance rate of interaction, 18 cases in the second significance rate, 1 case of the third significance rate, 4 cases of the fourth significance rate, and 7 cases of the fifth significance rate. According to onset of cases, 33 cases were of delayed onset, and according to severity of interactions, in 7 cases we noticed major severity interaction, in 19 cases moderate severity and in 8 cases minor severity. Conclusions: The presence of drug interactions is a permanent risk in the pediatric clinic. Then, we can conclude that continued education, computer system for prescriptions, pharmacotherapy monitoring of patients, and the pharmacist participation in the multidisciplinary team are some manners of improving the treatment to hospitalized patients. PMID:23326100

  1. 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. PMID:25267448

  2. Pharmacokinetic herb-drug interactions (part 2): drug interactions involving popular botanical dietary supplements and their clinical relevance.

    PubMed

    Gurley, Bill J; Fifer, Espero Kim; Gardner, Zoë

    2012-09-01

    In Part 2 of this review, a critical examination of the pertinent scientific literature is undertaken in order to assess the interaction risk that popular dietary supplements may pose when taken concomitantly with conventional medications. Botanicals most likely to produce clinically important herb-drug interactions are those whose phytochemicals act as mechanism-based inhibitors of cytochrome P450 enzyme activity (e.g., Hydrastis canadensis, Piper nigrum, Schisandra chinensis) or function as ligands for orphan nuclear receptors (e.g., Hypericum perforatum). In addition, several external factors unrelated to phytochemical pharmacology can augment the drug interaction potential of botanical supplements. PMID:22565299

  3. Computational modelling of protein interactions: energy minimization for the refinement and scoring of association decoys.

    PubMed

    Dibrov, Alexander; Myal, Yvonne; Leygue, Etienne

    2009-12-01

    The prediction of protein-protein interactions based on independently obtained structural information for each interacting partner remains an important challenge in computational chemistry. Procedures where hypothetical interaction models (or decoys) are generated, then ranked using a biochemically relevant scoring function have been garnering interest as an avenue for addressing such challenges. The program PatchDock has been shown to produce reasonable decoys for modeling the association between pig alpha-amylase and the VH-domains of camelide antibody raised against it. We designed a biochemically relevant method by which PatchDock decoys could be ranked in order to separate near-native structures from false positives. Several thousand steps of energy minimization were used to simulate induced fit within the otherwise rigid decoys and to rank them. We applied a partial free energy function to rank each of the binding modes, improving discrimination between near-native structures and false positives. Sorting decoys according to strain energy increased the proportion of near-native decoys near the bottom of the ranked list. Additionally, we propose a novel method which utilizes regression analysis for the selection of minimization convergence criteria and provides approximation of the partial free energy function as the number of algorithmic steps approaches infinity. PMID:19774465

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

    PubMed Central

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

    2014-01-01

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

  5. Physiologically based pharmacokinetic modeling framework for quantitative prediction of an herb-drug interaction.

    PubMed

    Brantley, S J; Gufford, B T; Dua, R; Fediuk, D J; Graf, T N; Scarlett, Y V; Frederick, K S; Fisher, M B; Oberlies, N H; Paine, M F

    2014-01-01

    Herb-drug interaction predictions remain challenging. Physiologically based pharmacokinetic (PBPK) modeling was used to improve prediction accuracy of potential herb-drug interactions using the semipurified milk thistle preparation, silibinin, as an exemplar herbal product. Interactions between silibinin constituents and the probe substrates warfarin (CYP2C9) and midazolam (CYP3A) were simulated. A low silibinin dose (160 mg/day × 14 days) was predicted to increase midazolam area under the curve (AUC) by 1%, which was corroborated with external data; a higher dose (1,650 mg/day × 7 days) was predicted to increase midazolam and (S)-warfarin AUC by 5% and 4%, respectively. A proof-of-concept clinical study confirmed minimal interaction between high-dose silibinin and both midazolam and (S)-warfarin (9 and 13% increase in AUC, respectively). Unexpectedly, (R)-warfarin AUC decreased (by 15%), but this is unlikely to be clinically important. Application of this PBPK modeling framework to other herb-drug interactions could facilitate development of guidelines for quantitative prediction of clinically relevant interactions.CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e107; doi:10.1038/psp.2013.69; advance online publication 26 March 2014. PMID:24670388

