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1

Assessing drug distribution in tissues expressing P-glycoprotein through physiologically based pharmacokinetic modeling: model structure and parameters determination  

PubMed Central

Background The expression and activity of P-glycoproteins due to genetic or environmental factors may have a significant impact on drug disposition, drug effectiveness or drug toxicity. Hence, characterization of drug disposition over a wide range of conditions of these membrane transporters activities is required to better characterize drug pharmacokinetics and pharmacodynamics. This work aims to improve our understanding of the impact of P-gp activity modulation on tissue distribution of P-gp substrate. Methods A PBPK model was developed in order to examine activity and expression of P-gp transporters in mouse brain and heart. Drug distribution in these tissues was first represented by a well-stirred (WS) model and then refined by a mechanistic transport-based (MTB) model that includes P-gp mediated transport of the drug. To estimate transport-related parameters, we developed an original three-step procedure that allowed extrapolation of in vitro measurements of drug permeability to the in vivo situation. The model simulations were compared to a limited set of data in order to assess the model ability to reproduce the important information of drug distributions in the considered tissues. Results This PBPK model brings insights into the mechanism of drug distribution in non eliminating tissues expressing P-gp. The MTB model accounts for the main transport mechanisms involved in drug distribution in heart and brain. It points out to the protective role of P-gp at the blood-brain barrier and represents thus a noticeable improvement over the WS model. Conclusion Being built prior to in vivo data, this approach brings an interesting alternative to fitting procedures, and could be adapted to different drugs and transporters. The physiological based model is novel and unique and brought effective information on drug transporters.

Fenneteau, Frederique; Turgeon, Jacques; Couture, Lucie; Michaud, Veronique; Li, Jun; Nekka, Fahima

2009-01-01

2

Simultaneous confocal fluorescence microscopy and optical coherence tomography for drug distribution and tissue integrity assessment  

NASA Astrophysics Data System (ADS)

The effectiveness of microbicidal gels, topical products developed to prevent infection by sexually transmitted diseases including HIV/AIDS, is governed by extent of gel coverage, pharmacokinetics of active pharmaceutical ingredients (APIs), and integrity of vaginal epithelium. While biopsies provide localized information about drug delivery and tissue structure, in vivo measurements are preferable in providing objective data on API and gel coating distribution as well as tissue integrity. We are developing a system combining confocal fluorescence microscopy with optical coherence tomography (OCT) to simultaneously measure local concentrations and diffusion coefficients of APIs during transport from microbicidal gels into tissue, while assessing tissue integrity. The confocal module acquires 2-D images of fluorescent APIs multiple times per second allowing analysis of lateral diffusion kinetics. The custom Fourier domain OCT module has a maximum a-scan rate of 54 kHz and provides depth-resolved tissue integrity information coregistered with the confocal fluorescence measurements. The combined system is validated by imaging phantoms with a surrogate fluorophore. Time-resolved API concentration measured at fixed depths is analyzed for diffusion kinetics. This multimodal system will eventually be implemented in vivo for objective evaluation of microbicide product performance.

Rinehart, Matthew T.; Lacroix, Jeffrey; Henderson, Marcus; Katz, David; Wax, Adam

2011-02-01

3

Drug Threat Assessment: Kentucky.  

National Technical Information Service (NTIS)

This report is a brief update to the Kentucky Drug Threat Assessment, which is a strategic assessment of the status and outlook of the drug threat to Kentucky. Analytical judgment determined the threat posed by each drug type or category, taking into acco...

2002-01-01

4

Drug Threat Assessment: Wisconsin. Update.  

National Technical Information Service (NTIS)

This report is a brief update to the Wisconsin Drug Threat Assessment, which is a strategic assessment of the status and outlook of the drug threat to Wisconsin. Analytical judgment determined the threat posed by each drug type or category, taking into ac...

2002-01-01

5

A Quantitative Assessment of Nanoparticle Ligand Distributions: Implications for Targeted Drug and Imaging Delivery in Dendrimer Conjugates  

PubMed Central

Functional nanoparticles often contain ligands including targeting molecules, fluorophores, and/or active moieties such as drugs. Characterizing the number of these ligands bound to each particle, and the distribution of nanoparticle-ligand species, is important for understanding the nanomaterial’s function. In this study, the amide coupling methods commonly used to conjugate ligands to poly(amidoamine) (PAMAM) dendrimers were examined. A skewed Poisson distribution was observed and quantified using HPLC for two sets of dendrimer-ligand samples prepared using the amine terminated form of the PAMAM dendrimer and a partially acetylated form of the PAMAM dendrimer that has been used for targeted in vivo drug delivery. The prepared samples had an average number of ligands per dendrimer ranging from 0.4 to 13. Distributions identified by HPLC are in excellent agreement with the mean ligand/dendrimer ratio, measured by 1H NMR, gel permeation chromatography (GPC), and potentiometric titration. These results provide insight into the heterogeneity of distributions that are obtained for many classes of nanomaterials to which ligands are conjugated and belie the use of simple cartoon models that present the “average” number of ligands bound as a physically meaningful representation for the material.

Mullen, Douglas G.; Fang, Ming; Desai, Ankur; Baker, James R.; Orr, Bradford G.; Banaszak Holl, Mark M.

2010-01-01

6

Drug Threat Assessment Update: South Carolina.  

National Technical Information Service (NTIS)

This report is a brief update to the South Carolina Drug Threat Assessment, which is a strategic assessment of the status and outlook of the drug threat to South Carolina. Analytical judgment determined the threat posed by each drug type or category, taki...

2002-01-01

7

National Drug Threat Assessment, 2003.  

National Technical Information Service (NTIS)

The trafficking and abuse of illicit drugs and diverted pharmaceuticals pose a serious threat to the United States because of the adverse effects of drug abuse on the lives of millions of Americans and the substantial resources consumed in combating illic...

2003-01-01

8

National Drug Threat Assessment, 2004.  

National Technical Information Service (NTIS)

The trafficking and abuse of illicit drugs and diverted pharmaceuticals pose a serious threat to the United States because of the adverse effects of drug abuse on the lives of millions of Americans and the substantial resources consumed in combating illic...

2004-01-01

9

National Drug Threat Assessment, 2005.  

National Technical Information Service (NTIS)

The trafficking and abuse of illicit drugs and diverted pharmaceuticals pose a serious threat to the United States because of the adverse effects of drug abuse on the lives of millions of Americans and the substantial resources consumed in combating illic...

2005-01-01

10

Appropriately assessing renal function for drug dosing.  

PubMed

Chronic kidney disease affects millions of Americans. Many drugs are eliminated from the body by the kidneys. As renal function declines due to the disease, drugs that are normally eliminated by the kidneys can accumulate, potentially leading to toxicity. Assessing kidney function in patients is essential in determining the appropriate dose of medications to achieve the desired clinical outcome while minimizing the potential for toxicity. PMID:20629469

Dong, Kimberly; Quan, David J

2010-01-01

11

Effects of Drug Transporters on Volume of Distribution  

Microsoft Academic Search

Recently, drug transporters have emerged as significant modifiers of a patient’s pharmacokinetics. In cases where the functioning\\u000a of drug transporters is altered, such as by drug-drug interactions, by genetic polymorphisms, or as evidenced in knockout\\u000a animals, the resulting change in volume of distribution can lead to a significant change in drug effect or likelihood of toxicity,\\u000a as well as a

Anita Grover; Leslie Z. Benet

2009-01-01

12

The effect of critical illness on drug distribution.  

PubMed

The complexity of managing critically ill patients has increased since the early establishment of intensive care units in the 1950s. Despite of the fact that the number of drugs available to clinicians has increased, the understanding of the pharmacokinetics of individual drugs in specific disease states is still a matter of concern. Among the pharmacokinetic processes which may be affected in this patient population, drug distribution is a very important one. Changes in drug distribution may cause inadequate drug exposure at the infection site and consequently influence clinical outcome. Since drug distribution is dependent on a plethora of factors, including the physicochemical characteristics of the drug, we will focus on the most common mechanisms responsible for altered tissue distribution. These include changes in protein binding, fluid shifts, and pH changes. Although less common, alterations in organ perfusion may also play a role, particularly in heart failure patients. Despite great advances in understanding the distribution of antibacterial drugs, further studies are needed to define the consequences of changed drug distribution in critically ill patients on dosing regimens and clinical outcome. PMID:21554214

Gonzalez, Daniel; Conrado, Daniela J; Theuretzbacher, Ursula; Derendorf, Hartmut

2011-12-01

13

Rapid assessment of drug metabolism in the drug discovery process  

Microsoft Academic Search

For a few years, in vitro models have been used as part of high-throughput screening (HTS) programs to characterize metabolic stability, drug permeability and drug solubility. This has allowed the rapid selection of lead candidates based not only on pharmacological endpoints but also on biopharmaceutical specifications. What has now become clear is that the huge amount of data produced to

Marc Bertrand; Peter Jackson; Bernard Walther

2000-01-01

14

Technology Assessment of Distributed Systems.  

National Technical Information Service (NTIS)

There are multiple advantages to configuring the available resources as distributed system as opposed to a simple network. Performance is improved with a distributed system since the storage space, processors, and communications devices are equally loaded...

1989-01-01

15

Pharmacological Mechanism-Based Drug Safety Assessment and Prediction  

Microsoft Academic Search

Advances in cheminformatics, bioinformatics, and pharmacology in the context of biological systems are now at a point that these tools can be applied to mechanism-based drug safety assessment and prediction. The development of such predictive tools at the US Food and Drug Administration (FDA) will complement ongoing efforts in drug safety that are focused on spontaneous adverse event reporting and

D R Abernethy; J Woodcock; L J Lesko; Abernethy

2011-01-01

16

Transporters: Importance in Drug Absorption, Distribution, and Removal  

Microsoft Academic Search

\\u000a There is an increasing appreciation of the role that transport proteins play in the absorption, distribution, and elimination\\u000a of a wide variety of drugs in clinical use. These transporters can be divided into efflux transporters belonging to the ATP-binding\\u000a cassette (ABC) family and solute carrier (SLC) family members that mediate the influx or bidirectional movement of drugs across\\u000a the cell

Frans G. M. Russel

17

Modeling the dynamics of incentives in community drug distribution programs.  

PubMed

Neglected tropical disease (NTD) control programs rely on an army of volunteers, or community drug distributors (CDDs), to distribute preventative drug packages through community and school-based platforms. Both monetary and non-monetary incentives are frequently provided to CDDs, although the impact on program performance is not well documented or understood. This article presents a descriptive framework to help visualize the dynamics of incentives as part of mass drug administration (MDA) campaigns and to guide future research in this area. PMID:24793100

Downs, Philip W; Bardin, Lauren E; McFarland, Deborah A

2014-07-01

18

21 CFR 203.50 - Requirements for wholesale distribution of prescription drugs.  

Code of Federal Regulations, 2013 CFR

...distribution of prescription drugs. (a) Identifying statement for sales by unauthorized distributors...identifying each prior sale, purchase, or trade of such drug. This identifying...identifying the previous sales of the component drug or drugs....

2013-04-01

19

49 CFR 32.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

... To whom must I distribute my drug-free workplace statement? 32.210 Section...GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) ...To whom must I distribute my drug-free workplace statement? You must...

2013-10-01

20

38 CFR 48.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...false To whom must I distribute my drug-free workplace statement? 48.210 Section... GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements...210 To whom must I distribute my drug-free workplace statement? You must...

2013-07-01

21

29 CFR 94.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...false To whom must I distribute my drug-free workplace statement? 94.210 Section... GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements...210 To whom must I distribute my drug-free workplace statement? You must...

2013-07-01

22

32 CFR 26.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...false To whom must I distribute my drug-free workplace statement? 26.210 Section... GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements...210 To whom must I distribute my drug-free workplace statement? You must...

2013-07-01

23

22 CFR 312.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...true To whom must I distribute my drug-free workplace statement? 312.210 Section... GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements...210 To whom must I distribute my drug-free workplace statement? You must...

2013-04-01

24

22 CFR 1509.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...true To whom must I distribute my drug-free workplace statement? 1509.210 Section... GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements...210 To whom must I distribute my drug-free workplace statement? You must...

2013-04-01

25

29 CFR 1472.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...false To whom must I distribute my drug-free workplace statement? 1472.210 Section... GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements...210 To whom must I distribute my drug-free workplace statement? You must...

2013-07-01

26

22 CFR 1008.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...true To whom must I distribute my drug-free workplace statement? 1008.210 Section... GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements...210 To whom must I distribute my drug-free workplace statement? You must...

2013-04-01

27

31 CFR 20.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...false To whom must I distribute my drug-free workplace statement? 20.210 Section... GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements...210 To whom must I distribute my drug-free workplace statement? You must...

2013-07-01

28

45 CFR 630.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

... To whom must I distribute my drug-free workplace statement? 630.210 Section...GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) ...To whom must I distribute my drug-free workplace statement? You must...

2013-10-01

29

36 CFR 1212.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

... To whom must I distribute my drug-free workplace statement? 1212.210 ...GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) ...To whom must I distribute my drug-free workplace statement? You must...

2013-07-01

30

45 CFR 1155.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

... To whom must I distribute my drug-free workplace statement? 1155.210 ...GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) ...To whom must I distribute my drug-free workplace statement? You must...

2013-10-01

31

Assessing Website Pharmacy Drug Quality: Safer Than You Think?  

PubMed Central

Background Internet-sourced drugs are often considered suspect. The World Health Organization reports that drugs from websites that conceal their physical address are counterfeit in over 50 percent of cases; the U.S. Food and Drug Administration (FDA) works with the National Association of Boards of Pharmacy (NABP) to regularly update a list of websites likely to sell drugs that are illegal or of questionable quality. Methods and Findings This study examines drug purchasing over the Internet, by comparing the sales of five popular drugs from a selection of websites stratified by NABP or other ratings. The drugs were assessed for price, conditions of purchase, and basic quality. Prices and conditions of purchase varied widely. Some websites advertised single pills while others only permitted the purchase of large quantities. Not all websites delivered the exact drugs ordered, some delivered no drugs at all; many websites shipped from multiple international locations, and from locations that were different from those advertised on the websites. All drug samples were tested against approved U.S. brand formulations using Raman spectrometry. Many (17) websites substituted drugs, often in different formulations from the brands requested. These drugs, some of which were probably generics or perhaps non-bioequivalent copy versions, could not be assessed accurately. Of those drugs that could be assessed, none failed from “approved”, “legally compliant” or “not recommended” websites (0 out of 86), whereas 8.6% (3 out of 35) failed from “highly not recommended” and unidentifiable websites. Conclusions Of those drugs that could be assessed, all except Viagra® passed spectrometry testing. Of those that failed, few could be identified either by a country of manufacture listed on the packaging, or by the physical location of the website pharmacy. If confirmed by future studies on other drug samples, then U.S. consumers should be able to reduce their risk by relying on credentialing agencies recommended lists and by using common sense when examining packaging and pills.

Bate, Roger; Hess, Kimberly

2010-01-01

32

National Drug Threat Assessment, 2005. Executive Summary.  

National Technical Information Service (NTIS)

The trafficking and abuse of illicit drugs and diverted pharmaceuticals pose a serious threat to the United States because of the adverse effects of drug abuse on the lives of millions of Americans and the substantial resources consumed in combating illic...

2005-01-01

33

National Drug Threat Assessment, 2005. Summary Report.  

National Technical Information Service (NTIS)

The trafficking and abuse of illicit drugs and diverted pharmaceuticals pose a serious threat to the United States because of the adverse effects of drug abuse on the lives of millions of Americans and the substantial resources consumed in combating illic...

2005-01-01

34

Tissue distribution of basic drugs: accounting for enantiomeric, compound and regional differences amongst beta-blocking drugs in rat.  

PubMed

The purpose of this research was to identify the major factors controlling the distribution of beta-blockers (acebutolol, betaxolol, bisoprolol, metoprolol, oxprenolol, pindolol, propranolol and timolol) in rats, across tissues, compounds and enantiomers. Tissue distribution was assessed at steady state by infusing cassette doses of beta-blockers into the jugular vein via an indwelling catheter at a constant rate. Blood was sampled via an indwelling catheter in the carotid artery, and 12 tissues excised at the end of dose infusion (4 or 8 h). Drug concentrations were quantified using a novel chiral LC-MS method and the tissue-to-plasma (Kp) and tissue-to-plasma water (Kpu) values were calculated for each tissue. Differences between Kp were observed between many enantiomeric pairs, and largely explained by enantiomeric differences in plasma protein binding. Across compounds, Kpu values were generally highest in lung and lowest in adipose, and were higher for the more lipophilic drugs betaxolol and propranolol. For any tissue, Kpu differences between the individual beta-blockers correlated well with the corresponding affinity for blood cells. For all compounds, regional tissue distribution correlated well with tissue acidic phospholipid concentrations, with phosphatidylserine appearing to have the strongest influence. This information may be used as the basis for predicting the tissue distribution of basic drugs. PMID:15858851

Rodgers, Trudy; Leahy, David; Rowland, Malcolm

2005-06-01

35

Application of intracerebral microdialysis to study regional distribution kinetics of drugs in rat brain.  

PubMed Central

1. The purpose of the present study was to determine whether intracerebral microdialysis can be used for the assessment of local differences in drug concentrations within the brain. 2. Two transversal microdialysis probes were implanted in parallel into the frontal cortex of male Wistar rats, and used as a local infusion and detection device respectively. Within one rat, three different concentrations of atenolol or acetaminophen were infused in randomized order. By means of the detection probe, concentration-time profiles of the drug in the brain were measured at interprobe distances between 1 and 2 mm. 3. Drug concentrations were found to be dependent on the drug as well as on the interprobe distance. It was found that the outflow concentration from the detection probe decreased with increasing lateral spacing between the probes and this decay was much steeper for acetaminophen than for atenolol. A model was developed which allows estimation of kbp/Deff (transfer coefficient from brain to blood/effective diffusion coefficient in brain extracellular fluid), which was considerably larger for the more lipohilic drug, acetaminophen. In addition, in vivo recovery values for both drugs were determined. 4. The results show that intracerebral microdialysis is able to detect local differences in drug concentrations following infusion into the brain. Furthermore, the potential use of intracerebral microdialysis to obtain pharmacokinetic parameters of drug distribution in brain by means of monitoring local concentrations of drugs in time is demonstrated.

de Lange, E. C.; Bouw, M. R.; Mandema, J. W.; Danhof, M.; de Boer, A. G.; Breimer, D. D.

1995-01-01

36

Assessing Alcohol and Drug Problems among Adolescents: Current Practices.  

ERIC Educational Resources Information Center

Surveyed current methods and problems in the assessment of alcohol and drug abuse among adolescents through interviews with professionals from 70 facilities. Results showed that methods used to assess adolescents varied greatly and that the professionals surveyed were receptive toward the idea of more standardized methods of assessment. (LLL)

Owen, Patricia L.; Nyberg, Leslie R.

1983-01-01

37

Experienced drug users assess the relative harms and benefits of drugs: a web-based survey.  

PubMed

A web-based survey was used to consult the opinions of experienced drug users on matters related to drug harms. We identified a rare sample of 93 drug users with personal experience with 11 different illicit drugs that are widely used in the UK. Asked to assess the relative harms of these drugs, they ranked alcohol and tobacco as the most harmful, and three "Class A" drugs (MDMA, LSD, and psilocybin) and one class B (cannabis) were ranked as the four least harmful drugs. When asked to assess the relative potential for benefit of the 11 drugs, MDMA, LSD, psilocybin, and cannabis were ranked in the top four; and when asked why these drugs are beneficial, rather than simply report hedonic properties, they referred to potential therapeutic applications (e.g., as tools to assist psychotherapy). These results provide a useful insight into the opinions of experienced drug users on a subject about which they have a rare and intimate knowledge. PMID:24377171

Carhart-Harris, Robin Lester; Nutt, David John

2013-01-01

38

Absorption, distribution, metabolism and excretion pharmacogenomics of drugs of abuse.  