  6. Physiologically Based Pharmacokinetic Modeling Framework for Quantitative Prediction of an Herb–Drug Interaction

    PubMed Central

    Brantley, S J; Gufford, B T; Dua, R; Fediuk, D J; Graf, T N; Scarlett, Y V; Frederick, K S; Fisher, M B; Oberlies, N H; Paine, M F

    2014-01-01

    Herb–drug interaction predictions remain challenging. Physiologically based pharmacokinetic (PBPK) modeling was used to improve prediction accuracy of potential herb–drug interactions using the semipurified milk thistle preparation, silibinin, as an exemplar herbal product. Interactions between silibinin constituents and the probe substrates warfarin (CYP2C9) and midazolam (CYP3A) were simulated. A low silibinin dose (160 mg/day × 14 days) was predicted to increase midazolam area under the curve (AUC) by 1%, which was corroborated with external data; a higher dose (1,650 mg/day × 7 days) was predicted to increase midazolam and (S)-warfarin AUC by 5% and 4%, respectively. A proof-of-concept clinical study confirmed minimal interaction between high-dose silibinin and both midazolam and (S)-warfarin (9 and 13% increase in AUC, respectively). Unexpectedly, (R)-warfarin AUC decreased (by 15%), but this is unlikely to be clinically important. Application of this PBPK modeling framework to other herb–drug interactions could facilitate development of guidelines for quantitative prediction of clinically relevant interactions. PMID:24670388

  7. Drug interactions involving cimetidine--mechanisms, documentation, implications.

    PubMed

    Greene, W

    1984-01-01

    In summary, cimetidine is a potent inhibitor of liver microsomal activity, which may also decrease hepatic blood flow. Other effects of the drug include inhibition of gastric secretion and intrinsic toxic properties. These effects, combined with the common use of cimetidine in clinical practice, make the risk of adverse drug interactions a relatively frequent risk in the clinical setting. Although a multitude of interactions with cimetidine has been evaluated, many of these are incompletely described or understood. At the present time, a potentially significant alteration of absorption appears to exist with only ketoconazole, elemental iron, vitamin B12 (long-term therapy), and pancreatic enzyme supplements (increased activity). Significant metabolic inhibition or decreased excretion appears to exist with warfarin, propranolol, theophylline, phenytoin, quinidine, possibly lidocaine and procainamide, and certain benzodiazepines. Other potential, but less well ascertained interactions may involve the narcotic analgesics, caffeine, ethanol, pentobarbital, imipramine, chlormethiazole, and metronidazole. In these settings, the clinician must be aware of interaction potential, and astutely monitor the patient during combination therapy. Other data indicate that concomitant administration of antacids may reduce the absorption of cimetidine, that the drug may protect against the toxic effects of acetaminophen overdose, and that combination with certain other myelosuppressants may carry a significant risk. Thus, in regard to these reports, cimetidine is a drug with complex effects on the absorption, elimination, and toxicity of other drugs. When used in the setting of multiple drug therapy, the clinician must be alert to potentially increased or decreased effects of the drugs mentioned in this review. In addition, one must be aware that other hepatically metabolised agents not mentioned here may be affected by the addition of cimetidine therapy. Because of the therapeutic

  8. Quantitative monitoring of drug-tissue interaction in perfused organs

    NASA Astrophysics Data System (ADS)

    Kessler, Manfred D.; Nastac, Dumitru I.; Frank, Klaus H.