PubMed

Pharmacologic and toxic effects of xenobiotics, such as drugs of abuse, depend on the genotype and phenotype of an individual, and conversely on the isoenzymes involved in their metabolism and transport. The current knowledge of such isoenzymes of frequently abused therapeutics such as opioids (oxycodone, hydrocodone, methadone, fentanyl, buprenorphine, tramadol, heroin, morphine and codeine), anesthetics (?-hydroxybutyric acid, propofol, ketamine and phencyclidine) and cognitive enhancers (methylphenidate and modafinil), and some important plant-derived hallucinogens (lysergide, salvinorin A, psilocybin and psilocin), as well as of nicotine in humans are summarized in this article. The isoenzymes (e.g., cytochrome P450, glucuronyltransferases, esterases and reductases) involved in the metabolism of drugs and some pharmacokinetic data are discussed. The relevance of such data is discussed for predicting possible interactions with other xenobiotics, understanding pharmacokinetic behavior and pharmacogenomic variations, assessing toxic risks, developing suitable toxicological analysis procedures, and finally for interpretating drug testing results. PMID:21332315

Meyer, Markus R; Maurer, Hans H

2011-02-01

39

77 FR 59156 - Antimicrobial Animal Drug Sales and Distribution Reporting; Extension of Comment Period  

Federal Register 2010, 2011, 2012, 2013

...HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 514 [Docket...FDA-2012-N-0447] Antimicrobial Animal Drug Sales and Distribution Reporting; Extension of Comment Period AGENCY: Food and Drug Administration, HHS. ACTION:...

2012-09-26

40

The pKa Distribution of Drugs: Application to Drug Discovery  

PubMed Central

The acid-base dissociation constant (pKa) of a drug is a key physicochemical parameter influencing many biopharmaceutical characteristics. While this has been well established, the overall proportion of non-ionizable and ionizable compounds for drug-like substances is not well known. Even less well known is the overall distribution of acid and base pKa values. The current study has reviewed the literature with regard to both the proportion of ionizable substances and pKa distributions. Further to this a set of 582 drugs with associated pKa data was thoroughly examined to provide a representative set of observations. This was further enhanced by delineating the compounds into CNS and non-CNS drugs to investigate where differences exist. Interestingly, the distribution of pKa values for single acids differed remarkably between CNS and non-CNS substances with only one CNS compound having an acid pKa below 6.1. The distribution of basic substances in the CNS set also showed a marked cut off with no compounds having a pKa above 10.5. The pKa distributions of drugs are influenced by two main drivers. The first is related to the nature and frequency of occurrence of the functional groups that are commonly observed in pharmaceuticals and the typical range of pKa values they span. The other factor concerns the biological targets these compounds are designed to hit. For example, many CNS targets are based on seven transmembrane G protein-coupled receptors (7TM GPCR) which have a key aspartic acid residue known to interact with most ligands. As a consequence, amines are mostly present in the ligands that target 7TM GPCR’s and this influences the pKa profile of drugs containing basic groups. For larger screening collections of compounds, synthetic chemistry and the working practices of the chemists themselves can influence the proportion of ionizable compounds and consequent pKa distributions. The findings from this study expand on current wisdom in pKa research and have implications for discovery research with regard to the composition of corporate databases and collections of screening compounds. Rough guidelines have been suggested for the profile of compound collections and will evolve as this research area is expanded.

Manallack, David T.

2007-01-01

41

Assessment of drug information resource preferences of pharmacy students and faculty  

PubMed Central

A 39-item survey instrument was distributed to faculty and students at Wingate University School of Pharmacy to assess student and faculty drug information (DI) resource use and access preferences. The response rate was 81% (n?=?289). Faculty and professional year 2 to 4 students preferred access on laptop or desktop computers (67% and 75%, respectively), followed by smartphones (27% and 22%, respectively). Most faculty and students preferred using Lexicomp Online for drug information (53% and 74%, respectively). Results indicate that DI resources use is similar between students and faculty; laptop or desktop computers are the preferred platforms for accessing drug information.

Hanrahan, Conor T.; Cole, Sabrina W.

2014-01-01

42

Assessment of drug information resource preferences of pharmacy students and faculty.  

PubMed

A 39-item survey instrument was distributed to faculty and students at Wingate University School of Pharmacy to assess student and faculty drug information (DI) resource use and access preferences. The response rate was 81% (n?=?289). Faculty and professional year 2 to 4 students preferred access on laptop or desktop computers (67% and 75%, respectively), followed by smartphones (27% and 22%, respectively). Most faculty and students preferred using Lexicomp Online for drug information (53% and 74%, respectively). Results indicate that DI resources use is similar between students and faculty; laptop or desktop computers are the preferred platforms for accessing drug information. PMID:24860270

Hanrahan, Conor T; Cole, Sabrina W

2014-04-01

43

A hybrid approach to advancing quantitative prediction of tissue distribution of basic drugs in human.  

PubMed

A general toxicity of basic drugs is related to phospholipidosis in tissues. Therefore, it is essential to predict the tissue distribution of basic drugs to facilitate an initial estimate of that toxicity. The objective of the present study was to further assess the original prediction method that consisted of using the binding to red blood cells measured in vitro for the unbound drug (RBCu) as a surrogate for tissue distribution, by correlating it to unbound tissue:plasma partition coefficients (Kpu) of several tissues, and finally to predict volume of distribution at steady-state (V(ss)) in humans under in vivo conditions. This correlation method demonstrated inaccurate predictions of V(ss) for particular basic drugs that did not follow the original correlation principle. Therefore, the novelty of this study is to provide clarity on the actual hypotheses to identify i) the impact of pharmacological mode of action on the generic correlation of RBCu-Kpu, ii) additional mechanisms of tissue distribution for the outlier drugs, iii) molecular features and properties that differentiate compounds as outliers in the original correlation analysis in order to facilitate its applicability domain alongside the properties already used so far, and finally iv) to present a novel and refined correlation method that is superior to what has been previously published for the prediction of human V(ss) of basic drugs. Applying a refined correlation method after identifying outliers would facilitate the prediction of more accurate distribution parameters as key inputs used in physiologically based pharmacokinetic (PBPK) and phospholipidosis models. PMID:21034759

Poulin, Patrick; Ekins, Sean; Theil, Frank-Peter

2011-01-15

44

A hybrid approach to advancing quantitative prediction of tissue distribution of basic drugs in human  

SciTech Connect

A general toxicity of basic drugs is related to phospholipidosis in tissues. Therefore, it is essential to predict the tissue distribution of basic drugs to facilitate an initial estimate of that toxicity. The objective of the present study was to further assess the original prediction method that consisted of using the binding to red blood cells measured in vitro for the unbound drug (RBCu) as a surrogate for tissue distribution, by correlating it to unbound tissue:plasma partition coefficients (Kpu) of several tissues, and finally to predict volume of distribution at steady-state (V{sub ss}) in humans under in vivo conditions. This correlation method demonstrated inaccurate predictions of V{sub ss} for particular basic drugs that did not follow the original correlation principle. Therefore, the novelty of this study is to provide clarity on the actual hypotheses to identify i) the impact of pharmacological mode of action on the generic correlation of RBCu-Kpu, ii) additional mechanisms of tissue distribution for the outlier drugs, iii) molecular features and properties that differentiate compounds as outliers in the original correlation analysis in order to facilitate its applicability domain alongside the properties already used so far, and finally iv) to present a novel and refined correlation method that is superior to what has been previously published for the prediction of human V{sub ss} of basic drugs. Applying a refined correlation method after identifying outliers would facilitate the prediction of more accurate distribution parameters as key inputs used in physiologically based pharmacokinetic (PBPK) and phospholipidosis models.

Poulin, Patrick, E-mail: patrick-poulin@videotron.ca [Quebec City, Quebec (Canada); Ekins, Sean [Collaborations in Chemistry, 601 Runnymede Avenue, Jenkintown, PA 19046 (United States); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, MD 21201 (United States); Department of Pharmacology, University of Medicine and Dentistry of New Jersey (UMDNJ)-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854 (United States); Theil, Frank-Peter [Genentech, South San Francisco (United States)

2011-01-15

45

Managed care pharmacy, socioeconomic assessments and drug adoption decisions  

Microsoft Academic Search

A telephone survey of a representative national sample of 51 large managed care organizations in the U.S. (> 50,000 enrollees) was undertaken (1) to understand the role of socioeconomic assessments on drug adoption decisions; (2) to determine the sources of these assessments and the reliance of managed care pharmacy on each; and (3) to determine the resources for internally versus

Alan Lyles; Bryan R. Luce; Anne M. Rentz

1997-01-01

46

Radiolabeled absorption, distribution, metabolism, and excretion studies in drug development: why, when, and how?  

PubMed

Absorption, distribution, metabolism, and excretion (ADME) studies are an integral part of the comprehensive safety evaluation of a new molecular entity, and they represent a standard suite of studies included in the registration package for all new small molecule drugs. In vivo studies in preclinical toxicology species and humans using radiolabeled ((3)H or (14)C) compound provide quantitative assessments of overall routes of excretion of drug-related material, pharmacokinetics of total drug-derived radioactivity in circulation, relative to parent compound and quantitation, and characterization of metabolites in excreta and circulation. These data serve as the starting point for metabolite in safety testing (MIST). These studies involve the administration of a radiolabeled drug to laboratory animals and humans followed by a quantitative collection of excreta and blood. Using appropriate plasma-pooling strategies, these studies could allow for modeling the metabolite exposure at the steady state. Information from the radiolabeled human study is used to design clinical drug-drug interaction (DDI) studies and to obtain a waiver for bioequivalence studies. This article describes the various aspects of conducting ADME studies and the use of radiolabeled analogues of drug candidates to investigate their metabolism and how to compare the exposures of metabolites in humans and toxicology species. PMID:22309195

Penner, Natalia; Xu, Lin; Prakash, Chandra

2012-03-19

47

Assessing proarrhythmic potential of drugs when optimal studies are infeasible.  

PubMed

Assessing the potential for a new drug to cause life-threatening arrhythmias is now an integral component of premarketing safety assessment. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Guideline (ICH) E14 recommends the "Thorough QT Study" (TQT) to assess clinical QT risk. Such a study calls for careful evaluation of drug effects on the electrocardiographic QT interval at multiples of therapeutic exposure and with a positive control to confirm assay sensitivity. Yet for some drugs and diseases, elements of the TQT Study may be impractical or unethical. In these instances, alternative approaches to QT risk assessment must be considered. This article presents points to consider for evaluation of QT risk when alternative approaches are needed. PMID:19376308

Rock, Edwin P; Finkle, John; Fingert, Howard J; Booth, Brian P; Garnett, Christine E; Grant, Stephen; Justice, Robert L; Kovacs, Richard J; Kowey, Peter R; Rodriguez, Ignacio; Sanhai, Wendy R; Strnadova, Colette; Targum, Shari L; Tsong, Yi; Uhl, Kathleen; Stockbridge, Norman

2009-05-01

48

Heterogeneous distribution of Plasmodium falciparum drug resistance haplotypes in subsets of the host population  

Microsoft Academic Search

BACKGROUND: The emergence of drug resistance is a major problem in malaria control. For mathematical modelling of the transmission and spread of drug resistance the determinant parameters need to be identified and measured. The underlying hypothesis is that mutations associated with drug resistance incur fitness costs to the parasite in absence of drug pressure. The distribution of drug resistance haplotypes

Sonja Schoepflin; Jutta Marfurt; Mary Goroti; Moses Baisor; Ivo Mueller; Ingrid Felger

2008-01-01

49

Assessment of QT liabilities in drug development  

Microsoft Academic Search

Since the publication, in 1997, of the CPMP (Committee for Proprietary Medicinal Products) Points to Consider document on\\u000a “The assessment of potential for QT prolongation by non-cardiovascular medicinal products,” both regulatory bodies and the\\u000a pharmaceutical industry have paid increasing attention to the conduct of careful preclinical studies on the subject. Regulatory\\u000a attention has focused on the drafting of Safety Pharmacology

C. Arrigoni; P. Crivori

2007-01-01

50

Assessment of drug abuser treatment needs in Rhode Island.  

PubMed Central

BACKGROUND. Rhode Island's Division of Substance Abuse asked us to assess the State's drug treatment needs and make recommendations regarding its treatment system for the next three years. METHODS. We used a statewide telephone drug use survey of 5,176 households supplemented by drug-related hospital discharges, Division of Drug Control statistics, and interviews with providers, state officials, and out-of-state experts. Drug abuse was measured with items from the Diagnostic Interview Schedule. Abusers were asked if they were receiving or wanted to receive treatment. RESULTS. Survey responses, used to estimate the unmet need for drug treatment, indicated a need to triple drug treatment services. Regression models using survey data indicated that the treatment network was overly centralized in the Providence area. Interviews with state officials, clinicians, and out-of-state experts provided material for recommendations on reimbursement policy, treatment mix, quality assurance, and cost containment. CONCLUSIONS. The RI Department of Health's certificate-of-need program adopted our overall recommendation for tripling the drug treatment system as its guideline in evaluating proposals for new treatment facilities. With State funding of a new adolescent center and expansion of outpatient slots in the private sector, this recommendation has now been fully implemented.

McAuliffe, W E; Breer, P; Ahmadifar, N W; Spino, C

1991-01-01

51

Excipient quantitation and drug distribution during formulation optimization.  

PubMed

An oral granules formulation experienced high drug content and increased variability when the process was scaled up from lab scale to clinical manufacturing scale. It was suspected that mannitol, due to its smaller particle size and lower density, was preferentially lost during the top spray granulation process, thereby causing active enrichment in the remaining granules. In order to troubleshoot the problem, rapidly evaluate solutions, and further optimize the formulation, a simple and rapid analytical technique was required. Since mannitol does not have a UV chromophore, conventional HPLC/UV analysis could not be used. Three alternative analytical techniques were evaluated in terms of ease of use, reproducibility, linear dynamic range and rapidity. The HPLC/RID (refractive index detector) and HPLC/ELSD (evaporative light scattering detector) provided rapid, reproducible alternate techniques to HPLC/UV, whereas LC/MS showed poor reproducibility. Analysis of the sieve samples of the granulations by HPLC/RID and HPLC/ELSD confirmed that poor active drug distribution was due to mannitol losses in the filter bag, as well as increased low size granules low in active drug content. The resultant formulation process was modified and a reduction in the initial air flow at start-up reduced losses of mannitol in the granulator filters. PMID:16487674

Forget, Robert; Spagnoli, Suzanne

2006-06-01

52

Modelling intravascular delivery from drug-eluting stents with biodurable coating: investigation of anisotropic vascular drug diffusivity and arterial drug distribution.  

PubMed

In-stent restenosis occurs in coronary arteries after implantation of drug-eluting stents with non-uniform restenosis thickness distribution in the artery cross section. Knowledge of the spatio-temporal drug uptake in the arterial wall is useful for investigating restenosis growth but may often be very expensive/difficult to acquire experimentally. In this study, local delivery of a hydrophobic drug from a drug-eluting stent implanted in a coronary artery is mathematically modelled to investigate the drug release and spatio-temporal drug distribution in the arterial wall. The model integrates drug diffusion in the coating and drug diffusion with reversible binding in the arterial wall. The model is solved by the finite volume method for both high and low drug loadings relative to its solubility in the stent coating with varied isotropic-anisotropic vascular drug diffusivities. Drug release profiles in the coating are observed to depend not only on the coating drug diffusivity but also on the properties of the surrounding arterial wall. Time dependencies of the spatially averaged free- and bound-drug levels in the arterial wall on the coating and vascular drug diffusivities are discussed. Anisotropic vascular drug diffusivities result in slightly different average drug levels in the arterial wall but with very different spatial distributions. Higher circumferential vascular diffusivity results in more uniform drug loading in the upper layers and is potentially beneficial in reducing in-stent restenosis. An analytical expression is derived which can be used to determine regions in the arterial with higher free-drug concentration than bound-drug concentration. PMID:22512464

Zhu, Xiaoxiang; Pack, Daniel W; Braatz, Richard D

2014-01-01

53

Comparison of Fusion Imaging Using a Combined SPECT/CT System and Intra-arterial CT: Assessment of Drug Distribution by an Implantable Port System in Patients Undergoing Hepatic Arterial Infusion Chemotherapy  

SciTech Connect

Hepatic arterial infusion (HAI) chemotherapy is effective for treating primary and metastatic carcinoma of the liver. We compared the perfusion patterns of HAI chemotherapy on intra-arterial port-catheter computed tomography (iapc-CT) and fused images obtained with a combined single-photon emission computed tomography/computed tomography (SPECT/CT) system. We studied 28 patients with primary or metastatic carcinoma of the liver who bore an implantable HAI port system. All underwent abdominal SPECT using Tc-99m-MAA (185 Mbq); the injection rate was 1 mL/min, identical to the chemotherapy infusion rate, and 0.5 mL/sec for iapc-CT. Delivery was through an implantable port. We compared the intrahepatic perfusion (IHP) and extrahepatic perfusion (EHP) patterns of HAI chemotherapy on iapc-CT images and fused images obtained with a combined SPECT/CT system. In 23 of 28 patients (82%), IHP patterns on iapc-CT images and fused images were identical. In 5 of the 28 patients (18%), IHP on fusion images was different from IHP on iapc-CT images. EHP was seen on fused images in 12 of the 28 patients (43%) and on iapc-CT images in 8 patients (29%). In 17 patients (61%), upper gastrointestinal endoscopy revealed gastroduodenal mucosal lesions. EHP was revealed on fused images in 10 of these patients; 9 of them manifested gastroduodenal toxicity at the time of subsequent HAI chemotherapy. Fusion imaging using the combined SPECT/CT system reflects the actual distribution of the infused anticancer agent. This information is valuable not only for monitoring adequate drug distribution but also for avoiding potential extrahepatic complications.

Ikeda, Osamu, E-mail: osamu-3643ik@do9.enjoy.ne.jp; Kusunoki, Shinichiroh; Nakaura, Takeshi; Shiraishi, Shinya; Kawanaka, Kouichi; Tomiguchi, Seiji; Yamashita, Yasuyuki [Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Department of Diagnostic Radiology (Japan); Takamori, Hiroshi; Chikamoto, Akira; Kanemitsu, Keiichiro [Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Gastroenterological Surgery (Japan)

2006-06-15

54

Assessment of FDA's (Food and Drug Administration) Total Diet Study.  

National Technical Information Service (NTIS)

The Total Diet Study is used by the Food and Drug Administration as a monitoring and early warning system for contaminant and nutrient composition of 234 food items that serve as proxies for items consumed by the U.S. population. This assessment of the st...

M. Brown K. Johnson N. Linsky J. Bell

1983-01-01

55

Mental Health, Alcohol and Drug Abuse Needs Assessment Report.  

National Technical Information Service (NTIS)

A mental health, alcohol, and drug abuse (MHADA) needs assessment study was conducted from July 1979 through May 1980 in southern New Jersey. Study goals were to determine the prevalence of MHADA problems among the service area's population, to evaluate t...

1980-01-01

56

Aligning New Tuberculosis Drug Regimens and Drug Susceptibility Testing: A Needs Assessment and Roadmap for Action  

PubMed Central

New tuberculosis drug regimens are creating new priorities for drug susceptibility testing (DST) and surveillance. To minimise turnaround time, rapid DST will need to be prioritised, but developers of these assays will need better data about the molecular mechanisms of resistance. Efforts are underway to link mutations with drug resistance and to develop strain collections to enable assessment of new diagnostic assays. In resource-limited settings, DST might not be appropriate for all patients with tuberculosis. Surveillance data and modelling will help country stakeholders to design appropriate DST algorithms and to decide whether to change drug regimens. Finally, development of practical DST assays is needed so that, in countries where surveillance and modelling show that DST is advisable, these assays can be used to guide clinical decisions for individual patients. If combined judiciously during both development and implementation, new tuberculosis regimens and new DST assays have enormous potential to improve patient outcomes and reduce the burden of disease.