    2002-06-01

    In pharmacology many optical sensors are applied for investigations in vitro and in reduced systems. Due to a lack of sensors for optical imaging of functional structures in capillaries as well as in subcellular spaces the drug-tissue interaction in organs could not be monitored systematically. However, recent developments opened the door of this microcosm of life in its smallest entities. This will enable a better understanding of the questions of area and quality of drug action in tissue.

  9. 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. PMID:24997296

  10. 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

  11. Investigation of drug-porous adsorbent interactions in drug mixtures with selected porous adsorbents.

    PubMed

    Madieh, Shadi; Simone, Michael; Wilson, Wendy; Mehra, Dev; Augsburger, Larry

    2007-04-01

    The adsorption of drugs onto porous substrates may prove to be a convenient method by which to enhance the dissolution rate of certain poorly water-soluble drugs in body fluids. The purpose of this research is to provide a better understanding of the type of interactions occurring between drugs and certain pharmaceutically acceptable porous adsorbents that leads to enhanced drug dissolution rates. The interactions between ibuprofen (acidic drug), acetaminophen (acidic drug), dipyridamole (basic drug), and the porous adsorbents used (calcium silicate and silica gel) were investigated using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier Transform infrared spectroscopy (FTIR). DSC and PXRD results indicated a significant loss of crystallinity of both ibuprofen and acetaminophen but not dipyridamole. In the case of ibuprofen, FTIR results indicated the ionization of the carboxylic group based on the shift in the FTIR carboxylic band. Dissolution of ibuprofen from its mixtures with porous adsorbents was found to be significantly higher compared to the neat drug, whereas dipyridamole dissolution from its mixtures with porous adsorbents was not significantly different from that of the neat drug. PMID:17221849

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

    PubMed

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

    2016-03-01

    Drug-drug interactions (DDIs) may result in the alteration of therapeutic response. Sometimes they may increase the untoward effects of many drugs. Hospitalized cardiac patients need more attention regarding drug-drug interactions due to complexity of their disease and therapeutic regimen. This research was performed to find out types, prevalence and association between various predictors of potential drug-drug interactions (pDDIs) in the Department of Cardiology and to report common interactions. This study was performed in the hospitalized cardiac patients at Ayub Teaching Hospital, Abbottabad, Pakistan. Patient charts of 2342 patients were assessed for pDDIs using Micromedex® Drug Information. Logistic regression was applied to find predictors of pDDIs. The main outcome measure in the study was the association of the potential drug-drug interactions with various factors such as age, gender, polypharmacy, and hospital stay of the patients. We identified 53 interacting-combinations that were present in total 5109 pDDIs with median number of 02 pDDIs per patient. Overall, 91.6% patients had at least one pDDI; 86.3% were having at least one major pDDI, and 84.5% patients had at least one moderate pDDI. Among 5109 identified pDDIs, most were of moderate (55%) or major severity (45%); established (24.2%), theoretical (18.8%) or probable (57%) type of scientific evidence. Top 10 common pDDIs included 3 major and 7 moderate interactions. Results obtained by multivariate logistic regression revealed a significant association of the occurrence of pDDIs in patient with age of 60 years or more (p < 0.001), hospital stay of 7 days or longer (p < 0.001) and taking 7 or more drugs (p < 0.001). We found a high prevalence for pDDIs in the Department of Cardiology, most of which were of moderate severity. Older patients, patients with longer hospital stay and with elevated number of prescribed drugs were at higher risk of pDDIs. PMID:27013915