Wells, William A.; Boehme, Catharina C.; Cobelens, Frank G.J.; Daniels, Colleen; Dowdy, David; Gardiner, Elizabeth; Gheuens, Jan; Kim, Peter; Kimerling, Michael E.; Kreiswirth, Barry; Lienhardt, Christian; Mdluli, Khisi; Pai, Madhukar; Perkins, Mark D.; Peter, Trevor; Zignol, Matteo; Zumla, Alimuddin; Schito, Marco

2014-01-01

57

Statistical assessment of Monte Carlo distributional tallies  

SciTech Connect

Four tests are developed to assess the statistical reliability of distributional or mesh tallies. To this end, the relative variance density function is developed and its moments are studied using simplified, non-transport models. The statistical tests are performed upon the results of MCNP calculations of three different transport test problems and appear to show that the tests are appropriate indicators of global statistical quality.

Kiedrowski, Brian C [Los Alamos National Laboratory; Solomon, Clell J [Los Alamos National Laboratory

2010-12-09

58

28 CFR 83.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

...false To whom must I distribute my drug-free workplace statement? 83.210 Section...GOVERNMENT-WIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (GRANTS) Requirements for...210 To whom must I distribute my drug-free workplace statement? You must...

2013-07-01

59

IVAN: Intelligent Van for the Distribution of Pharmaceutical Drugs  

PubMed Central

This paper describes a telematic system based on an intelligent van which is capable of tracing pharmaceutical drugs over delivery routes from a warehouse to pharmacies, without altering carriers' daily conventional tasks. The intelligent van understands its environment, taking into account its location, the assets and the predefined delivery route; with the capability of reporting incidences to carriers in case of failure according to the established distribution plan. It is a non-intrusive solution which represents a successful experience of using smart environments and an optimized Radio Frequency Identification (RFID) embedded system in a viable way to resolve a real industrial need in the pharmaceutical industry. The combination of deterministic modeling of the indoor vehicle, the implementation of an ad-hoc radiating element and an agile software platform within an overall system architecture leads to a competitive, flexible and scalable solution.

Moreno, Asier; Angulo, Ignacio; Perallos, Asier; Landaluce, Hugo; Zuazola, Ignacio Julio Garcia; Azpilicueta, Leire; Astrain, Jose Javier; Falcone, Francisco; Villadangos, Jesus

2012-01-01

60

IVAN: intelligent van for the distribution of pharmaceutical drugs.  

PubMed

This paper describes a telematic system based on an intelligent van which is capable of tracing pharmaceutical drugs over delivery routes from a warehouse to pharmacies, without altering carriers' daily conventional tasks. The intelligent van understands its environment, taking into account its location, the assets and the predefined delivery route; with the capability of reporting incidences to carriers in case of failure according to the established distribution plan. It is a non-intrusive solution which represents a successful experience of using smart environments and an optimized Radio Frequency Identification (RFID) embedded system in a viable way to resolve a real industrial need in the pharmaceutical industry. The combination of deterministic modeling of the indoor vehicle, the implementation of an ad-hoc radiating element and an agile software platform within an overall system architecture leads to a competitive, flexible and scalable solution. PMID:22778659

Moreno, Asier; Angulo, Ignacio; Perallos, Asier; Landaluce, Hugo; García Zuazola, Ignacio Julio; Azpilicueta, Leire; Astrain, José Javier; Falcone, Francisco; Villadangos, Jesús

2012-01-01

61

Biopsy assessment of drug efficacy in the gastrointestinal tract  

PubMed Central

When using biopsy pathology in clinical pharmacology to assess drug efficacy in the gastrointestinal tract, a number of questions must be answered: Is the biopsy necessary or more effective than macroscopic views by endoscopy? Can we extract maximal information from the specimen? Are there surrogate serum or other markers that give an overall measure of disease and/or improvement? Indeed, clinicopathological correlation is of paramount importance. If biopsy is to be used, it is important to utilize appropriate scoring systems. Many grading systems use continuous spectra, which are ordinal categorical variables and therefore a grading system of assigned ‘numbers’ which cannot be used in processes that require continuous variables such as linear regression. The use of grading vs a ‘true’ score with real numbers must be carefully considered, the site and number of biopsies must be precisely chosen and interobserver reproducibility of results evaluated before undertaking drug trials. Immunocytochemistry and in situ hybridization, however, can provide quantifiable molecular information related to mechanisms of drug action. The biopsy is of significant value as it is a true in vivo assessment if the above caveats are taken into account. However, further work is needed to determine sound histological criteria to assess the efficacy of drugs for use in gastrointestinal disease.

Walker, Marjorie M

2003-01-01

62

A model for predicting size distributions delivered from pMDIs with suspended drug.  

PubMed

A new model has been developed for predicting size distributions delivered from pressurized metered dose inhalers (pMDIs) that contain suspended drug particles. This model enables the residual particle size distribution to be predicted for a broad range of formulations. It expands on previous models by allowing for polydisperse micronized input drug, multiple suspended drugs, dissolved drug, and dissolved or suspended excipient to be included in the formulation. The model indicates that for most pMDI configurations, the majority of droplets contain no drug or a single drug particle and the residual particle size distribution delivered from the pMDI is essentially equivalent to the size distribution of the micronized drug used in the formulation. However, for pMDIs with a high drug concentration or that use small micronized drug particles, there can be a substantial fraction of the droplets that contain multiple drug particles. The residual particle size distribution obtained from these pMDIs can be substantially larger than the size distribution of the micronized drug. Excellent agreement was observed between size distributions predicted using this model and those obtained from experimental cascade impactor measurements (r(2)=0.97), thus demonstrating the ability of the model to accurately predict the size distributions obtained from suspension pMDIs. PMID:22044537

Stein, Stephen W; Sheth, Poonam; Myrdal, Paul B

2012-01-17

63

Herb-drug interactions: Review and assessment of report reliability  

PubMed Central

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.

Fugh-Berman, Adriane; Ernst, E

2001-01-01

64

41 CFR 105-74.210 - To whom must I distribute my drug-free workplace statement?  

Code of Federal Regulations, 2013 CFR

... To whom must I distribute my drug-free workplace statement? 105-74.210...74-GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) ...To whom must I distribute my drug-free workplace statement? You must...

2013-07-01

65

Assessing cardiovascular drug safety for clinical decision-making.  

PubMed

Optimal therapeutic decision-making requires integration of patient-specific and therapy-specific information at the point of care, particularly when treating patients with complex cardiovascular conditions. The formidable task for the prescriber is to synthesize information about all therapeutic options and match the best treatment with the characteristics of the individual patient. Computerized decision support systems have been developed with the goal of integrating such information and presenting the acceptable therapeutic options on the basis of their effectiveness, often with limited consideration of their safety for a specific patient. Assessing the safety of therapies relative to each patient is difficult, and sometimes impossible, because the evidence required to make such an assessment is either imperfect or does not exist. In addition, many of the alerts sent to prescribers by decision-support systems are not perceived as credible, and 'alert fatigue' causes warnings to be ignored putting patients at risk of harm. The CredibleMeds.org and BrugadaDrugs.org websites are prototypes for evidence-based sources of safety information that rank drugs for their risk of a specific form of drug toxicity-in these cases, drug-induced arrhythmias. Broad incorporation of this type of information in electronic prescribing algorithms and clinical decision support could speed the evolution of safe personalized medicine. PMID:23591268

Woosley, Raymond L; Romero, Klaus

2013-06-01

66

Probabilistic modeling of percutaneous absorption for risk-based exposure assessments and transdermal drug delivery.  

SciTech Connect

Chemical transport through human skin can play a significant role in human exposure to toxic chemicals in the workplace, as well as to chemical/biological warfare agents in the battlefield. The viability of transdermal drug delivery also relies on chemical transport processes through the skin. Models of percutaneous absorption are needed for risk-based exposure assessments and drug-delivery analyses, but previous mechanistic models have been largely deterministic. A probabilistic, transient, three-phase model of percutaneous absorption of chemicals has been developed to assess the relative importance of uncertain parameters and processes that may be important to risk-based assessments. Penetration routes through the skin that were modeled include the following: (1) intercellular diffusion through the multiphase stratum corneum; (2) aqueous-phase diffusion through sweat ducts; and (3) oil-phase diffusion through hair follicles. Uncertainty distributions were developed for the model parameters, and a Monte Carlo analysis was performed to simulate probability distributions of mass fluxes through each of the routes. Sensitivity analyses using stepwise linear regression were also performed to identify model parameters that were most important to the simulated mass fluxes at different times. This probabilistic analysis of percutaneous absorption (PAPA) method has been developed to improve risk-based exposure assessments and transdermal drug-delivery analyses, where parameters and processes can be highly uncertain.

Ho, Clifford Kuofei

2004-06-01

67

Assessment Issues in Adolescent Drug Abuse Treatment Research  

Microsoft Academic Search

Experimentation with alcohol and other drugs (AOD) is commonplace among American adolescents. Despite reduction efforts, the\\u000a use of AOD by adolescents has increased over the past decade. A number of youth experience significant negative personal,\\u000a societal, economic, and health ramifications, but continue to abuse AOD and develop substance use disorders (SUD). Accurate\\u000a assessment of adolescent AOD use is essential in

Ken C. Winters; Tamara Fahnhorst

68

Understanding pharmacokinetics using realistic computational models of fluid dynamics: biosimulation of drug distribution within the CSF space for intrathecal drugs.  

PubMed

We introduce how biophysical modeling in pharmaceutical research and development, combining physiological observations at the tissue, organ and system level with selected drug physiochemical properties, may contribute to a greater and non-intuitive understanding of drug pharmacokinetics and therapeutic design. Based on rich first-principle knowledge combined with experimental data at both conception and calibration stages, and leveraging our insights on disease processes and drug pharmacology, biophysical modeling may provide a novel and unique opportunity to interactively characterize detailed drug transport, distribution, and subsequent therapeutic effects. This innovative approach is exemplified through a three-dimensional (3D) computational fluid dynamics model of the spinal canal motivated by questions arising during pharmaceutical development of one molecular therapy for spinal cord injury. The model was based on actual geometry reconstructed from magnetic resonance imaging data subsequently transformed in a parametric 3D geometry and a corresponding finite-volume representation. With dynamics controlled by transient Navier-Stokes equations, the model was implemented in a commercial multi-physics software environment established in the automotive and aerospace industries. While predictions were performed in silico, the underlying biophysical models relied on multiple sources of experimental data and knowledge from scientific literature. The results have provided insights into the primary factors that can influence the intrathecal distribution of drug after lumbar administration. This example illustrates how the approach connects the causal chain underlying drug distribution, starting with the technical aspect of drug delivery systems, through physiology-driven drug transport, then eventually linking to tissue penetration, binding, residence, and ultimately clearance. Currently supporting our drug development projects with an improved understanding of systems physiology, biophysical models are being increasingly used to characterize drug transport and distribution in human tissues where pharmacokinetic measurements are difficult or impossible to perform. Importantly, biophysical models can describe emergent properties of a system, i.e. properties not identifiable through the study of the system's components taken in isolation. PMID:21132572

Kuttler, Andreas; Dimke, Thomas; Kern, Steven; Helmlinger, Gabriel; Stanski, Donald; Finelli, Luca A

2010-12-01

69

Drug safety assessment in clinical trials: methodological challenges and opportunities  

PubMed Central

Randomized controlled trials are the principal means of establishing the efficacy of drugs. However pre-marketing trials are limited in size and duration and exclude high-risk populations. They have limited statistical power to detect rare but potentially serious adverse events in real-world patients. We summarize the principal methodological challenges in the reporting, analysis and interpretation of safety data in clinical trials using recent examples from systematic reviews. These challenges include the lack of an evidentiary gold standard, the limited statistical power of randomized controlled trials and resulting type 2 error, the lack of adequate ascertainment of adverse events and limited generalizability of trials that exclude high risk patients. We discuss potential solutions to these challenges. Evaluation of drug safety requires careful examination of data from heterogeneous sources. Meta-analyses of drug safety should include appropriate statistical methods and assess the optimal information size to avoid type 2 errors. They should evaluate outcome reporting biases and missing data to ensure reliable and accurate interpretation of findings. Regulatory and academic partnerships should be fostered to provide an independent and transparent evaluation of drug safety.

2012-01-01

70

Direct assessment of drug penetration into tissue using a novel application of three-dimensional cell culture.  

PubMed

The failure of many anticancer drugs to control growth of solid cancers may stem in part from inadequate delivery to tumor regions distant from vasculature. Although the identification of new anticancer drug targets has led to the development of many new drug candidates, there is a lack of methodology for identifying drugs that adequately penetrate tumor tissue. We have developed a novel multilayered cell culture-based assay, which detects the penetration of anticancer drugs based on their effect within tissue. Drug exposures are made over 1 hour to one side of a disk of tissue approximately 150-microm thick, with the other side temporarily closed off, and penetration is then assessed 1-3 days later via bromodeoxyuridine-based detection of S-phase cells. Using this assay, the tissue distribution of a selection of anthracycline analogues was assessed. At clinically relevant exposures, none of the agents were able to affect cells on the far side of the culture at levels approaching that seen on the near (exposed) side. Doxorubicin and epirubicin exhibited approximately 10-fold decreases in the drug exposure seen by the cells on the far side relative to those on the near side of the cultures, whereas for daunorubicin and mitoxantrone, approximately 30-fold and >30-fold decreases were observed respectively. Results were consistent with the observed gradients in drug-derived fluorescence of doxorubicin, epirubicin, and daunorubicin. This model could be applied as a simple anticancer drug development screen to discover drugs that exhibit desirable penetration properties. PMID:15342419

Kyle, Alastair H; Huxham, Lynsey A; Chiam, Aaron S J; Sim, David H; Minchinton, Andrew I

2004-09-01

71

Drug assessment by a Pharmacy and Therapeutics committee: from drug selection criteria to use in clinical practice  

PubMed Central

Background In Spain, hospital medicines are assessed and selected by local Pharmacy and Therapeutics committees (PTCs). Of all the drugs assessed, cancer drugs are particularly important because of their budgetary impact and the sometimes arguable added value with respect to existing alternatives. This study analyzed the PTC drug selection process and the main objective was to evaluate the degree of compliance of prescriptions for oncology drugs with their criteria for use. Methods This was a retrospective observational study (May 2007 to April 2010) of PTC-assessed drugs. The variables measured to describe the committee’s activity were number of drugs assessed per year and number of drugs included in any of these settings: without restrictions, with criteria for use, and not included in formulary. These drugs were also analyzed by therapeutic group. To assess the degree of compliance of prescriptions, a score was calculated to determine whether prescriptions for bevacizumab, cetuximab, trastuzumab, and bortezomib were issued in accordance with PTC drug use criteria. Results The PTC received requests for inclusion of 40 drugs, of which 32 were included in the hospital formulary (80.0%). Criteria for use were established for 28 (87.5%) of the drugs included. In total, 293 patients were treated with the four cancer drugs in eight different therapeutic indications. The average prescription compliance scores were as follows: bevacizumab, 83% for metastatic colorectal cancer, 100% for metastatic breast cancer, and 82.3% for non-small-cell lung cancer; cetuximab, 62.0% for colorectal cancer and 50% for head and neck cancer; trastuzumab, 95.1% for early breast cancer and 82.4% for metastatic breast cancer; and bortezomib, 63.7% for multiple myeloma. Conclusion The degree of compliance with criteria for use of cancer drugs was reasonably high. PTC functions need to be changed so that they can carry out more innovative tasks, such as monitoring conditions for drug use.

Lozano-Blazquez, Ana; Calvo-Pita, Cecilia; Carbajales-Alvarez, Monica; Suarez-Gil, Patricio; Martinez-Martinez, Fernando; Calleja-Hernandez, Miguel Angel

2014-01-01

72

Novel approach to in vitro drug susceptibility assessment of clinical strains of Leishmania spp.  

PubMed

Resistance to antimonial drugs has been documented in Leishmania isolates transmitted in South America, Europe, and Asia. The frequency and distribution of resistance to these and other antileishmanial drugs are unknown. Technical constraints have limited the assessment of drug susceptibility of clinical strains of Leishmania. Susceptibility of experimentally selected lines and 130 clinical strains of Leishmania panamensis, L. braziliensis, and L. guyanensis to meglumine antimoniate and miltefosine was determined on the basis of parasite burden and percentage of infected U-937 human macrophages. Reductions of infection at single predefined concentrations of meglumine antimoniate and miltefosine and 50% effective doses (ED(50)s) were measured and correlated. The effects of 34°C and 37°C incubation temperatures and different parasite-to-host cell ratios on drug susceptibility were evaluated at 5, 10, and 20 parasites/cell. Reduction of the intracellular burden of Leishmania amastigotes in U-937 cells exposed to the predefined concentrations of meglumine antimoniate or miltefosine discriminated sensitive and experimentally derived resistant Leishmania populations and was significantly correlated with ED(50) values of clinical strains (for meglumine antimoniate, ? = -0.926 and P < 0.001; for miltefosine, ? = -0.906 and P < 0.001). Incubation at 37°C significantly inhibited parasite growth compared to that at 34°C in the absence of antileishmanial drugs and resulted in a significantly lower ED(50) in the presence of drugs. Susceptibility assessment was not altered by the parasite-to-cell ratio over the range evaluated. In conclusion, measurement of the reduction of parasite burden at a single predetermined drug concentration under standardized conditions provides an efficient and reliable strategy for susceptibility evaluation and monitoring of clinical strains of Leishmania. PMID:22518860

Fernández, Olga; Diaz-Toro, Yira; Valderrama, Liliana; Ovalle, Clemencia; Valderrama, Mabel; Castillo, Harry; Perez, Mauricio; Saravia, Nancy Gore

2012-07-01

73

Impact of flow pulsatility on arterial drug distribution in stent-based therapy  

PubMed Central

Drug-eluting stents reside in a dynamic fluid environment where the extent to which drugs are distributed within the arterial wall is critically modulated by the blood flowing through the arterial lumen. Yet several factors associated with the pulsatile nature of blood flow and their impact on arterial drug deposition has not been fully investigated. We employed an integrated framework comprising bench-top and computational models to explore the factors governing the time-varying fluid dynamic environment within the vasculature and their effects on arterial drug distribution patterns. A custom-designed bench-top framework comprising a model of a single drug-eluting stent strut and a poly-vinyl alcohol-based hydrogel as a model tissue bed simulated fluid flow and drug transport under fully apposed strut settings. Bench-top experiments revealed a relative independence between drug distribution and the factors governing pulsatile flow and these findings were validated with the in silico model. Interestingly, computational models simulating suboptimal deployment settings revealed a complex interplay between arterial drug distribution, Womersley number and the extent of malapposition. In particular, for a stent strut offset from the wall, total drug deposition was sensitive to changes in the pulsatile flow environment, with this dependence increasing with greater wall displacement. Our results indicate that factors governing pulsatile luminal flow on arterial drug deposition should be carefully considered in conjunction with device deployment settings for better utilization of drug-eluting stent therapy for various arterial flow regimes.

O'Brien, Caroline C.; Kolachalama, Vijaya B.; Barber, Tracie J.; Simmons, Anne; Edelman, Elazer R.

2013-01-01

74

The Development of a Test to Assess Drug Using Behavior.  