  13. 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

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

    PubMed Central

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

    2011-01-01

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

  15. 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. PMID:23773634

  16. A global view of drug-therapy interactions

    PubMed Central

    Nacher, Jose C; Schwartz, Jean-Marc

    2008-01-01

    Background Network science is already making an impact on the study of complex systems and offers a promising variety of tools to understand their formation and evolution in many disparate fields from technological networks to biological systems. Even though new high-throughput technologies have rapidly been generating large amounts of genomic data, drug design has not followed the same development, and it is still complicated and expensive to develop new single-target drugs. Nevertheless, recent approaches suggest that multi-target drug design combined with a network-dependent approach and large-scale systems-oriented strategies create a promising framework to combat complex multi-genetic disorders like cancer or diabetes. Results We here investigate the human network corresponding to the interactions between all US approved drugs and human therapies, defined by known relationships between drugs and their therapeutic applications. Our results show that the average paths in this drug-therapy network are shorter than three steps, indicating that distant therapies are separated by a surprisingly low number of chemical compounds. We also identify a sub-network composed by drugs with high centrality measures in the drug-therapy network, which represent the structural backbone of this system and act as hubs routing information between distant parts of the network. Conclusion These findings provide for the first time a global map of the large-scale organization of all known drugs and associated therapies, bringing new insights on possible strategies for future drug development. Special attention should be given to drugs which combine the two properties of (a) having a high centrality value in the drug-therapy network and (b) acting on multiple molecular targets in the human system. PMID:18318892

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

    PubMed Central

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

    2016-01-01

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

  18. 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

  19. 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

  20. 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

  1. 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). PMID:26526838

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2012-05-01

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

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

    PubMed

    Lepist, Eve-Irene; Ray, Adrian S

    2016-07-01

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

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

    PubMed Central

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

    2014-01-01

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

  6. Drug interactions with the newer antiepileptic drugs (AEDs)--Part 2: pharmacokinetic and pharmacodynamic interactions between AEDs and drugs used to treat non-epilepsy disorders.

    PubMed

    Patsalos, Philip N

    2013-12-01

    Since antiepileptic drugs (AEDs) are prescribed to treat various non-epilepsy-related disorders in addition to the fact that patients with epilepsy may develop concurrent disorders that will need treatment, the propensity for AEDs to interact with non-AEDs is considerable and indeed can present a difficult clinical problem. The present review details the pharmacokinetic and pharmacodynamic interactions that have been reported to occur with the new AEDs (eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, pregabalin, retigabine (ezogabine), rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide) and drugs used to treat non-epilepsy disorders. Interaction study details are described, as necessary, so as to allow the reader to take a view as to the possible clinical significance of particular interactions. Pharmacokinetic interactions relate to hepatic enzyme induction or inhibition and involved a variety of drugs including psychoactive drugs, cardioactive drugs, oral contraceptives, antituberculous agents, analgesics and antineoplastic drugs. A total of 68 pharmacokinetic interactions have been described, with lamotrigine (n = 22), topiramate (n = 18) and oxcarbazepine (n = 7) being associated with most, whilst lacosamide, pregabalin, stiripentol and vigabatrin are associated with none. Overall, only three pharmacodynamic interactions have been described and occur with oxcarbazepine, perampanel and pregabalin. PMID:23794036

  7. [Anti-osteoporotic drugs and their interactions with multiple organs].

    PubMed

    Takeuchi, Yasuhiro

    2016-08-01

    Anti-osteoporotic drugs directly control bone metabolism. Then, they are possibly involved in interactions between bone and many other tissues. It is not, however, clear how they influence several organs other than bone, or what clinical significance they have. Recently, accumulating evidence suggests that osteocalcin as a humoral factor from bone is actively involved in glucose metabolism. Since interaction between osteoporosis and diabetes mellitus is an emerging clinical issue, there are several clinical questions under vigorous investigations. PMID:27461502

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

    PubMed

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

    2006-12-01

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

  9. 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.

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

    PubMed

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

    2016-01-01

    Decision support systems for alert drug-drug interactions have been shown as valid strategy to reduce medical error. Even so the use of these systems has not been as expected, probably due to the lack of a suitable design. This study compares two interfaces, one of them developed using participatory design techniques (based on user centered design processes). This work showed that the use of these techniques improves satisfaction, effectiveness and efficiency in an alert system for drug-drug interactions, a fact that was evident in specific situations such as the decrease of errors to meet the specified task, the time, the workload optimization and users overall satisfaction with the system. PMID:27577343

  11. 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

  12. Drug Interactions of Direct-Acting Oral Anticoagulants.

    PubMed

    Fitzgerald, John Leonard; Howes, Laurence Guy

    2016-09-01

    In recent years, new direct-acting oral anticoagulants (DOACs) have been introduced into clinical practice that specifically inhibit either factor Ia or Xa. These drugs have, to a large extent, replaced warfarin for the treatment of venous thrombosis, pulmonary embolism, and non-valvular atrial fibrillation. They have potential advantages over warfarin in providing more stable anticoagulation and the lack of a need for regular venesection to monitor activity. They also have the promise of less drug and food interactions. All of these drugs are substrates for the permeability glycoprotein (P-gp) excretion system, and several are metabolised, in part, by cytochrome P450 (CYP) 3A4. This current article assesses the interactions that do or may occur with the DOACs, particularly with respect to the P-gp and CYP3A4 systems. PMID:27435452

  13. Interactive perspective: drug development and FDA approval, 1938-2013.

    PubMed

    2015-02-01

    Interactive Perspective: Drug Development and FDA Approval, 1938-2013 (June 26, 2014;370:e39). The order of authors was incorrect; Dr. Darrow should have been listed first, and Dr. Kesselheim second. The article is correct at NEJM.org. PMID:25651270

  14. 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...

  15. 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. PMID:26489070

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

    PubMed

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

    2010-10-01

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

  17. Nanoassembly of surfactants with interfacial drug-interactive motifs as tailor-designed drug carriers.

    PubMed

    Gao, Xiang; Huang, Yixian; Makhov, Alexander M; Epperly, Michael; Lu, Jianqin; Grab, Sheila; Zhang, Peijun; Rohan, Lisa; Xie, Xiang-Qun; Wipf, Peter; Greenberger, Joel; Li, Song

    2013-01-01

    PEGylated lipopeptide surfactants carrying drug-interactive motifs specific for a peptide-nitroxide antioxidant, JP4-039, were designed and constructed to facilitate the solubilization of this drug candidate as micelles and emulsion nanoparticles. A simple screening process based on the ability that prevents the formation of crystals of JP4-039 in aqueous solution was used to identify agents that have potential drug-interactive activities. Several protected lysine derivatives possessing this activity were identified, of which α-Fmoc-ε-t-Boc lysine is the most potent, followed by α-Cbz- and α-iso-butyloxycarbonyl-ε-t-Boc-lysine. Using a polymer-supported liquid-phase synthesis approach, a series of synthetic lipopeptide surfactants with PEG headgroup, varied numbers and geometries of α-Fmoc or α-Cbz-lysyl groups located at interfacial region as the drug-interactive domains, and oleoyl chains as the hydrophobic tails were synthesized. All α-Fmoc-lysyl-containing lipopeptide surfactants were able to solubilize JP4-039 as micelles, with enhanced solubilizing activity for surfactants with increased numbers of α-Fmoc groups. The PEGylated lipopeptide surfactants with α-Fmoc-lysyl groups alone tend to form filamentous or wormlike micelles. The presence of JP4-039 transformed α-Fmoc-containing filamentous micelles into dots and barlike mixed micelles with substantially reduced sizes. Fluorescence quenching and NMR studies revealed that the drug and surfactant molecules were in close proximity in the complex. JP4-039-loaded emulsion carrying α-Cbz-containing surfactants demonstrated enhanced stability over drug-loaded emulsion without lipopeptide surfactants. JP4-039 emulsion showed a significant mitigation effect on mice exposed to a lethal dose of radiation. PEGylated lipopeptides with an interfacially located drug-interactive domain are therefore tailor-designed formulation materials potentially useful for drug development. PMID:23244299

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

    PubMed

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

    2013-05-16

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

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

    PubMed

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

    2016-06-01

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

  20. In vitro interaction of lithotripter shock waves and cytotoxic drugs.

    PubMed Central

    Gambihler, S.; Delius, M.