ERIC Educational Resources Information Center

The objective of the study was to develop a test which could measure both the qualitative and quantitative aspects of drug-using behavior, including such factors as attitudes toward drugs, experience with drugs, and knowledge about drugs. The Drug Use Scale was developed containing 134 items and dealing with five classes of drugs: marijuana,…

Althoff, Michael E.

75

Validation of pharmacy records in drug exposure assessment  

Microsoft Academic Search

The validity of drug exposure measurement based on pharmacy records was investigated taking into account completeness of data, drug compliance, and different methods of drug exposure measurement in pharmacy records. Data on prescription drug use were collected from home inventories and community pharmacies in a survey on drug use and compliance in 115 elderly people. To compare drug exposure in

Hong S. Lau; Anthonius de Boer; Karin S. Beuning; Arijan Porsius

1997-01-01

76

Physics and instrumentation for imaging in-vivo drug distribution  

Microsoft Academic Search

Several imaging methods are currently available to measure drugs noninvasively. Of these, two techniques are today central to such measurements: nuclear imaging and magnetic resonance imaging\\/spectroscopy (MRI and MRS). While other methods, such as optical techniques, are rapidly gaining in interest, they have not yet attained the degree of development that makes them effective in measuring drugs in living systems,

Manbir Singh; Victor Waluch

2000-01-01

77

Examination of drug release and distribution from drug-eluting stents with a vessel-simulating flow-through cell.  

PubMed

The recently introduced vessel-simulating flow-through cell offers new possibilities to examine the release from drug-eluting stents in vitro. In comparison with standard dissolution methods, the additional compartment allows for the examination of distribution processes and creates dissolution conditions which simulate the physiological situation at the site of implantation. It was shown previously that these conditions have a distinct influence on the release rate from the stent coating. In this work, different preparation techniques were developed to examine the spatial distribution within the compartment simulating the vessel wall. These methods allowed for the examination of diffusion depth and the distribution resulting in the innermost layer of the compartment simulating the vessel wall. Furthermore, the in vitro release and distribution examined experimentally were modelled mathematically using finite element (FE) methods to gain further insight into the release and distribution behaviour. The FE modelling employing the experimentally determined diffusion coefficients yielded a good general description of the experimental data. The results of the modelling also provided important indications that inhomogeneous coating layer thicknesses around the strut may result from the coating process which influence release and distribution behaviour. Taken together, the vessel-simulating flow-through cell in combination with FE modelling represents a unique method to analyse drug release and distribution from drug-eluting stents in vitro with particular opportunities regarding the examination of spatial distributions within the vessel-simulating compartment. PMID:21182943

Seidlitz, Anne; Nagel, Stefan; Semmling, Beatrice; Grabow, Niels; Martin, Heiner; Senz, Volkmar; Harder, Claus; Sternberg, Katrin; Schmitz, Klaus-Peter; Kroemer, Heyo K; Weitschies, Werner

2011-05-01

78

Physicochemical property space distribution among human metabolites, drugs and toxins  

Microsoft Academic Search

BACKGROUND: The current approach to screen for drug-like molecules is to sieve for molecules with biochemical properties suitable for desirable pharmacokinetics and reduced toxicity, using predominantly biophysical properties of chemical compounds, based on empirical rules such as Lipinski's \\

Varun Khanna; Shoba Ranganathan

2009-01-01

79

Spatial distribution and characteristics of injecting drug users (IDU) in five Northeastern states of India  

PubMed Central

Background Injecting drugs is the major driving force of human immunodeficiency virus (HIV) epidemic in Northeastern India. We have assessed the spatial distribution of locations where injecting drug users (IDU) congregate, as well as the risk behaviour and key characteristics of IDUs to develop new strategies strengthening intervention measures for HIV prevention in this region. Methods Locations of IDUs congregation for buying and injecting drugs were identified through Key Informants (KI). Verification of the location and its characteristics were confirmed through field visits. We also conducted semi-structured and structured interviews with IDUs to learn more about their injecting behaviour and other characteristics. Results Altogether, 2462 IDU locations were identified in 5 states. The number of IDU locations was found to be greater in the states bordering Myanmar. Private houses, parks, abandoned buildings, pharmacies, graveyards, and isolated places were the most frequently chosen place for injecting drugs. Many injecting locations were visited by IDUs of varying ages, of which about 10-20% of locations were for females. In some locations, female IDUs were also involved in sex work. Sharing of needle and syringes was reported in all the states by large proportion of IDUs, mainly with close friends. However, even sharing with strangers was not uncommon. Needle and syringes were mainly procured from pharmacies, drug peddlers and friends. Lack of access to free sterile needles and syringes, and inconsistent supplies from intervention programs, were often given as the cause of sharing or re-use of needles and syringes by IDUs. Most of the IDUs described a negative attitude of the community towards them. Conclusion We highlight the injection of drugs as a problem in 5 Northeastern India states where this is the major driving force of an HIV epidemic. Also highlighted are the large numbers of females that are unrecognized as IDUs and the association between drug use and sex work. Understanding of risk behaviours and other key charecteristics of IDUs in the region will help in strengthening harm reduction efforts that can prevent HIV transmission.

2011-01-01

80

Assessment of Distributed Photovoltaic Electric-Power Systems. Final Report.  

National Technical Information Service (NTIS)

The purpose of this study was to develop a methodology for assessing the potential impacts of distributed photovoltaic (PV) systems on electric utility systems, including subtransmission and distribution networks, and to apply that methodology to several ...

R. W. Neal P. F. DeDuck R. N. Marshall

1982-01-01

81

Genetic polymorphism in drug metabolism and toxicity: Linking animal research and risk assessment in man  

Microsoft Academic Search

One of the major challenges facing toxicology is to bridge the gap between animal research and risk assessment in man. In this meeting, the genetic polymorphism of drug metabolizing enzymes in relation to drug toxicity will be described.

Tetsuo Satoh

82

Oncology drug health technology assessment recommendations: Canadian versus UK experiences  

PubMed Central

Background Canada has two health technology assessment (HTA) agencies responsible for oncology drug funding recommendations: the Institut National d’Excellence en Santé et Services Sociaux (INESSS) for the province of Québec and the pan-Canadian Oncology Drug Review for the rest of Canada. The objective of the research was to review and compare the recommendations of these two agencies alongside an international comparator – the National Institute for Health and Care Excellence (NICE) in the United Kingdom – with respect to their recommendations records and the influence of clinical and cost-effectiveness evidence on the recommendations. Methods Recommendations were identified from the three agencies from January 1, 2002 to June 1, 2013. Recommendations were limited to five cancer sites (lung, breast, colon, kidney, blood) and to metastatic/advanced settings. Descriptive analyses examined the frequency of positive recommendations and factors related to a positive recommendation. For each recommendation, only publicly available information posted on the agency website was used to abstract data. Results There was a wide variation in the rate of positive recommendations, ranging from 48% for NICE to 95% for Canada’s national process (among the 74% of its recommendations that were publicly posted). Interagency agreement was low, with full agreement for only six of the 14 drugs commonly reviewed by all three agencies. Evidence of a survival gain was not necessary for a positive recommendation; progression-free survival was acceptable. Different approaches were taken when addressing unacceptable cost-effectiveness. NICE was most likely to yield a negative recommendation on these grounds, whereas Canada’s national process was most likely to yield a positive recommendation with a required pricing arrangement. Conclusion In this analysis, the primary reason for the observed divergence between agency recommendations appeared to be the availability of mechanisms in each jurisdiction to address cost-effectiveness subsequent to the HTA assessment process. Furthermore, caution is needed when interpreting cross-agency comparisons between HTA agencies, as recommendations may not correspond directly to subsequent funding decisions and actual patient access. This may be a concern, given the high international profile of assessments conducted by the reviewed HTA agencies.

Chabot, Isabelle; Rocchi, Angela

2014-01-01

83

Assessing drug-likeness--what are we missing?  

PubMed

The concept of drug-likeness helps to optimise pharmacokinetic and pharmaceutical properties, for example, solubility, chemical stability, bioavailability and distribution profile. A number of molecular descriptors have emerged as reasonably informative and predictive, for example, the Rule-of-Five. Here, we review some current approaches, then discuss their major shortcoming, namely the static nature of the structural features and physicochemical properties they encode. As we demonstrate, molecules are not 'frozen statues' but 'dancing ballerinas', and several of their computable physicochemical properties are conformation-dependent and lead to the concept of property spaces. Molecular sensitivity (namely, how much a given computable physicochemical property varies as a function of flexibility) appears as a promising descriptor to encode some of the information contained in molecular property spaces. PMID:18405840

Vistoli, Giulio; Pedretti, Alessandro; Testa, Bernard

2008-04-01

84

Reducing attrition in drug development: smart loading preclinical safety assessment.  

PubMed

Entry into the crucial preclinical good laboratory practice (GLP) stage of toxicology testing triggers significant R&D investment yet >20% of AstraZeneca's potential new medicines have been stopped for safety reasons in this GLP phase alone. How could we avoid at least some of these costly failures? An analysis of historical toxicities that caused stopping ('stopping toxicities') showed that >50% were attributable to target organ toxicities emerging within 2 weeks of repeat dosing or to acute cardiovascular risks. By frontloading 2-week repeat-dose toxicity studies and a comprehensive assessment of cardiovascular safety, we anticipate a potential 50% reduction in attrition in the GLP phase. This will reduce animal use overall, save significant R&D costs and improve drug pipeline quality. PMID:24269835

Roberts, Ruth A; Kavanagh, Stefan L; Mellor, Howard R; Pollard, Christopher E; Robinson, Sally; Platz, Stefan J

2014-03-01

85

21 CFR 212.90 - What actions must I take to control the distribution of PET drug products?  

Code of Federal Regulations, 2010 CFR

...to control the distribution of PET drug products? 212.90 ...ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED...to control the distribution of PET drug products? (a) Written...the control of distribution of PET drug products shipped from...

2010-04-01

86

Open drug scenes and drug-related public nuisance: a visual rapid assessment research study in Dublin, Ireland.  

PubMed

The research was undertaken at a time of increasing public concerns for drug- and alcohol-related public nuisance in the city center of Dublin, Ireland. Rapid Assessment Research was conducted involving qualitative interviewing with drug service users; business, transport, community, voluntary, and statutory stakeholders (n = 61); and an environmental mapping exercise. The interplay between homelessness, loitering, an influx of drug users via city metro systems, transient open drug scenes, street drinking, drug injecting, intimidation, knife crime, and prescribed medication abuse was evident. Potential strategies to address drug and alcohol related public nuisance are advised to include the relocation of treatment services, targeted harm reduction initiatives, urban regeneration, improved community rehabilitation pathways, and heightened policing intensity. PMID:23768432

Van Hout, Marie Claire; Bingham, Tim

2013-01-01

87

Causality assessment in hepatotoxicity by drugs and dietary supplements  

PubMed Central

Structured causality assessment of hepatotoxicity by drugs and dietary supplements (DDS) is a major clinical challenge, since temporal associations as the sole criteria for a valid evaluation are not acceptable. Initially, a clear intuition for an ad hoc evaluation is necessary, but only provisional, and must be followed by a diagnostic algorithm using a pretest, main test and post test. The evaluation is based on a variety of items such as latency period, course of alanine aminotransferase and alkaline phosphatase after DDS discontinuation, risk factors, co-medication, previous information on hepatotoxicity of the DDS, response to rechallenge, and exclusion of other diseases. It is essential that practising and hospital physicians as well as other key health professionals, such as pharmacists, gather all information required for a sound causality assessment, obviating major discussions by expert panels, manufacturers and health agencies in face of scanty and fragmentary data. Because pharmacogenetic alterations may trigger metabolic hepatotoxicity by a few DDS, levels in plasma and urine should be measured and may be helpful for diagnosis. Concomitant genotyping of cytochrome P450 and other enzymes may also be useful in future to minimize the risk of unwanted side-effects, including toxic liver disease elicited by DDS.

Teschke, Rolf; Schwarzenboeck, Alexander; Hennermann, Karl-Heinz

2008-01-01

88

Compartmental Pharmacokinetics and Tissue Drug Distribution of the Pradimicin Derivative BMS 181184 in Rabbits  

PubMed Central

The pharmacokinetics of the antifungal pradimicin derivative BMS 181184 in plasma of normal, catheterized rabbits were characterized after single and multiple daily intravenous administrations of dosages of 10, 25, 50, or 150 mg/kg of body weight, and drug levels in tissues were assessed after multiple dosing. Concentrations of BMS 181184 were determined by a validated high-performance liquid chromatography method, and plasma data were modeled into a two-compartment open model. Across the investigated dosage range, BMS 181184 demonstrated nonlinear, dose-dependent kinetics with enhanced clearance, reciprocal shortening of elimination half-life, and an apparently expanding volume of distribution with increasing dosage. After single-dose administration, the mean peak plasma BMS 181184 concentration (Cmax) ranged from 120 ?g/ml at 10 mg/kg to 648 ?g/ml at 150 mg/kg; the area under the concentration-time curve from 0 to 24 h (AUC0–24) ranged from 726 to 2,130 ?g · h/ml, the volume of distribution ranged from 0.397 to 0.799 liter/kg, and the terminal half-life ranged from 4.99 to 2.31 h, respectively (P < 0.005 to P < 0.001). No drug accumulation in plasma occurred after multiple daily dosing at 10, 25, or 50 mg/kg over 15 days, although mean elimination half-lives were slightly longer. Multiple daily dosing at 150 mg/kg was associated with enhanced total clearance and a significant decrease in AUC0–24 below the values obtained at 50 mg/kg (P < 0.01) and after single-dose administration of the same dosage (P < 0.05). Assessment of tissue BMS 181184 concentrations after multiple dosing over 16 days revealed substantial uptake in the lungs, liver, and spleen and, most notably, dose-dependent accumulation of the drug within the kidneys. These findings are indicative of dose- and time-dependent elimination of BMS 181184 from plasma and renal accumulation of the compound after multiple dosing.

Groll, Andreas H.; Sein, Tin; Petraitis, Vidas; Petraitiene, Ruta; Callender, Diana; Gonzalez, Corina E.; Giri, Neelam; Bacher, John; Piscitelli, Stephen; Walsh, Thomas J.

1998-01-01

89

Development and assessment of mini projectiles as drug carriers.  

PubMed

This paper describes a novel technology for the delivery of drugs into the subcutaneous and intramuscular tissue of farmed animals. The technology comprises small, hollow mini projectiles into which drug formulations can be loaded and administered using compressed air from an administration device which is held a few millimeters (3-10 mm) from the surface of the animals' skin. The design of the mini projectiles and administration procedure allows administration without contacting the skin, thereby avoiding cross-contamination between handlings and ensuring safe injection practice in livestock. In vitro experiments are described which investigate the parameters that affect mini projectile penetration into excised porcine and bovine skin. These include shape and weight of the mini projectiles and species type and injection site of the animal. An in vitro skin model for assessing mini projectile administration is described which permits visualization of the penetration of the mini projectiles through excised bovine or porcine skin into an underlying tissue simulant made from gelatin. The quantities of energy necessary to inject mini projectiles through excised porcine and bovine skin into the tissue simulant of the in vitro skin model were determined. The paper also describes the processes that occur during the administration of mini projectiles. The results suggest that tissue damage caused during administration of mini projectiles is comparable to the tissue damage caused by conventional syringe-needle injections. Finally, three different formulations of the model vaccine BSA, without adjuvant, are loaded into mini projectiles and administered to pigs. A seroconversion was shown for all three formulations, thus demonstrating proof of concept for the miniprojectiles. PMID:12480320

van de Wijdeven, Gijsbert G P

2002-12-13

90

Assessing Website Pharmacy Drug Quality: Safer Than You Think?  

Microsoft Academic Search

BackgroundInternet-sourced drugs are often considered suspect. The World Health Organization reports that drugs from websites that conceal their physical address are counterfeit in over 50 percent of cases; the U.S. Food and Drug Administration (FDA) works with the National Association of Boards of Pharmacy (NABP) to regularly update a list of websites likely to sell drugs that are illegal or

Roger Bate; Kimberly Hess

2010-01-01

91

High concentrations of drug in target tissues following local controlled release are utilized for both drug distribution and biologic effect: an example with epicardial inotropic drug delivery.  

PubMed

Local drug delivery preferentially loads target tissues with a concentration gradient from the surface or point of release that tapers down to more distant sites. Drug that diffuses down this gradient must be in unbound form, but such drug can only elicit a biologic effect through receptor interactions. Drug excess loads tissues, increasing gradients and driving penetration, but with limited added biological response. We examined the hypothesis that local application reduces dramatically systemic circulating drug levels but leads to significantly higher tissue drug concentration than might be needed with systemic infusion in a rat model of local epicardial inotropic therapy. Epinephrine was infused systemically or released locally to the anterior wall of the heart using a novel polymeric platform that provides steady, sustained release over a range of precise doses. Epinephrine tissue concentration, upregulation of cAMP, and global left ventricular response were measured at equivalent doses and at doses equally effective in raising indices of contractility. The contractile stimulation by epinephrine was linked to drug tissue levels and commensurate cAMP upregulation for IV systemic infusion, but not with local epicardial delivery. Though cAMP was a powerful predictor of contractility with local application, tissue epinephrine levels were high and variable--only a small fraction of the deposited epinephrine was utilized in second messenger signaling and biologic effect. The remainder of deposited drug was likely used in diffusive transport and distribution. Systemic side effects were far more profound with IV infusion which, though it increased contractility, also induced tachycardia and loss of systemic vascular resistance, which were not seen with local application. Local epicardial inotropic delivery illustrates then a paradigm of how target tissues differentially handle and utilize drug compared to systemic infusion. PMID:23872515

Maslov, Mikhail Y; Edelman, Elazer R; Wei, Abraham E; Pezone, Matthew J; Lovich, Mark A

2013-10-28

92

Distribution of genetic polymorphisms of genes encoding drug metabolizing enzymes & drug transporters - a review with Indian perspective.  

PubMed

Phase I and II drug metabolizing enzymes (DME) and drug transporters are involved in the absorption, distribution, metabolism as well as elimination of many therapeutic agents, toxins and various pollutants. Presence of genetic polymorphisms in genes encoding these proteins has been associated with marked inter-individual variability in their activity that could result in variation in drug response, toxicity as well as in disease predisposition. The emergent field pharmacogenetics and pharmacogenomics (PGx) is a promising discipline, as it predicts disease risk, selection of proper medication with regard to response and toxicity, and appropriate drug dosage guidance based on an individual's genetic make-up. Consequently, genetic variations are essential to understand the ethnic differences in disease occurrence, development, prognosis, therapeutic response and toxicity. For that reason, it is necessary to establish the normative frequency of these genes in a particular population before unraveling the genotype-phenotype associations. Although a fair amount of allele frequency data are available in Indian populations, the existing pharmacogenetic data have not been compiled into a database. This review was intended to compile the normative frequency distribution of the variants of genes encoding DMEs (CYP450s, TPMT, GSTs, COMT, SULT1A1, NAT2 and UGTs) and transporter proteins (MDR1, OCT1 and SLCO1B1) with Indian perspective. PMID:24604039

Umamaheswaran, Gurusamy; Kumar, Dhakchinamoorthi Krishna; Adithan, Chandrasekaran

2014-01-01

93

Distribution of genetic polymorphisms of genes encoding drug metabolizing enzymes & drug transporters - a review with Indian perspective  

PubMed Central

Phase I and II drug metabolizing enzymes (DME) and drug transporters are involved in the absorption, distribution, metabolism as well as elimination of many therapeutic agents, toxins and various pollutants. Presence of genetic polymorphisms in genes encoding these proteins has been associated with marked inter-individual variability in their activity that could result in variation in drug response, toxicity as well as in disease predisposition. The emergent field pharmacogenetics and pharmacogenomics (PGx) is a promising discipline, as it predicts disease risk, selection of proper medication with regard to response and toxicity, and appropriate drug dosage guidance based on an individual's genetic make-up. Consequently, genetic variations are essential to understand the ethnic differences in disease occurrence, development, prognosis, therapeutic response and toxicity. For that reason, it is necessary to establish the normative frequency of these genes in a particular population before unraveling the genotype-phenotype associations. Although a fair amount of allele frequency data are available in Indian populations, the existing pharmacogenetic data have not been compiled into a database. This review was intended to compile the normative frequency distribution of the variants of genes encoding DMEs (CYP450s, TPMT, GSTs, COMT, SULT1A1, NAT2 and UGTs) and transporter proteins (MDR1, OCT1 and SLCO1B1) with Indian perspective.

Umamaheswaran, Gurusamy; Kumar, Dhakchinamoorthi Krishna; Adithan, Chandrasekaran

2014-01-01

94

Mean Interconversion Times and Distribution Rate Parameters for Drugs Undergoing Reversible Metabolism  

Microsoft Academic Search

The mean interconversion time and recycling numbers are introduced as intrinsic metabolic interconversion and distribution parameters for drugs undergoing linear reversible metabolism. Equations for these parameters, the distribution clearance, and the mean transit time in the central and peripheral compartments are derived for a metabolic pair where interconversion and elimination occur in central compartments. These parameters can be calculated from

Haiyung Cheng; William J. Jusko

1990-01-01

95

A Marginal Structural Modeling Approach to Assess the Cumulative Effect of Drug Treatment on the Later Drug Use Abstinence  

PubMed Central

In this article, we applied a marginal structural model (MSM) to estimate the effect on later drug use of drug treatments occurring over 10 years following first use of the primary drug. The study was based on the longitudinal data that were collected in three projects among 421 subjects and covered 15 years since first use of their primary drug. The cumulative treatment effect was estimated by the inverse-probability of treatment weighted estimators of MSM as well as the traditional regression analysis. Contrary to the traditional regression analysis, results of the MSM showed that the cumulative treatment occurring over the 10 years significantly increased the likelihood of drug use abstinence in the subsequent 5-year period. From both the statistical and empirical point of view, MSM is a better approach to assessing cumulative treatment effects, considering its advantage of controlling for self-selection bias over time.

Li, Libo; Evans, Elizabeth; Hser, Yih-ing

2010-01-01

96

Quantitative Assessment of the Transport of Elastic and Rigid Vesicle Components and a Model Drug from these Vesicle Formulations into Human Skin In Vivo  

Microsoft Academic Search

The aim of this study was to quantitatively assess the distribution profiles of elastic and rigid vesicle material in human skin in vivo. Furthermore, the distribution profiles of the model drug ketorolac applied in these vesicle formulations was investigated. A deuterium-labelled phospholipid was incorporated into these vesicles to serve as a marker for the vesicle material. The vesicles were loaded

P. Loan Honeywell-Nguyen; Gert S. Gooris; Joke A. Bouwstra

2004-01-01

97

Rapid assessment and response to injecting drug use in Madras, south India  

Microsoft Academic Search

HIV infection among injecting drug users (IDUs) is preventable, and in order to develop appropriate interventions, an assessment was carried out at Madras, South India using the Rapid Assessment and Response Guide on Injecting Drug Use developed by WHO. Data were collected with multiple methods from multiple sources using the principles of triangulation and induction. A total of 100 IDUs

M. Suresh Kumar; Shakuntala Mudaliar; S. P Thyagarajan; Senthil Kumar; Arun Selvanayagam; Desmond Daniels

2000-01-01

98

Rapid Assessment of Drug Susceptibilities of Mycobacterium tuberculosis by Means of Luciferase Reporter Phages  

Microsoft Academic Search

Effective chemotherapy of tuberculosis requires rapid assessment of drug sensitivity because of the emergence of multidrug-resistant Mycobacterium tuberculosis. Drug susceptibility was assessed by a simple method based on the efficient production of photons by viable mycobacteria infected with specific reporter phages expressing the firefly luciferase gene. Light production was dependent on phage infection, expression of the luciferase gene, and the

William R. Jacobs Jr.; Raul G. Barletta; Rupa Udani; John Chan; Gary Kalkut; Gabriel Sosne; Tobias Kieser; Gary J. Sarkis; Graham F. Hatfull; Barry R. Bloom

1993-01-01

99

Outpatient drug policy by clinical assessment rather than financial constraints?  

Microsoft Academic Search

Since 1991, the Dutch Price Reference System (DPRS) has aimed at a growth reduction of out-patient drug costs without loss of medical quality. New drugs are excluded unless they pass legally anchored clinical criteria, i.e. substitutability with accepted drugs (DPRS-list 1a, implies a reimbursement maximum), ‘unique and valuable’ (DPRS-list 1b, liberal price setting), or lack of value (rejected). We analysed

Marja H. Pronk; Gouke J. Bonsel

2004-01-01

100

Assessment of Excess Flow Valves in Gas Distribution Service Lines.  

National Technical Information Service (NTIS)

A background study, a survey of the gas industry, an assessment of the impact of upgrading distribution systems to suit available excess flow valves (EFV), a cost analysis, and short-term tests were performed to characterize EFV.

C. Blazek E. D. Bolzan N. C. Saha P. R. Collette W. J. Jasionowski

1985-01-01

101

Nurse Resource Service Distribution Assessment (NRSDA) Model Systems Documentation.  

National Technical Information Service (NTIS)

The components of the Online Model System (OMS) of the Nurse Resource Service Distribution Assessment (NSRDA) Model are described. The OMS consists of four COBOL computer programs and a subsystem stored at the National Institutes of Health Department of C...

1978-01-01

102

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

PubMed

Interactions between co-administered medicines can reduce efficacy or lead to adverse effects. Understanding and managing such interactions is essential in bringing safe and effective medicines to the market. Ideally, interaction potential should be recognized early and minimized in compounds that reach late stages of drug development. Physiologically based pharmacokinetic models combine knowledge of physiological factors with compound-specific properties to simulate how a drug behaves in the human body. These software tools are increasingly used during drug discovery and development and, when integrating relevant in vitro data, can simulate drug interaction potential. This article provides some background and presents illustrative examples. Physiologically based models are an integral tool in the discovery and development of drugs, and can significantly aid our understanding and prediction of drug interactions. PMID:22458685

Baneyx, Guillaume; Fukushima, Yumi; Parrott, Neil

2012-04-01

103

Assessing intraepithelial neoplasia and drug safety in cancer-preventive drug development  

Microsoft Academic Search

Despite significant interest from the research community and the population in general, drug approvals for cancer prevention and\\/or cancer risk reduction are few. This is due, in part, to the requirement that new cancer-preventive drugs must first be shown to be efficacious in reducing cancer incidence or mortality. Moreover, such drugs need to have proven safety for long-term administration. This

Caroline C. Sigman; Gary J. Kelloff

2007-01-01

104

Critical Assessment of Belgian Reimbursement Dossiers of Orphan Drugs  

Microsoft Academic Search

Background: Orphan medicinal products are designed to diagnose or treat rare diseases that are serious, life threatening or chronically debilitating and that affect 50 or fewer people in every 100?000 in the EU. In Belgium, the Drug Reimbursement Committee (DRC) evaluates reimbursement requests for orphan drugs based on multiple criteria: the therapeutic value, price and proposed reimbursement tariff; the importance

Alain Denis; Lut Mergaert; Christel Fostier; Irina Cleemput; Frank Hulstaert; Steven Simoens

2011-01-01

105

Development and assessment of mini projectiles as drug carriers  

Microsoft Academic Search

This paper describes a novel technology for the delivery of drugs into the subcutaneous and intramuscular tissue of farmed animals. The technology comprises small, hollow mini projectiles into which drug formulations can be loaded and administered using compressed air from an administration device which is held a few millimeters (3–10 mm) from the surface of the animals’ skin. The design

Gijsbert G. P van de Wijdeven

2002-01-01

106

An Assessment of Drug Testing within the Construction Industry.  

ERIC Educational Resources Information Center

Investigates the efficacy of workplace drug-testing programs in reducing injury incident rates and workers' compensation experience-rating modification factors within the construction industry. Analyses indicate that companies with drug-testing programs experienced a 51 percent reduction in incident rates within two years of implementation.…

Gerber, Jonathan K.; Yacoubian, George S., Jr.

2002-01-01

107

Assessment of AIDS Risk among Treatment Seeking Drug Abusers.  

ERIC Educational Resources Information Center

Intravenous (IV) drug abusers are at risk for contracting transmittable diseases such as acquired immunodeficiency syndrome (AIDS) and hepatitis B. This study was conducted to investigate the prevalence of risk behaviors for acquiring and transmitting AIDS and hepatitis B among treatment-seeking drug abusers (N=168). Subjects participated in a…

Black, John L.; And Others

108

Impact of anti-drug antibodies in preclinical pharmacokinetic assessment.  

PubMed

The administration of human biotherapeutics is often associated with a higher incidence of immunogenicity in preclinical species. The presence of anti-drug antibodies (ADAs) in the test samples can affect the accurate measurement of therapeutic protein (TP) in bioanalytical methods designed to support pharmacokinetic (PK) and toxicokinetic (TK) assessments. The impact can vary depending on the bioanalytical method platform and study dosing design. The goal of this study is to evaluate the impact of ADA response on the bioanalytical methods in support of PK/TK and the associated study data interpretation. Sprague Dawley rats were administered with four weekly doses of 50 mg/kg TP, a humanized monoclonal antibody. The TP in serum samples was measured using three bioanalytical methods that quantified bound and/or unbound TP to ADA. The ADA response in the animals was classified into negative, low, medium, and high based on the magnitude of the response. The presence of ADA in samples led to discrepant TP measurements between the methods, especially at time points where the TP concentrations were low. This could be due to ADA interference to the accurate measurement of ADA-bound TP concentrations. The TP concentration at last time point (C last) was reduced by 82.8%, 98.6%, and 99.8%, respectively, for samples containing low, medium, and high levels of ADA. The interfering effects of the ADA on bioanalytical methods and exposure were evident as early as 2 weeks post-dosing. This modeling approach can provide the better understanding of ADA impact on PK exposure in multiple doses. PMID:23653044

Thway, Theingi M; Magana, Ivan; Bautista, Ami; Jawa, Vibha; Gu, Wen; Ma, Mark

2013-07-01

109

Assessing Long Term Drug Safety: Lessons (Re) Learned from Raptiva  

PubMed Central

Efalizumab was approved for moderate to severe psoriasis in 2003 based on studies in approximately 2,700 patients of whom only 218 were exposed to the drug for more than one year. In 2009, after over 46,000 patients were exposed to efalizumab, the drug was withdrawn from the market after 3 confirmed and one suspected case of progressive multifocal leukoencephalopathy (PML) were spontaneously reported. As PML is very rare, it is extremely unlikely that the four reported cases were due to chance and given that PML occurs primarily in patients who are immunosuppressed, the association is likely causal. The identification of PML as a serious, but statistically rare risk of efalizumab demonstrates the strengths and weaknesses of the current drug approval and pharmacovigilance processes for fully measuring the safety of a drug. Patients and clinicians need to be aware of the relative completeness and limitations of existing safety data of a drug when selecting a treatment.

Seminara, Nicole; Gelfand, Joel M

2010-01-01

110

Plasmodium falciparum Drug Resistance Phenotype as Assessed by Patient Antimalarial Drug Levels and Its Association With pfmdr1 Polymorphisms  

PubMed Central

Background.?Multidrug-resistant Plasmodium falciparum is a major threat to global malaria control. Parasites develop resistance by gradually acquiring genetic polymorphisms that decrease drug susceptibility. The aim of this study was to investigate the extent to which parasites with different genetic characteristics are able to withstand individual drug blood concentrations. Methods.?We analyzed 2 clinical trials that assessed the efficacy and effectiveness of artemether-lumefantrine. As a proof of concept, we used measured day 7 lumefantrine concentrations to estimate the concentrations at which reinfections multiplied. P. falciparum multidrug resistance gene 1 (pfmdr1) genotypes of these parasites were then correlated to drug susceptibility. Results.?Reinfecting parasites with the pfmdr1 N86/184F/D1246 haplotype were able to withstand lumefantrine blood concentrations 15-fold higher than those with the 86Y/Y184/1246Y haplotype. Conclusions.?By estimating drug concentrations, we were able to quantify the contribution of pfmdr1 single-nucleotide polymorphisms to reduced lumefantrine susceptibility. The method can be applied to all long–half-life antimalarial drugs, enables early detection of P. falciparum with reduced drug susceptibility in vivo, and represents a novel way for unveiling molecular markers of antimalarial drug resistance.

Malmberg, Maja; Ferreira, Pedro E.; Tarning, Joel; Ursing, Johan; Ngasala, Billy; Bjorkman, Anders; Martensson, Andreas; Gil, Jose P.

2013-01-01

111

Influence of surface chemistry of mesoporous alumina with wide pore distribution on controlled drug release.  

PubMed

The crucial role of the drug carrier surface chemical moeities on the uptake and in vitro release of drug is discussed here in a systematic manner. Mesoporous alumina with a wide pore size distribution (2-7 nm) functionalized with various hydrophilic and hydrophobic surface chemical groups was employed as the carrier for delivery of the model drug ibuprofen. Surface functionalization with hydrophobic groups resulted in low degree of drug loading (approximately 20%) and fast rate of release (85% over a period of 5 h) whereas hydrophilic groups resulted in a significantly higher drug payloads (21%-45%) and slower rate of release (12%-40% over a period of 5 h). Depending on the chemical moiety, the diffusion controlled ( proportional, varianttime(-)(0.5)) drug release was additionally observed to be dependent on the mode of arrangement of the functional groups on the alumina surface as well as on the pore characteristics of the matrix. For all mesoporous alumina systems the drug dosages were far lower than the maximum recommended therapeutic dosages (MRTD) for oral delivery. We envisage that the present study would aid in the design of delivery systems capable of sustained release of multiple drugs. PMID:19654029

Kapoor, Shobhna; Hegde, Rajesh; Bhattacharyya, Aninda J

2009-11-16

112

Kinetic model of drug distribution in the urinary bladder wall following intravesical instillation.  

PubMed

Intravesical administration of cytotoxic agents is commonly used in urological practice for treatment of superficial bladder cancer. The leading motive is optimisation of drug delivery near the site of action and reduction of systemic toxicity. Bladder pharmacokinetics is complicated by several mechanisms. The objectives of this work were to develop a kinetic model of drug distribution in the bladder wall following intravesical instillation and to study the effect of various parameters on tissue and systemic drug exposure and explore the potential benefits of permeability enhancing effects of chitosan (CH) and polycarbophil (PC) through simulation. Key elements of the model are variable urinary drug concentration due to urine formation and voiding, biphasic diffusion in the bladder tissue and systemic absorption. Model parameters were estimated from bladder-tissue concentration profiles obtained in previous in vitro experiments with pipemidic acid (PPA) as a model drug. The results support further investigations on application of CH and PC in intravesical drug delivery. Both polymers increase permeability of the bladder wall by diffusion enhancement in the urothelium and presumably by improving the contact with the bladder surface. The developed mathematical model could serve for optimisation of intravesical drug delivery and future development of intravesical drug delivery systems. PMID:16806751

Grabnar, I; Bogataj, M; Belic, A; Logar, V; Karba, R; Mrhar, A

2006-09-28

113

Assessment of the Potential Drug Etiology of Breast Cancer: Analyses of Data from a Case-Control Drug Surveillance Study.  

National Technical Information Service (NTIS)

The purpose of the present study is to assess the potential drug etiology of breast cancer through analyses of data from our hospital-based Case-Control Surveillance Study. We carried out computer 'screens' of the data to detect unsuspected associations: ...

L. Rosenberg

1997-01-01

114

Quantitative Assessment of Distributed Energy Resource Benefits  

SciTech Connect

Distributed energy resources (DER) offer many benefits, some of which are readily quantified. Other benefits, however, are less easily quantifiable because they may require site-specific information about the DER project or analysis of the electrical system to which the DER is connected. The purpose of this study is to provide analytical insight into several of the more difficult calculations, using the PJM power pool as an example. This power pool contains most of Pennsylvania, New Jersey, Maryland, and Delaware. The techniques used here could be applied elsewhere, and the insights from this work may encourage various stakeholders to more actively pursue DER markets or to reduce obstacles that prevent the full realization of its benefits. This report describes methodologies used to quantify each of the benefits listed in Table ES-1. These methodologies include bulk power pool analyses, regional and national marginal cost evaluations, as well as a more traditional cost-benefit approach for DER owners. The methodologies cannot however determine which stakeholder will receive the benefits; that must be determined by regulators and legislators, and can vary from one location to another.

Hadley, S.W.

2003-05-22

115

Assessment of mechanical integrity for drug-eluting renal stent with micro-sized drug reservoirs.  

PubMed

The drug-eluting stent (DES) has become the gold standard worldwide for the treatment of cardiovascular diseases. In recent years, an innovative variation of the DES with micro-sized drug reservoirs has been introduced. It allows programmable drug delivery with both spatial and temporal control and has several potential advantages over traditional DESs. However, creating such reservoirs on the stent struts may weaken the structure of the stent scaffolding and compromise its mechanical integrity. In this study, we propose to use this innovative stent concept in the renal indication for potential treatment of both renal artery stenosis (upstream) and its associated kidney diseases (downstream) at the same time. The effects of these micro-sized drug reservoirs on several key clinically relevant functional attributes of the drug-eluting renal stent were systematically and quantitatively investigated. Finite element models were developed to predict the mechanical integrity of a balloon-expandable stent at various stages. Results show that (1) creating drug reservoirs on a stent could impact the stent fatigue resistance to certain degrees; (2) drug reservoirs on the stent crowns lead to greater loss in all key stent attributes than reservoirs on either bar arms or connectors and (3) the proposed optimised depot stent was proven to be feasible and could triple drug capacity than the current DESs, with marginal trade-off in its key clinical attributes. These results can serve as the guidelines to help future stent designs to achieve the best combination of stent structural integrity and smart drug delivery in the future. PMID:22436070

Hsiao, Hao-Ming; Chiu, Yi-Hsiang

2013-01-01

116

Agreement Between Drugs-to-Avoid Criteria and Expert Assessments of Problematic Prescribing  

PubMed Central

Background Drugs-to-avoid criteria are commonly used to evaluate prescribing quality in elders. However, few studies have evaluated the concordance between these criteria and individualized patient assessments as measures of problem prescribing. Methods We used data on 256 outpatients from the Iowa City VA Medical Center who were age 65 and older and taking 5 or more medications. After a comprehensive patient interview, a physician/pharmacist study team recommended that certain drugs be discontinued, substituted, or reduced in dose. We evaluated the degree to which drugs considered potentially inappropriate by the drugs-to-avoid criteria of Beers and Zhan were also considered problematic by the study team, and vice versa. Results In the study cohort, 256 patients were using 3678 medications. The physician/pharmacist team identified 563 drugs (15%) as problematic, the Beers criteria flagged 214 drugs (6%) as potentially inappropriate, and the Zhan criteria flagged 91 drugs (2.5%). Kappa statistics for concordance between drugs-to-avoid criteria and expert assessments were 0.10–0.14, indicating “slight” agreement between these measures. Sixty-one percent of drugs identified as potentially inappropriate by the Beers criteria and 49% of drugs flagged by the Zhan criteria were not judged problematic by the expert reviewers. Correspondence between drugs-to-avoid criteria and expert assessment varied widely across different types of drugs. Conclusions Drugs-to-avoid criteria have limited power to differentiate between drugs and patients with and without prescribing problems identified on individualized expert review. While these criteria are useful as guides for initial prescribing decisions, they are insufficiently accurate to use as stand-alone measures of prescribing quality.

Steinman, Michael A.; Rosenthal, Gary E.; Landefeld, C. Seth; Bertenthal, Daniel; Kaboli, Peter J.