    1992-01-01

    The effect of a combination of lithotripter shock waves and cytotoxic drugs was examined in vitro. L1210 cells in suspension were exposed to shock waves during incubation with cislatin, doxorubicin, daunorubicin, THP-doxorubicin, or aclacinomycin. Proliferation was determined using the 3-4,5 dimethylthiazol-2,5 diphenyl tetrazolium bromide assay. Dose enhancement ratios were calculated for each drug in order to determine the effect of the additional exposure to shock waves. In addition, partition coefficients and IC50s of the drugs were determined. It was found, that the dose enhancement ratios increased for the drugs with decreasing cytotoxicity. The effect of all five drugs was enhanced by shock waves to a higher degree at 7 min incubation as compared to 50 min incubation. The effect of cisplatin was most significantly enhanced, with a dose enhancement ratio of 6.7 at 7 min incubation. The enhancement increased with the operating voltage used for generating the shock waves, and was only present when cells were exposed to shock waves during the incubation with the drug. An increase in cellular membrane permeability is proposed as the mechanism of interaction between shock waves and drugs. PMID:1637679

  1. 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. PMID:23889048

  2. Minimally Invasive Swine Experimental Model for the In Vivo Study of Liver Metabolism of Drugs

    PubMed Central

    Piazza, O; Romano, R; Scarpati, G; Esposito, C; Cavaglià, E; Corona, M

    2012-01-01

    Purpose To develop a clinically relevant porcine model for the study of hepatic metabolism of drugs by means of hepatic vein catheterization. Materials and Methods: review of literature and elaboration of a hypothesis, design of an experimental method. Results: recent clinical studies were conducted by withdrawing cirrhotic patients’ blood from right hepatic vein during hepatic vein pressure gradient measurements. Basing on our personal clinical experience and evaluation of research needs, an experimental model is proposed. Conclusions: contemporary measurement of peripheral and hepatic concentration of drugs by peripheral vein and hepatic vein catheterization can be used to create a reliable and reproducible porcine model to study liver metabolism of drugs in vivo. PMID:23905064

  3. 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

  4. 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

  5. Clinical significance of pharmacokinetic interactions between antiepileptic and psychotropic drugs.

    PubMed

    Spina, Edoardo; Perucca, Emilio

    2002-01-01

    As antiepileptic drugs (AEDs) and psychotropic agents are increasingly used in combination, the possibility of pharmacokinetic interactions between these compounds is relatively common. Most pharmacokinetic interactions between AEDs and psychoactive drugs occur at a metabolic level, and usually involve changes in the activity of the cytochrome P450 mixed-function oxidases (CYP) involved in their biotransformation. As a consequence of CYP inhibition or induction, plasma concentrations of a given drug may reach toxic or subtherapeutic levels, and dosage adjustments may be required to avoid adverse effects or clinical failure. Enzyme-inducing AEDs, such as carbamazepine (CBZ), phenytoin (PHT), and barbiturates, stimulate the oxidative biotransformation of many concurrently prescribed psychotropics. In particular, these AEDs may decrease the plasma concentrations of tricyclic antidepressants, many antipsychotics, including traditional compounds, i.e., haloperidol and chlorpromazine, and newer agents, i.e., clozapine, risperidone, olanzapine, quetiapine, and ziprasidone, and some benzodiazepines. Conversely, new AEDs appear to have a lower potential for interactions with all psychotropic drugs. While antipsychotics and anxiolytics do not significantly influence the pharmacokinetics of most AEDs, some newer antidepressants, such as viloxazine, fluoxetine, and fluvoxamine, may lead to higher serum levels of some AEDs, namely CBZ and PHT, through inhibition of CYP enzymes. No significant pharmacokinetic interactions have been documented between AEDs and lithium. Information about CYP enzymes responsible for the biotransformation of individual agents and about the effects of these compounds on the activity of specific CYP enzymes may help in predicting and avoiding clinically significant interactions. Apart from careful clinical observation, serum level monitoring of AEDs and psychotropic drugs can be useful in determining the need for dosage adjustments, especially if