2009-01-01

117

Designing a tool allowing for a standardized assessment of resistance to drug diversion.  

PubMed

Objectives: Drug diversion is a growing problem in numerous countries. Some laboratories have developed tamper-resistant formulations. The problem for healthcare authorities is now to assess new formulations developed to limit the risk of diversion for administration by another mode and intended mode. It would be helpful to have a pertinent panel of in vitro tests allowing assessment of how a formulation may be altered, both for healthcare authorities and for laboratories, so as to implement adequate sanitary measures. We designed a methodology/tool allowing assessment, in a standardized manner, of the formulation's resistance to drug diversion. We present the various steps leading to the construction of the scale and to its first use. Methods: Creating a Steering Committee - Choosing assays or parameters - standardized by a monograph of the European Pharmacopoeia and pragmatic assays related to users' behaviors - for the assessment of formulation resistance to drug diversion. Designing a scale: i) applying all these tests to a panel of formulations; ii) applying a score by drug and by test; and iii) attribution of weighting per test and calculating the total score for a drug. Results: Eight tests or parameters and 14 drugs (diverted drugs and controls) were chosen. Buprenorphine Subutex® had the lowest score and flunitrazepam Rohypnol® the highest. Conclusions: Our tool allowed classification of the various drugs selected. This classification correlated with results of postmarketing authorization assessment. Rohypnol®, which was the object of many measures, including formulation changes, obtained the highest score in our study. PMID:24820178

Victorri-Vigneau, Caroline; Collin, Cedric; Messina-Gourlot, Catherine; Raffournier, Christel; Mallaret, Michel; Besse, Jérôme; Courne, Marie-Anne; Richard, Nathalie; Sébille, Véronique; Arnaud, Philippe

2014-07-01

118

Failure-mode and effects analysis in improving a drug distribution system.  

PubMed

The medication error rate in an existing ward stock drug distribution system and in an alternative system developed after failure-mode and effects analysis (FMEA) was applied to the ward stock system was studied. In the ward stock system of a large teaching hospital in Western Australia, bulk drug packs were stored in cupboards on the wards, and drug products were transferred to drug trolleys before dose administration by nurses. A pharmacist used the disguised-observer technique to determine the error rate in the ward stock system for a medical ward and a surgical ward. The errors and each step in the system were studied by FMEA. A unit supply individual-patient dispensing (USIPD) system was formulated to respond to the failure modes identified. In this system, a five-day supply of medication was dispensed for each patient from a satellite pharmacy close to the ward. Medication charts were reviewed by a pharmacist, and drugs were dispensed in labeled vials that were placed in a locked drawer at the patient's bedside. The error rate under the USIPD system was determined. Problem areas in the ward stock system identified by FMEA included drug availability, review of orders, drug selection, patient-related issues, and use of nurses' time. The percentage of opportunities during which any error occurred was significantly lower under the USIPD system on both wards. FMEA was used to identify deficiencies in the ward stock system that led to medication errors in an Australian hospital. An alternative drug distribution system designed to address the problems identified was associated with fewer errors. PMID:9117805

McNally, K M; Page, M A; Sunderland, V B

1997-01-15

119

Assessing the barriers to image-guided drug delivery.  

PubMed

Imaging has become a cornerstone for medical diagnosis and the guidance of patient management. A new field called image-guided drug delivery (IGDD) now combines the vast potential of the radiological sciences with the delivery of treatment and promises to fulfill the vision of personalized medicine. Whether imaging is used to deliver focused energy to drug-laden particles for enhanced, local drug release around tumors, or it is invoked in the context of nanoparticle-based agents to quantify distinctive biomarkers that could risk stratify patients for improved targeted drug delivery efficiency, the overarching goal of IGDD is to use imaging to maximize effective therapy in diseased tissues and to minimize systemic drug exposure in order to reduce toxicities. Over the last several years, innumerable reports and reviews covering the gamut of IGDD technologies have been published, but inadequate attention has been directed toward identifying and addressing the barriers limiting clinical translation. In this consensus opinion, the opportunities and challenges impacting the clinical realization of IGDD-based personalized medicine were discussed as a panel and recommendations were proffered to accelerate the field forward. PMID:24339356

Lanza, Gregory M; Moonen, Chrit; Baker, James R; Chang, Esther; Cheng, Zheng; Grodzinski, Piotr; Ferrara, Katherine; Hynynen, Kullervo; Kelloff, Gary; Lee, Yong-Eun Koo; Patri, Anil K; Sept, David; Schnitzer, Jan E; Wood, Bradford J; Zhang, Miqin; Zheng, Gang; Farahani, Keyvan

2014-01-01

120

Truncated shifted pareto distribution in assessing size distribution of oil and gas fields  

SciTech Connect

The truncated shifted Pareto (TSP) distribution, a variant of the two-parameter Pareto distribution, in which one parameter is added to shift the distribution right and left and the right-hand side is truncated, is used to model size distributions of oil and gas fields for resource assessment. Assumptions about limits to the left-hand and right-hand side reduce the number of parameters to two. The TSP distribution has advantages over the more customary lognormal distribution because it has a simple analytic expression, allowing exact computation of several statistics of interest, has a J-shape, and has more flexibility in the thickness of the right-hand tail. Oil field sizes from the Minnelusa play in the Powder River Basin, Wyoming and Montana, are used as a case study. Probability plotting procedures allow easy visualization of the fit and help the assessment.

Houghton, J.C.

1988-11-01

121

An informatics approach to assess pediatric pharmacotherapy: design and implementation of a hospital drug utilization system.  

PubMed

Drug utilization in the inpatient setting can provide a mechanism to assess drug prescribing trends, efficiency, and cost-effectiveness of hospital formularies and examine subpopulations for which prescribing habits may be different. Such data can be used to correlate trends with time-dependent or seasonal changes in clinical event rates or the introduction of new pharmaceuticals. It is now possible to provide a robust, dynamic analysis of drug utilization in a large pediatric inpatient setting through the creation of a Web-based hospital drug utilization system that retrieves source data from our accounting database. The production implementation provides a dynamic and historical account of drug utilization at the authors' institution. The existing application can easily be extended to accommodate a multi-institution environment. The creation of a national or even global drug utilization network would facilitate the examination of geographical and/or socioeconomic influences in drug utilization and prescribing practices in general. PMID:17656617

Zuppa, Athena; Vijayakumar, Sundararajan; Jayaraman, Bhuvana; Patel, Dimple; Narayan, Mahesh; Vijayakumar, Kalpana; Mondick, John T; Barrett, Jeffrey S

2007-09-01

122

Assessment of potential drug interactions by characterization of human drug metabolism pathways using non-invasive bile sampling  

PubMed Central

Aim Characterization of the biliary disposition of GSK1325756, using a non-invasive bile sampling technique and spectrometric analyses, to inform the major routes of metabolic elimination and to enable an assessment of victim drug interaction risk. Method Sixteen healthy, elderly subjects underwent non-invasive bile capture using a peroral string device (Entero-Test®) prior to and following a single oral dose of GSK1325756 (100 mg). The device was swallowed by each subject and once the weighted string was judged to have reached the duodenum, gallbladder contraction was stimulated in order to release bile. The string was then retrieved via the mouth and bile samples were analyzed for drug-related material using spectrometric and spectroscopic techniques following solvent extraction. Results Nuclear magnetic resonance spectroscopy (NMR) indicated that the O-glucuronide metabolite was the major metabolite of GSK1325756, representing approximately 80% of drug-related material in bile. As bile is the major clearance route for GSK1325756 (only 4% of the administered dose was excreted in human urine), this result indicates that uridine 5'-diphospho-glucuronosyltransferases (UGTs) are the major drug metabolizing enzymes responsible for drug clearance. The relatively minor contribution made by oxidative routes reduces the concern of CYP-mediated victim drug interactions. Conclusion The results from this study demonstrate the utility of deploying the Entero-Test® in early human studies to provide information on the biliary disposition of drugs and their metabolites. This technique can be readily applied in early clinical development studies to provide information on the risk of interactions for drugs that are metabolized and eliminated in bile.

Bloomer, Jackie C; Nash, Mike; Webb, Alison; Miller, Bruce E; Lazaar, Aili L; Beaumont, Claire; Guiney, William J

2013-01-01

123

Quality assessment of drug sales data: the case of antibacterials in Iceland  

Microsoft Academic Search

Background: Two sets of drug sales data, published by the Icelandic Ministry of Health, did not match for antibacterials in 1989. The search for causes turned out to be a project in itself. Objective: To analyze quality problems in the sales data on antibacterials and describe a method for systematic quality assessment of drug sales data. Methods: Documentary analysis based

Ingunn Björnsdóttir; Ebba Holme Hansen; Almar Grímsson

1999-01-01

124

ADVANCED TOOLS FOR ASSESSING SELECTED PRESCRIPTION AND ILLICIT DRUGS IN TREATED SEWAGE EFFLUENTS AND SOURCE WATERS  

EPA Science Inventory

The purpose of this poster is to present the application and assessment of advanced technologies in a real-world environment - wastewater effluent and source waters - for detecting six drugs (azithromycin, fluoxetine, omeprazole, levothyroxine, methamphetamine, and methylenedioxy...

125

In silico approaches to predicting cancer potency for risk assessment of genotoxic impurities in drug substances.  

PubMed

The current risk assessment approach for addressing the safety of very small concentrations of genotoxic impurities (GTIs) in drug substances is the threshold of toxicological concern (TTC). The TTC is based on several conservative assumptions because of the uncertainty associated with deriving an excess cancer risk when no carcinogenicity data are available for the impurity. It is a default approach derived from a distribution of carcinogens and does not take into account the properties of a specific chemical. The purpose of the study was to use in silico tools to predict the cancer potency (TD(50)) of a compound based on its structure. Structure activity relationship (SAR) models (classification/regression) were developed from the carcinogenicity potency database using MultiCASE and VISDOM. The MultiCASE classification models allowed the prediction of carcinogenic potency class, while the VISDOM regression models predicted a numerical TD(50). A step-wise approach is proposed to calculate predicted numerical TD(50) values for compounds categorized as not potent. This approach for non-potent compounds can be used to establish safe levels greater than the TTC for GTIs in a drug substance. PMID:20363275

Bercu, Joel P; Morton, Stuart M; Deahl, J Thom; Gombar, Vijay K; Callis, Courtney M; van Lier, Robert B L

2010-01-01

126

Discrete quality assessment in IPTV content distribution networks  

Microsoft Academic Search

Maintaining the quality of videos in resource-intensive IPTV services is challenging due to the nature of packet-based content distribution networks (CDN). Network impairments are unpredictable and highly detrimental to the quality of video content. Quality of the end user experience (QoE) has become a critical service differentiator. An efficient real-time quality assessment service in distribution networks is the foundation of

Mu Mu; Andreas Mauthe; Robert Haley; Francisco Garcia

2011-01-01

127

Gelatin-carrageenan hydrogels: role of pore size distribution on drug delivery process.  

PubMed

Naturally occurring biomaterials, such as gelatin and carrageenan are known to act as good drug delivering agents. The physical properties of these hydrogels are derived from their pore network. The effect of pore size distribution of hydrogel on the drug delivery process has been studied in this work. Gelatin-carrageenan hydrogel has been characterized using DSC, TGA and SEM. Thermoporometry technique has been used since it offers the measurement to be carried out in native state without drying the sample. Release of quercetin (Q,3,5,7,3',4'-pentahydroxyflavone), a member of the flavonoids family, which exerts many beneficial health effects has been studied using gelatin-carrageenan hydrogel. The addition of gelatin to carrageenan is found to improve the thermal stability of the gelatin-carrageenan fibers in the composite hydrogels. The in vitro drug release studies have shown that an increase in porosity results in the improved drug release. The tuning of pore size distribution for drug delivery applications using thermoporometry is feasible. PMID:24126319

Varghese, Jina Susan; Chellappa, Nisha; Fathima, Nishter Nishad

2014-01-01

128

Assessing Drug Abuse Among Gay–Bisexual Young Men  

Microsoft Academic Search

The utility of an adolescent drug abuse screening tool was explored in a sample (N = 501) of young gay–bisexual men at risk for HIV–AIDS transmission. The Personal Experience Screening Questionnaire (PESQ; K. C. Winters, 1992) revealed favorable evidence of internal consistency reliability (coefficient alpha) and convergent validity with alternative measures of problem severity and delinquency behaviors. Nearly 20% of

Ken C. Winters; Gary Remafedi; Benjamin Y. Chan

1996-01-01

129

A convenient five-drug cocktail for the assessment of major drug metabolizing enzymes: a pilot study  

PubMed Central

Aims To assess the feasibility of administering at the same time low doses of five probe drugs, metoprolol (25 mg), chlorzoxazone (250 mg), tolbutamide (250 mg), dapsone (100 mg) and caffeine (100 mg) to determine simultaneously the activities of CYP2D6, CYP2E1, CYP2C9, CYP3A4, CYP1A2, N-acetyltransferase-2 and xanthine oxidase. Methods Ten healthy young non-smoking males received the following drugs or combinations of drugs over a 5-week period: week 1) metoprolol; 2) tolbutamide; 3) caffeine, chlorzoxazone and dapsone; 4) caffeine, chlorzoxazone, dapsone and metoprolol; 5) caffeine, chlorzoxazone, dapsone, metoprolol and tolbutamide. The drugs were self-administered at bedtime and urine was collected for the following 8 h. Results Mean molar phenotypic ratios obtained after administering metoprolol (mean change of ?11%) or tolbutamide (mean change of ?0.3%) alone, were not significantly different from those obtained when other drugs were co-administered (P > 0.05). The mean within-subject coefficients of variation were 33%, 18%, 22%, 13%, 16%, 13% and 5% for CYP3A4, CYP2D6, CYP2C9, CYP2E1, CYP1A2, N-acetyltransferase 2 and xanthine oxidase metabolic ratios, respectively. No significant interactions (P > 0.5) were observed during the simultaneous administration of various combinations of the five probe drugs. Conclusions We propose that this cocktail, composed of five widely available drugs, constitutes a promising means of simultaneously determining the activities of the major CYP enzymes in large populations.

Sharma, Ashish; Pilote, Sylvie; Belanger, Pierre M; Arsenault, Marie; Hamelin, Bettina A

2004-01-01

130

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

PubMed

Pradigastat, a novel diacylglycerol acyltransferase-1 inhibitor, was evaluated for both pharmacokinetic (PK) and pharmacodynamic (PD) drug-drug interactions when co-administered with digoxin or warfarin in healthy subjects. This open-label study included two parallel subject cohorts each with three sequential treatment periods. Forty subjects were enrolled in the study with 20 subjects allocated to each cohort. PK and PD (PT/INR for warfarin only) samples were collected in each period. The statistical analysis results showed that the 90% CIs of the geometric mean ratios of digoxin, R-warfarin, and S-warfarin PK parameters (AUC and Cmax ) were all within 0.80-1.25 interval. The 90% CIs of the geometric mean ratios of pradigastat PK parameters (AUC and Cmax ) were within 0.80-1.25 interval when co-administered with warfarin; while co-administration with digoxin slightly reduced pradigastat exposure (?15%). The results also showed that 90% CIs of the geometric mean ratios of warfarin PD parameters (AUCPT , PTmax , AUCINR , and INRmax ) were within 0.80-1.25 interval. Pradigastat and digoxin or warfarin had no relevant clinical PK or PD drug-drug interactions. Administration of pradigastat and warfarin or pradigastat and digoxin as a mono or combined treatment appears to be safe and tolerated. PMID:24619917

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

2014-07-01

131

The future of population-based postmarket drug risk assessment: a regulator's perspective.  

PubMed

The US Food and Drug Administration emphasizes the role of regulatory science in the fulfillment of its mission to promote and protect public health and foster innovation. With respect to the evaluation of drug effects in the real world, regulatory science plays an important role in drug risk assessment and management. This article discusses opportunities and challenges with population-based drug risk assessment as well as related regulatory science knowledge gaps in the following areas: (i) population-based data sources and methods to evaluate drug safety issues; (ii) evidence-based thresholds to account for uncertainty in postmarket data; (iii) approaches to optimize the integration and interpretation of evidence from different sources; and (iv) approaches to evaluate the real-world impact of regulatory decisions. Regulators should continue the ongoing dialogue with multiple stakeholders to strengthen regulatory safety science and address these and other critical knowledge gaps. PMID:23739537

Hammad, T A; Neyarapally, G A; Iyasu, S; Staffa, J A; Dal Pan, G

2013-09-01

132

Assessment of alcohol and other drug use behaviors in health professions students.  

PubMed

Alcohol and other drug (AOD) use behaviors of health professions students (HPS) were assessed by surveying both university-based HPS and other nursing programs in a Midwestern state in 1999. Response was 2,646 (56.4%) of surveyed students. Family history of alcohol-related and drug-related problems were reported by 39.8% and 13.9%, respectively, with 42.6% of respondents reporting one or both. Among nursing respondents, 48.1%, 19.2% and 51.1%, respectively, reported family problems with alcohol, drugs, or one or both. Past-year alcohol use was comparable to undergraduate college students (UCS) nationally (83%); heavy drinking, tobacco and recreational drug use by HPS were lower. Past year drug use was highest among medical students. Marijuana was the predominant illicit drug; medical students and males most often reported use. Health professions educational systems should proactively address student AOD prevention, education and assistance needs. PMID:17135178

Baldwin, Jeffrey N; Scott, David M; Agrawal, Sangeeta; Bartek, Jean K; Davis-Hall, R Ellen; Reardon, Thomas P; DeSimone, Edward M

2006-09-01

133

Assessing the effects of drug misuse on HIV/AIDS prevalence.  

PubMed

Drug misuse (injecting drug users-IDU) has been recognized to have a significant effect on the spread of HIV/AIDS epidemic. A deterministic model to assess the contribution of drug misuse and sex in the spread of HIV/AIDS is investigated. The threshold parameters of the model are determined and stabilities are analysed. Analysis of the reproduction number has shown that increase in drug misuse results in an increase in HIV infections. Furthermore, numerical simulations of the model show that drug misuse enhances HIV transmission and progression to AIDS. Thus, in a population with intravenous drug users, advocating for safe sex alone will not be enough to control the HIV/AIDS epidemic. PMID:23225069

Bhunu, C P; Mushayabasa, S

2013-06-01

134

[Drugs and criminal issues: assessment of research in Quebec].  

PubMed

Although research on the link between drugs and crime is not a major concern for many Quebec researchers, the last five years have been the scene of an increasing number of studies on the subject. These studies can be divided in four groups: 1) criminal policies; 2) studies on prevalence; 3) relation between drugs and crime; 4) intervention and its impact. Results of these studies put additional pressure for adequate treatment of addicts having problems with the law. Social workers in rehabilitation centres have thus noticed an increasing number of addicts who had or were going through problems with the law. Yet a great proportion of addicts having problems with the justice system are not reached by rehabilitation services: it is those people who present the most deteriorated bio-social profile. Is it really worthwhile to intervene with this type of clientele? The answer is yes as long they can be kept in treatment sufficiently long. In any case, the simple judiciarization of a person says nothing of his character (e.g. violent, liar or fraudulent) or of his pathology (e.g. psychopath, sociopath ...). In fact, given the illicit nature of certain drugs, the simple fact of using can lead to criminalization. The challenge in research in this field will consist in better defining factors related to perseverance in treatment and therapeutic ingredients associated to the desired impact. PMID:9534585

Brochu, S

1997-01-01

135

Condition Assessment Technologies for Water Transmission and Distribution Systems  

EPA Science Inventory

As part of the U.S. Environmental Protection Agency?s (EPA?s) Aging Water Infrastructure Research Program, this research was conducted to identify and characterize the state of the technology for structural condition assessment of drinking water transmission and distribution syst...

136

Condition Assessment of Drinking Water Transmission and Distribution Systems  

EPA Science Inventory

Condition assessment of water transmission and distribution mains is the collection of data and information through direct and/or indirect methods, followed by analysis of the data and information, to make a determination of the current and/or future structural, water quality, an...

137

Early benefit assessment of new drugs in Germany - Results from 2011 to 2012.  

PubMed

Rising drug costs in Germany led to the Act on the Reform of the Market for Medicinal Products (AMNOG) in January 2011. For new drugs, pharmaceutical companies have to submit dossiers containing all available evidence to demonstrate an added benefit versus an appropriate comparator therapy. The Federal Joint Committee (G-BA), the main decision-making body of the statutory healthcare system, is responsible for the overall procedure of "early benefit assessment". The Institute for Quality and Efficiency in Health Care (IQWiG) largely conducts the dossier assessments, which inform decisions by the G-BA on added benefit and support price negotiations. Of the 25 dossiers (excluding orphan drugs) assessed until 31 December 2012, 14 contained sufficient data from randomized active-controlled trials investigating patient-relevant outcomes or at least acceptable surrogates; 11 contained insufficient data. The most common indications were oncology (6) and viral infections (4). For the 14 drugs assessed, the extent of added benefit was rated as minor, considerable, and non-quantifiable in 3, 8, and 2 cases; the remaining drug showed no added benefit. Despite some shortcomings, for the first time it has been possible in Germany to implement a systematic procedure for assessing new drugs at market entry, thus providing support for price negotiations and informed decision-making for patients, clinicians and policy makers. PMID:24472328

Hörn, Helmut; Nink, Katrin; McGauran, Natalie; Wieseler, Beate

2014-06-01

138

Assessment of Pharmacists Knowledge, Attitude and Practices Regarding Herbal Drug Information Services  

PubMed Central

Rational: Research suggests that increased consumption of herbal drugs is raising important public health concerns such as safety issues that may involve adverse effects and herb-drug interactions. The main objective of this study is to investigate the role of Pharmacists in herbal drug information dissemination. Method: We investigated the demographics, knowledge, attitude and practices regarding herbal drug information and regulatory laws among Pharmacists living in the six (6) States that constitute the Niger-Delta region of Nigeria. A total of 300 self-administered questionnaires were distributed to Pharmacists aged 21 years and above. Findings: About half of the respondents (48.72 %) were Hospital based Pharmacists. Knowledge of herbal drugs was 46.33 % while 64 .0 % showed positive attitude towards its use. Most of the information on herbal drugs were sourced from the internet (23.08 %) while 53.48 % were aware of the laws and regulations controlling herbal drugs in Nigeria. 88.64 % were in favour of the establishment of a National Herbal Drug Research and Development Agency and 55.68 % strongly agreeing to the setting up of a Herbal Drug Information Centre. Conclusion: The availability of herbal drug information services will not only enhance the performance of the Pharmacists, but will also add value to the life of the patients.

Atavwoda, Abere Tavs; Gabriel, Aina Ayodele

2012-01-01

139

Assessing covariates of drug use trajectories among adolescents admitted to a drug addiction center: mental health problems, therapeutic alliance, and treatment persistence.  

PubMed

This study aimed to assess covariates of drug use trajectories among 102 adolescents admitted to a drug user treatment program between November 2005 and November 2006 in Québec, Canada. The influences of mental health, therapeutic alliance, and treatment persistence were examined. The Addiction Severity Index was used to measure drug use severity and mental health problems; the California Psychotherapy Alliance Scales was used for therapeutic alliance. latent growth curve analysis showed associations between (1) mental health and initial drug use severity; (2) therapeutic alliance and initial drug use severity; and (3) number of post-treatment sessions attended and drug use severity over time. PMID:23127200

Bertrand, Karine; Brunelle, Natacha; Richer, Isabelle; Beaudoin, Isabelle; Lemieux, Annie; Ménard, Jean-Marc

2013-01-01

140

In vitro assessment of drug-drug interaction potential of boceprevir associated with drug metabolizing enzymes and transporters.  

PubMed

The inhibitory effect of boceprevir (BOC), an inhibitor of hepatitis C virus nonstructural protein 3 protease was evaluated in vitro against a panel of drug-metabolizing enzymes and transporters. BOC, a known substrate for cytochrome P450 (P450) CYP3A and aldo-ketoreductases, was a reversible time-dependent inhibitor (k(inact) = 0.12 minute(-1), K(I) = 6.1 µM) of CYP3A4/5 but not an inhibitor of other major P450s, nor of UDP-glucuronosyltransferases 1A1 and 2B7. BOC showed weak to no inhibition of breast cancer resistance protein (BCRP), P-glycoprotein (Pgp), or multidrug resistance protein 2. It was a moderate inhibitor of organic anion transporting polypeptide (OATP) 1B1 and 1B3, with an IC(50) of 18 and 4.9 µM, respectively. In human hepatocytes, BOC inhibited CYP3A-mediated metabolism of midazolam, OATP1B-mediated hepatic uptake of pitavastatin, and both the uptake and metabolism of atorvastatin. The inhibitory potency of BOC was lower than known inhibitors of CYP3A (ketoconazole), OATP1B (rifampin), or both (telaprevir). BOC was a substrate for Pgp and BCRP but not for OATP1B1, OATP1B3, OATP2B1, organic cation transporter, or sodium/taurocholate cotransporting peptide. Overall, our data suggest that BOC has the potential to cause pharmacokinetic interactions via inhibition of CYP3A and CYP3A/OATP1B interplay, with the interaction magnitude lower than those observed with known potent inhibitors. Conversely, pharmacokinetic interactions of BOC, either as a perpetrator or victim, via other major P450s and transporters tested are less likely to be of clinical significance. The results from clinical drug-drug interaction studies conducted thus far are generally supportive of these conclusions. PMID:23293300

Chu, Xiaoyan; Cai, Xiaoxin; Cui, Donghui; Tang, Cuyue; Ghosal, Anima; Chan, Grace; Green, Mitchell D; Kuo, Yuhsin; Liang, Yuexia; Maciolek, Cheri M; Palamanda, Jairam; Evers, Raymond; Prueksaritanont, Thomayant

2013-03-01

141

INSTRUCTIONAL DESIGN AND ASSESSMENT Web-based Instruction on Substance Abuse and Drug Diversion  

Microsoft Academic Search

Objectives. To develop a pilot study to assess the effectiveness of a Web-based educational module on enhancing understanding of substance abuse and drug diversion, and to assess students' abilities and confidence in applying the information. Design. A Web-based instructional module was presented to students enrolled in their second pre- professional year, and students were informed that it was part of

Jennifer Reinhold; Mark Angeles; Grace Earl

2010-01-01

142

Establishing the Validity of the Personality Assessment Inventory Drug and Alcohol Scales in a Corrections Sample  

ERIC Educational Resources Information Center

Although not originally designed for implementation in correctional settings, researchers and clinicians have begun to use the Personality Assessment Inventory (PAI) to assess offenders. A relatively small number of studies have made attempts to validate the alcohol and drug abuse scales of the PAI, and only a very few studies have validated those…

Patry, Marc W.; Magaletta, Philip R.; Diamond, Pamela M.; Weinman, Beth A.

2011-01-01

143

Training Needs of Rehabilitation Counselors concerning Alcohol and Other Drugs Abuse Assessment and Treatment  

ERIC Educational Resources Information Center

Forty-two rehabilitation counselors participated in a study regarding perceived training needs concerning alcohol and other drug abuse (AODA) treatment and assessment. Participants reported that 85% of consumers with whom they worked had AODA issues, yet over half rated their graduate training in AODA treatment and assessment as poor, and their…

Ong, Lee Za; Cardoso, Elizabeth; Chan, Fong; Chronister, Julie; Chou, Chih Chin

2007-01-01

144

Assessment Instruments in Texas Alcohol\\/Other Drug Dependence Treatment Facilities  

Microsoft Academic Search

This study, based on the view that alcohol\\/other drug dependence is a biopsychosocial issue, determines the extent to which treatment facilities use a biopsychosocial model to guide their assessment\\/screening process. Analyses identify the extent to which various facilities follow a biopsychosocial model in their assessment process. Survey results indicate that facilities could expand the use of a biopsychosocial approach in

Brian Samford; Judith Fischer; Alan Reifman; Yvonne Caldera

2000-01-01

145

Distribution of Drug Molecules in Lipid Membranes: Neutron Diffraction and MD Simulations.  

NASA Astrophysics Data System (ADS)

Non-steroidal anti-inflammatory drugs (NSAIDs) e.g. Aspirin and Ibuprofen, with chronic usage cause gastro intestinal (GI) toxicity. It has been shown experimentally that NSAIDs pre-associated with phospholipids reduce the GI toxicity and also increase the therapeutic activity of these drugs compared to the unmodified ones. In this study, using neutron diffraction, the DOPC lipid bilayer structure (with and without drug) as well as the distribution of a model NSAID (Ibuprofen) as a function of its position along the membrane normal was obtained at sub-nanometer resolution. It was found that the bilayer thickness reduces as the drug is added. Further, the results are successfully compared with atomistic Molecular Dynamics simulations. Based on this successful comparison and motivated by atomic details from MD, quasi-molecular modeling of the lipid membrane is being carried out and will be presented. The above study is expected to provide an effective methodology to design drug delivery nanoparticles based on a variety of soft condensed matter such as lipids or polymers.

Boggara, Mohan; Mihailescu, Ella; Krishnamoorti, Ramanan

2009-03-01

146

Practical considerations for the pharmacokinetic and immunogenic assessment of antibody-drug conjugates.  

PubMed

Currently, the most bioanalytically challenging drugs are antibody-drug conjugates (ADCs), constructs comprising a monoclonal antibody and a cytotoxic drug connected by a linker. The bioanalytical challenges arise from the heterogeneous nature of ADCs and their complex in vivo behavior, resulting in a high number of analytes to be measured. Measuring the concentration of biologics in blood/plasma/serum is a necessity to properly assess their pharmacokinetic (PK)/pharmacodynamic behaviors in vivo. An additional bioanalytical challenge is to monitor the stability of the ADCs, as cytotoxic drugs released from the ADC in blood circulation may pose a potential safety risk because of their high cytotoxic potency. The nature of ADCs does not only complicate bioanalysis, but also immunogenicity assessment. Questions, such as 'Which part of the ADCs is the anti-drug antibodies directed against?' may arise, and their answer normally includes several immunogenicity risk assessment strategies. This review will focus on the bioanalytical challenges of ADCs, current approaches involving ligand-binding assays (LBAs), liquid chromatography and mass spectrometry platforms, and recommendations on which approach to use for which stage of drug development, and will close with immunogenicity assessment. In order to appropriately tackle the bioanalytical and immunogenic challenges of ADCs and consider every angle, the authors of this review have expertise in ligand binding and liquid chromatography-mass spectrometry. PMID:24842227

Sauerborn, Melody; van Dongen, William

2014-08-01

147

Phototoxicity assessment of drugs and cosmetic products using E. coli.  

PubMed

A gram negative bacteria Escherichia coli (Dh5alpha strain) was developed as an alternate test system of phototoxicity. Eight drugs (antibiotics) and cosmetic products (eight face creams) were examined for their phototoxicity using this test system. Five known phototoxic compounds were used to validate the test system. UVA-radiation induced phototoxicity of these compounds was tested by agar gel diffusion assay. Decrease in colony forming units (CFU) was taken as an end point of phototoxicity. The phototoxic compounds and antibiotics produced significant reduction in CFU (p<0.001) at 80 microg/ml concentrations under exposure to UVA-radiation (5.4-10.8 J/cm(2)). One face cream was found phototoxic and produced significant decrease in CFU of E. coli at 1.0mg/ml concentration under UVA exposure (10.8 J/cm(2)). The minimum effective concentration of tetracycline and dose of UVA-radiation were also determined by observing growth inhibition of E. coli through disc diffusion assay. The observations suggested that E. coli can be used as an alternative test system for phototoxicity evaluation of chemicals. A battery of test systems is required to conclude the toxic/phototoxic potential of a chemical agent. In view of the speed, easiness, sensitivity and low cost, E. coli is introduced as one of the alternate test system for phototoxicity studies in safety evaluation of various chemical ingredients or formulations used in cosmetics and drugs. PMID:17919881

Verma, K; Agrawal, N; Misra, R B; Farooq, M; Hans, R K

2008-02-01

148

High-throughput phase-distribution method to determine drug-cyclodextrin binding constants.  

PubMed

A high-throughput method has been developed to measure drug-cyclodextrin binding constants. It measures the distribution ratio of a drug between a polymer film [polyvinyl chloride (PVC) with 67% (w/w) dioctyl sebacate (DOS)] and a cyclodextrin-containing buffer in a 96-well format. Measurements of distribution ratios at several cyclodextrin concentrations lead to binding constants. Binding constants for econazole with six CDs have been determined in one 96-well microplate with four replications of each condition in 10 h. The K(1:1)/10(3) M(-1) values are 3.98 +/- 0.13, 3.90 +/- 0.22, 29.3 +/- 2.2, 0.66 +/- 0.04, 1.78 +/- 0.30, 4.08 +/- 0.50, with (2-hydroxyethyl)-beta-cyclodextrin, (2-hydroxypropyl)-beta-cyclodextrin, 2,6-di-O-methyl-beta-cyclodextrin, heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin, alpha-cyclodextrin, beta-cyclodextrin, respectively. It is likely that 1:2 complexes are also formed in some cases. This method has also been applied to study the binding behavior as a function of the drug concentration and pH. Binding weakens at higher drug concentration which may be due to the self-association of the drug. An acidic environment decreases the binding constant of CD with the basic econazole. The formation of the 1:2 complexes is completely suppressed in acid as well. This protocol is faster than the phase-solubility method. Moreover, the material requirement is up to four orders of magnitude lower. PMID:18428984

Chen, Zhi; Lu, Dujuan; Weber, Stephen G

2009-01-01

149

Drug Use Prevention Data, Missed Assessments and Survival Analysis.  

ERIC Educational Resources Information Center

Two missing data procedures, both of which allow the subsequent use of discrete time survival analysis, are compared, and each is applied to each of two data sets. Results illustrate the advantages of multiple imputation over artificial censoring as an approach when there are intermittent missed assessments (missing data). (SLD)

Bacik, Jennifer M.; Murphy, Susan A.; Anthony, James C.

1998-01-01

150

Drugs.  

ERIC Educational Resources Information Center

This document contains the third volume of "Today's Delinquent," an annual publication of the National Center for Juvenile Justice. This volume deals with the issue of drugs and includes articles by leading authorities in delinquency and substance abuse who share their views on causes and cures for the drug problem among youth in this country.…

Hurst, Hunter, Ed.; And Others

1984-01-01

151

[How alcohol and drug consumers see themselves: a personal and social self-assessment (author's transl)].  

PubMed

In a representative inquiry we found significant differences in the self-assessment of 4082 20-year-old Swiss men, as to whether their consumption of alcohol and drugs is high, low, or zero. The heavy users of alcohol and drugs describe themselves as men with frequent personal difficulties and psychosomatic disturbances. They tend to separate earlier from their family and prefer a less conventional, more consume-orientated, and passive way of life than the remainder. PMID:952601

Hell, D; Battegay, R; Mühlemann, R; Dillinger, A

1976-06-22

152

Perpetrators of pharmacokinetic drug-drug interactions arising from altered cytochrome P450 activity: a criteria-based assessment  

PubMed Central

AIMS To catalogue the perpetrators of CYP-mediated pharmacokinetic drug–drug interactions (PK-DDIs) using clinically relevant criteria, and to compare this with an analogous catalogue. METHODS Candidate inhibitors and inducers of CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A (‘perpetrators’) were evaluated using published clinical pharmacokinetic interaction studies. Studies were selected on the basis of ?six human subjects, use of a validated in vivo probe substrate for the CYP enzyme, and clinically relevant dosing. Inhibitors were described according to the FDA classifications of strong, moderate or weak, whereas inducers were classified as major (?twofold decrease in AUC) or weak (Drug Interaction Table (CDIT) were compared with the ‘accepted’ major perpetrators. RESULTS From a list of 216 candidate drugs (349 CYP-perpetrator pairs, CYP-PPs), 36 inhibitors and eight inducers were accepted as major perpetrators of PK-DDIs, resulting in 58 CYP-PPs. In comparison, the clinical version of the CDIT had a sensitivity of 33% and a positive predictive value of 68%. One hundred and ninety-nine CYP-PPs were rejected as major perpetrators, and 92 CYP-PPs had insufficient published human pharmacokinetic data for robust classification. CONCLUSIONS Using a criteria-based assessment, the number of drugs that are proven or likely major perpetrators of CYP-mediated PK-DDIs is relatively small. Current clinical decision support on PK-DDIs is inconsistent with the published evidence and can be improved using simple criteria.

Polasek, Thomas M; Lin, Frank P Y; Miners, John O; Doogue, Matthew P

2011-01-01

153

Mean interconversion times and distribution rate parameters for drugs undergoing reversible metabolism.  

PubMed

The mean interconversion time and recycling numbers are introduced as intrinsic metabolic interconversion and distribution parameters for drugs undergoing linear reversible metabolism. Equations for these parameters, the distribution clearance, and the mean transit time in the central and peripheral compartments are derived for a metabolic pair where interconversion and elimination occur in central compartments. These parameters can be calculated from plasma concentration versus time slopes and intercepts, AUC, and AUMC data of parent drug and its metabolite partner following iv administration of each compound. The mean time analysis is illustrated with disposition data obtained previously for methylprednisolone and methylprednisone in the rabbit. Examination of mean times and additional properties of the system reveals that total exposure time of methylprednisolone is weakly influenced by the metabolic interconversion process, whereas the total exposure time of methylprednisone is strongly influenced by the process. In addition, the tissue distribution process moderately influence the total exposure times of both compounds. The derived mean time parameters, along with previously evolved equations for clearances, volumes of distribution, moments, and mean residence times allow comprehensive analysis of linear, multicompartmental reversible metabolic systems. PMID:2281028

Cheng, H Y; Jusko, W J

1990-10-01

154

Assessment of urinary excretion of antimalarial drugs in large-scale chemotherapeutic eradication projects  

PubMed Central

Assessment of the urinary excretion of an antimalarial drug is a useful means of checking the amount of drug administered and the regularity of intake. The author describes the various methods available for the qualitative and quantitative estimation of antimalarial drugs in urine and discusses their relative merits, with special reference to their suitability for use in the field. He points out the difficulties involved in estimating the urinary excretion of antimalarials in large-scale chemotherapeutic eradication projects and stress the importance of simplifying testing techniques as far as possible.

Bruce-Chwatt, L. J.

1959-01-01

155

New drug adoption models: a review and assessment of future needs.  

PubMed

New drug products today are the key to survival in the pharmaceutical industry. However, the new product development process in the pharmaceutical industry also happens to be one of the riskiest and most expensive undertakings because of the huge research and development costs involved. Consequently market forecasting of new pharmaceutical products takes on added importance if the formidable investments are to be recovered. New drug adoption models provide the marketer with a means to assess new product potential. Although several adoption models are available in the marketing literature for assessing potential of common consumer goods, the unique characteristics of the prescription drug market makes it necessary to examine the current state of pharmaceutical innovations. The purpose of this study, therefore, is to: (1) review new drug adoption models in the pharmaceutical literature, (2) evaluate the existing models of new drug adoption using the ten criteria for a good model as prescribed by Zaltman and Wallendorf (1983), and (3) provide an overall assessment and a ¿prescription¿ for better forecasting of new drug products. PMID:10143893

Agrawal, M; Calantone, R J

1995-01-01

156

Assessment of on-chip wire-length distribution models  

Microsoft Academic Search

Ultralarge-scale integrated (ULSI) chip design data is needed for an assessment of existing on-chip wirelength distribution models. Data extracted from modern chips such as high-performance microprocessors provide information about actual wire length requirements in ULSI chip designs. These requirements are compared with wirelength estimates obtained by evaluating existing models as functions of Rent's parameters that are extracted from the designs.