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

    PubMed

    Langer, Oliver

    2016-07-01

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

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

    PubMed Central

    VandenBrink, Brooke M.; Isoherranen, Nina

    2010-01-01

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

  8. Charge transfer interaction using quasiatomic minimal-basis orbitals in the effective fragment potential method

    SciTech Connect

    Xu, Peng; Gordon, Mark S.

    2013-11-21

    The charge transfer (CT) interaction, the most time-consuming term in the general effective fragment potential method, is made much more computationally efficient. This is accomplished by the projection of the quasiatomic minimal-basis-set orbitals (QUAMBOs) as the atomic basis onto the self-consistent field virtual molecular orbital (MO) space to select a subspace of the full virtual space called the valence virtual space. The diagonalization of the Fock matrix in terms of QUAMBOs recovers the canonical occupied orbitals and, more importantly, gives rise to the valence virtual orbitals (VVOs). The CT energies obtained using VVOs are generally as accurate as those obtained with the full virtual space canonical MOs because the QUAMBOs span the valence part of the virtual space, which can generally be regarded as “chemically important.” The number of QUAMBOs is the same as the number of minimal-basis MOs of a molecule. Therefore, the number of VVOs is significantly smaller than the number of canonical virtual MOs, especially for large atomic basis sets. This leads to a dramatic decrease in the computational cost.

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

    PubMed

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

    2015-09-01

    Myopathy is a group of muscle diseases that can be induced or exacerbated by drug-drug interactions (DDIs). We sought to identify clinically important myopathic DDIs and elucidate their underlying mechanisms. Five DDIs were found to increase the risk of myopathy based on analysis of observational data from the Indiana Network of Patient Care. Loratadine interacted with simvastatin (relative risk 95% confidence interval [CI] = [1.39, 2.06]), alprazolam (1.50, 2.31), ropinirole (2.06, 5.00), and omeprazole (1.15, 1.38). Promethazine interacted with tegaserod (1.94, 4.64). In vitro investigation showed that these DDIs were unlikely to result from inhibition of drug metabolism by CYP450 enzymes or from inhibition of hepatic uptake via the membrane transporter OATP1B1/1B3. However, we did observe in vitro synergistic myotoxicity of simvastatin and desloratadine, suggesting a role in loratadine-simvastatin interaction. This interaction was epidemiologically confirmed (odds ratio 95% CI = [2.02, 3.65]) using the data from the US Food and Drug Administration Adverse Event Reporting System. PMID:25975815

  10. Prediction of Cancer Drugs by Chemical-Chemical Interactions

    PubMed Central

    Li, Hai-Peng; Feng, Kai-Yan; Chen, Lei; Zheng, Ming-Yue; Cai, Yu-Dong

    2014-01-01

    Cancer, which is a leading cause of death worldwide, places a big burden on health-care system. In this study, an order-prediction model was built to predict a series of cancer drug indications based on chemical-chemical interactions. According to the confidence scores of their interactions, the order from the most likely cancer to the least one was obtained for each query drug. The 1st order prediction accuracy of the training dataset was 55.93%, evaluated by Jackknife test, while it was 55.56% and 59.09% on a validation test dataset and an independent test dataset, respectively. The proposed method outperformed a popular method based on molecular descriptors. Moreover, it was verified that some drugs were effective to the ‘wrong’ predicted indications, indicating that some ‘wrong’ drug indications were actually correct indications. Encouraged by the promising results, the method may become a useful tool to the prediction of drugs indications. PMID:24498372