Mary Yvonne Lanzerotti; Giovanni Fiorenza; Rick A. Rand

2004-01-01

157

Advances in the Science of Adolescent Drug Involvement: Implications for Assessment and Diagnosis  

PubMed Central

Purpose of review Adolescence is a developmental period characterized by relatively high rates of substance use and substance use disorders. Precise assessment and classification of adolescent drug use behaviors is essential in gaining an accurate understanding of the nature and extent of adolescent drug use, and possible intervention or treatment needs. There have been a select group of recently published research reports and manuscripts that address critical and emerging issues pertaining to the classification and assessment of alcohol and other drug use behaviors among adolescents. An overview of these publications is provided and their clinical relevance is discussed. Recent findings The paper will focus on recent research, most from the U.S., that addresses four main issues. One is the application of the new DSM-5 criteria to adolescents, including the advantages and disadvantages of the new criteria for substance use disorders. The second issue pertains to advances in instrumentation that provide new tools for researchers and clinicians in assessing substance use in adolescents. A significant public health issue is addressed as the third theme in the paper – screening for alcohol abuse in college settings. Finally, the paper reviews how the emerging science of brain development can inform the assessment process. Summary Recent advances in the adolescent drug abuse assessment field continue to inform clinical service and research. As a whole these advances have strengthened the field, but continued research is needed to further refine assessment practices and standards and to better understand how to define a substance use disorder In youth.

Winters, Ken

2013-01-01

158

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

PubMed

The decision tree to determine whether the P-glycoprotein (P-gp)/multidrug resistance protein 1 (MDR1)-mediated drug-drug interaction (DDI) study is recommended has been proposed by the International Transporter Consortium. We, therefore, designed an in vitro P-gp inhibition assay and determined the appropriate risk criteria for P-gp-mediated DDI at the drug discovery stage. Effects of P-gp inhibitors on digoxin transport across a monolayer of MDR1-expressing cells were examined. The IC(50) (half-maximal inhibitory concentration) values generated from the efflux ratio (ER) were smaller than those generated from basolateral-to-apical directional apparent permeability. The difference in IC(50) values was kinetically described in a compartment model analysis. This analysis indicated that ER is a highly sensitive parameter that can be used for the degree of P-gp inhibition. Considering IC(50) values and the increase in digoxin exposure in clinical DDI studies, the risk criteria of [I(2)]/IC(50) = 30 ([I(2)], theoretically maximal gastrointestinal concentration) was the optimal cutoff value to predict a clinically relevant DDI. We also investigated whether the IC(50) value itself is applicable to assess the DDI risk. In conclusion, compounds with IC(50) values less than 2 ?M exhibit high risk for P-gp-mediated DDIs. However, compounds with IC(50) values greater than or equal to 2 ?M are inconclusive because clinical doses should be considered for the precise DDI risk assessment. PMID:21678427

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

2011-09-01

159

A proactive nonclinical drug abuse and dependence liability assessment strategy: a sponsor perspective.  

PubMed

This paper outlines a strategy and process for proactive nonclinical assessment of drug abuse and dependence liability of new compounds intended for clinical use. Documentation of the potential for causing abuse and dependence liability is required for registration of a new drug; hence, proactive timing and planning of these studies allows for appropriate documentation of nonclinical as well as clinical data in time for registration. In cases for which an abuse and dependence liability label may not be acceptable, a proactive approach to abuse and dependence liability assessment allows for replacement of selected compounds at an early stage of development, thereby saving time and resources and avoiding late attrition. PMID:23907375

Swedberg, Michael D B

2013-09-01

160

Developing and evaluating distributions for probabilistic human exposure assessments  

SciTech Connect

This report describes research carried out at the Lawrence Berkeley National Laboratory (LBNL) to assist the U. S. Environmental Protection Agency (EPA) in developing a consistent yet flexible approach for evaluating the inputs to probabilistic risk assessments. The U.S. EPA Office of Emergency and Remedial Response (OERR) recently released Volume 3 Part A of Risk Assessment Guidance for Superfund (RAGS), as an update to the existing two-volume set of RAGS. The update provides policy and technical guidance on performing probabilistic risk assessment (PRA). Consequently, EPA risk managers and decision-makers need to review and evaluate the adequacy of PRAs for supporting regulatory decisions. A critical part of evaluating a PRA is the problem of evaluating or judging the adequacy of input distributions PRA. Although the overarching theme of this report is the need to improve the ease and consistency of the regulatory review process, the specific objectives are presented in two parts. The objective of Part 1 is to develop a consistent yet flexible process for evaluating distributions in a PRA by identifying the critical attributes of an exposure factor distribution and discussing how these attributes relate to the task-specific adequacy of the input. This objective is carried out with emphasis on the perspective of a risk manager or decision-maker. The proposed evaluation procedure provides consistency to the review process without a loss of flexibility. As a result, the approach described in Part 1 provides an opportunity to apply a single review framework for all EPA regions and yet provide the regional risk manager with the flexibility to deal with site- and case-specific issues in the PRA process. However, as the number of inputs to a PRA increases, so does the complexity of the process for calculating, communicating and managing risk. As a result, there is increasing effort required of both the risk professionals performing the analysis and the risk manager reviewing it. For deterministic risk assessments, the use of default inputs has improved the ease and the consistency of both performing and reviewing assessments. By analogy, it is expected that similar advantage will be seen in the field of probabilistic risk assessment through the introduction of default distributions. In Part 2 of this report, we consider when a default distribution might be appropriate for use in PRA and work towards development of recommended task-specific distributions for several frequently used exposure factors. An approach that we develop using body weight and exposure duration as case studies offers a transparent way for developing task-specific exposure factor distributions. A third case study using water intake highlights the need for further study aimed at improving the relevance of ''short-term'' data before recommendations on task-specific distributions of water intake can be made.

Maddalena, Randy L.; McKone, Thomas E.

2002-08-01

161

Communication Needs Assessment for Distributed Turbine Engine Control  

NASA Technical Reports Server (NTRS)

Control system architecture is a major contributor to future propulsion engine performance enhancement and life cycle cost reduction. The control system architecture can be a means to effect net weight reduction in future engine systems, provide a streamlined approach to system design and implementation, and enable new opportunities for performance optimization and increased awareness about system health. The transition from a centralized, point-to-point analog control topology to a modular, networked, distributed system is paramount to extracting these system improvements. However, distributed engine control systems are only possible through the successful design and implementation of a suitable communication system. In a networked system, understanding the data flow between control elements is a fundamental requirement for specifying the communication architecture which, itself, is dependent on the functional capability of electronics in the engine environment. This paper presents an assessment of the communication needs for distributed control using strawman designs and relates how system design decisions relate to overall goals as we progress from the baseline centralized architecture, through partially distributed and fully distributed control systems.

Culley, Dennis E.; Behbahani, Alireza R.

2008-01-01

162

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

PubMed Central

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

2013-01-01

163

Drug susceptibility distributions in slowly growing non-tuberculous mycobacteria using MGIT 960 TB eXiST.  

PubMed

In general, uniform clinical antibiotic susceptibility breakpoints (CBPs) for slowly growing nontuberculous mycobacteria (NTM) have not been established. The aim of this study was to determine wild-type drug susceptibility distributions for relevant antibiotics using Bactec MGIT 960 equipped with EpiCenter TB eXiST and to derive epidemiological cut-offs (ECOFFs) from semi quantitative drug susceptibility measurements. One hundred and twenty-six NTM clinical isolates (Mycobacterium avium n=58, Mycobacterium intracellulare n=18, Mycobacterium kansasii n=50) were investigated in this study. Drug susceptibility distributions and MIC90 values were determined for clarithromycin, ethambutol, rifampicin, rifabutin, ofloxacin, moxifloxacin, and amikacin using Bactec MGIT 960/EpiCenter TB eXiST. For most species/drug combinations ECOFFs were determined. For some species/drug combinations ECOFFs were not defined as either the isolates were susceptible to the lowest drug concentration tested or because isolates, in part, had MIC levels exceeding the highest drug concentration tested. This study describes drug susceptibility distributions and MIC90 values of M. avium, M. intracellulare, and M. kansasii that may aid the definition of CBPs when correlating in vitro drug susceptibility with clinical outcomes in future studies. PMID:23689069

Hombach, Michael; Somoskövi, Akos; Hömke, Rico; Ritter, Claudia; Böttger, Erik C

2013-07-01

164

Cold air distribution in office buildings: Technology assessment for California  

SciTech Connect

This paper presents the results of a study to assess the current state of practice, and energy and operating cost implications of cold air distribution in California, and to identify the key research needs for the continued development of this technology in new commercial buildings in the state. Whole-building energy simulations were made to compare the energy performance of a prototypical office building in three California climates using conventional and cold air distribution, with and without ice storage, to show the impacts of load shifting, energy use, and utility costs for three typical utility rate structures. The merits of economizers and fan-powered mixing boxes were also studied when used in conjunction with cold air delivery. A survey was conducted to assess the perceived strengths and limitations of this technology, perceived barriers to its widespread use, and user experience. The survey was based on interviews with consulting engineers, equipment manufacturers, researchers, utility representatives, and other users of cold air distribution technology. Selected findings from the industry survey are also discussed. Cold air distribution (CoAD) is found to always reduce fan energy use in comparison to conventional 55[degrees]F (13[degrees]C) air distribution systems, when conditioned air is delivered directly to the space (no fan-powered mixing boxes). Total building energy use for ice storage/CoAD systems was always higher than a well-designed conventional system, but significantly lower than a commonly-installed packaged system. When a favorable utility rate structure was applied, the load-shifting benefits of ice storage/CoAD systems produced the lowest annual operating costs of all system-plant configurations studied.

Bauman, F.S.; LaBege, P. (California Univ., Berkeley, CA (United States). Center for Environmental Design Research); Borgers, T. (Humboldt State Univ., Arcata, CA (United States). Dept. of Chemistry); Gadgil, A.J. (Lawrence Berkeley Lab., CA (United States))

1992-06-01

165

Cold Air Distribution in Office Buildings: Technology Assessment for California  

SciTech Connect

This paper presents the results of a study to assess the current state of practice, and energy and operating cost implications of cold air distribution in California, and to identify the key research needs for the continued development of this technology in new commercial buildings in the state. Whole-building energy simulations were made to compare the energy performance of a prototypical office building in three California climates using conventional and cold air distribution, with and without ice storage, to show the impacts of load shifting, energy use, and utility costs for three typical utility rate structures. The merits of economizers and fan-powered mixing boxes were also studied when used in conjunction with cold air delivery. A survey was conducted to assess the perceived strengths and limitations of this technology, perceived barriers to its widespread use, and user experience. The survey was based on interviews with consulting engineers, equipment manufacturers, researchers, utility representatives, and other users of cold air distribution technology. Selected findings from the industry survey are also discussed. Cold air distribution (CoAD) is found to always reduce fan energy use in comparison to conventional 55 F (13 C) air distribution systems, when conditioned air is delivered directly to the space (no fan-powered mixing boxes). Total building energy use for ice storage/CoAD systems was always higher than a well-designed conventional system, but significantly lower than a commonly-installed packaged system. When a favorable utility rate structure was applied, the load-shifting benefits of ice storage/CoAD systems produced the lowest annual operating costs of all system-plant configurations studied.

Bauman, F.S.; Borgers, T.; LaBerge, P.; Gadgil, A.J.

1992-06-01

166

The feasibility of pharmacy-based naloxone distribution interventions: a qualitative study with injection drug users and pharmacy staff in rhode island.  

PubMed

This study analyzed qualitative data from a Rapid Policy Assessment and Response project to assess the feasibility of a potential pharmacy-based naloxone intervention to reduce opioid overdose mortality among injection drug users (IDUs). We conducted in-depth, semistructured interviews with 21 IDUs and 21 pharmacy staff (pharmacists and technicians). Although most participants supported the idea of a pharmacy-based naloxone intervention, several barriers were identified, including misinformation about naloxone, interpersonal relationships between IDUs and pharmacy staff, and costs of such an intervention. Implications for future pharmacy-based overdose prevention interventions for IDUs, including pharmacy-based naloxone distribution, are considered. The study's limitations are noted. PMID:23750660

Zaller, Nickolas D; Yokell, Michael A; Green, Traci Craig; Gaggin, Julia; Case, Patricia

2013-06-01

167

Genetic diversity of Plasmodium falciparum and distribution of drug resistance haplotypes in Yemen  

PubMed Central

Background Despite evident success of malaria control in many sites in the Arabian Peninsula, malaria remains endemic in a few spots, in Yemen and south-west of Saudi Arabia. In addition to local transmission, imported malaria sustains an extra source of parasites that can challenge the strengths of local control strategies. This study examined the genetic diversity of Plasmodium falciparum in Yemen and mutations of drug resistant genes, to elucidate parasite structure and distribution of drug resistance genotypes in the region. Methods Five polymorphic loci (MSP-2, Pfg377 and three microsatellites on chromosome 8) not involved in anti-malarial drug resistance, and four drug resistant genes (pfcrt, pfmdr1, dhfr and dhps) were genotyped in 108 P. falciparum isolates collected in three sites in Yemen: Dhamar, Hodeidah and Taiz. Results High diversity was seen in non-drug genes, pfg377 (He?=?0.66), msp-2 (He?=?0.80) and three microsatellites on chr 8, 7.7 kb (He?=?0.88), 4.3 kb (He?=?0.77) and 0.8 kb (He?=?0.71). There was a high level of mixed-genotype infections (57%), with an average 1.8 genotypes per patient. No linkage disequilibrium was seen between drug resistant genes and the non-drug markers (p?

2013-01-01

168

Surgical hemostatic agents: assessment of drugs and medical devices.  

PubMed

Surgical hemostatic agents are indicated to improve hemostasis when conventional techniques (compression, sutures or electrocoagulation) are inadequate. The National French Authority for Health (Haute Autorité de santé [HAS]) set out to assess these products (medical devices and agents) to determine their optimal utility. This evaluation included one class of products containing some form of human fibrinogen and thrombin and eight classes of medical devices and automated devices to prepare autologous fibrin. The assessment was based on a systematic review of the literature and expert opinion of health care professionals. The main measures of effectiveness of hemostatic agents were the success rate as expressed in terms of the time necessary to obtain adequate hemostasis, the volume of intra and/or postoperative blood loss, the need for blood transfusions, complication rate, duration of operations and hospital stay. A meta-analysis and 52 controlled randomized studies were selected involving cardiac or vascular surgery (19), ENT surgery (11), gastrointestinal surgery (5), urology (4), orthopedic surgery (4). Approximately half of the studies retained in this analysis evaluated blood derived agents (fibrin sealants) while the other half evaluated medical devices. The working group considered that there is not any evidence that these surgical hemostatic agents decrease the rates of transfusion, complications, reoperation, mortality, duration of operation and/or hospital stay. The working group considered that the use of surgical hemostatic agents to improve the safety of hemostasis in the absence of identified bleeding as an alternative to adequate conventional hemostasis was not justified. Surgical hemostatic agents can be used in ad hoc settings, as a complement to conventional methods to control persistent bleeding after conventional hemostatic techniques, or when abundant bleeding has led to biologic hemostatic disorders. The working group also distinguished several particular settings (mouth and dental care in patients under antiagregant or anticoagulation therapy, central nervous system surgery or acute aortic dissection). Comparative data are insufficient to determine if one product is superior to another for a specific use. To evaluate the clinical value of these products, methodologically sound clinical studies are necessary. PMID:22136914

Aubourg, R; Putzolu, J; Bouche, S; Galmiche, H; Denis, C; d'Andon, A; Maitrot, D; Partensky, C

2011-12-01

169

Life cycle assessment of overhead and underground primary power distribution.  

PubMed

Electrical power can be distributed in overhead or underground systems, both of which generate a variety of environmental impacts at all stages of their life cycles. While there is considerable literature discussing the trade-offs between both systems in terms of aesthetics, safety, cost, and reliability, environmental assessments are relatively rare and limited to power cable production and end-of-life management. This paper assesses environmental impacts from overhead and underground medium voltage power distribution systems as they are currently built and managed by Southern California Edison (SCE). It uses process-based life cycle assessment (LCA) according to ISO 14044 (2006) and SCE-specific primary data to the extent possible. Potential environmental impacts have been calculated using a wide range of midpoint indicators, and robustness of the results has been investigated through sensitivity analysis of the most uncertain and potentially significant parameters. The studied underground system has higher environmental impacts in all indicators and for all parameter values, mostly due to its higher material intensity. For both systems and all indicators the majority of impact occurs during cable production. Promising strategies for impact reduction are thus cable failure rate reduction for overhead and cable lifetime extension for underground systems. PMID:20553042

Bumby, Sarah; Druzhinina, Ekaterina; Feraldi, Rebe; Werthmann, Danae; Geyer, Roland; Sahl, Jack

2010-07-15

170

Simulated drug discovery process to conduct a synoptic assessment of pharmacy students.  

PubMed

OBJECTIVE. To implement and assess a task-based learning exercise that prompts pharmacy students to integrate their understanding of different disciplines. DESIGN. Master of pharmacy (MPharm degree) students were provided with simulated information from several preclinical science and from clinical trials and asked to synthesize this into a marketing authorization application for a new drug. Students made a link to pharmacy practice by creating an advice leaflet for pharmacists. ASSESSMENT. Students' ability to integrate information from different disciplines was evaluated by oral examination. In 2 successive academic years, 96% and 82% of students demonstrated an integrated understanding of their proposed new drug. Students indicated in a survey that their understanding of the links between different subjects improved. CONCLUSION. Simulated drug discovery provides a learning environment that emphasizes the connectivity of the preclinical sciences with each other and the practice of pharmacy. PMID:24672074

Richardson, Alan; Curtis, Anthony D M; Moss, Gary P; Pearson, Russell J; White, Simon; Rutten, Frank J M; Perumal, Dhaya; Maddock, Katie

2014-03-12

171

Applications of Genetically Modified Tools to Safety Assessment in Drug Development  

PubMed Central

The process of new drug development consists of several stages; after identifying potential candidate compounds, preclinical studies using animal models link the laboratory and human clinical trials. Among many steps in preclinical studies, toxicology and safety assessments contribute to identify potential adverse events and provide rationale for setting the initial doses in clinical trials. Gene modulation is one of the important tools of modern biology, and is commonly employed to examine the function of genes of interest. Advances in new drug development have been achieved by exploding information on target selection and validation using genetically modified animal models as well as those of cells. In this review, a recent trend of genetically modified methods is discussed with reference to safety assessments, and the exemplary applications of gene-modulating tools to the tests in new drug development were summarized.

Kay, Hee Yeon; Wu, Hongmin; Lee, Seo In

2010-01-01

172

New investigation of distribution imaging and content uniformity of very low dose drugs using hot-melt extrusion method.  

PubMed

The content uniformity of low dose drugs in dosage forms is very important for quality assurance. The aim of this study was to prepare uniformly and homogeneously distributed dosage forms of very low-dose drugs using twin screw hot-melt extrusion (HME) and to investigate the distribution of drugs using instrumental analyses. For the feasibility of HME method, a very low amount of coumarin-6, a fluorescent dye, was used to visualize distribution images using confocal laser scanning microscope (CLSM). Limaprost, tamsulosin and glimepiride were then used as low-dose model drugs to study the applicability of HME for content uniformity and distribution behaviors. Hydrophilic thermosensitive polymers with low melting point, such as Poloxamer188 and polyethylene glycol (PEG) 6000, were chosen as carriers. The melt extrusion was carried out around 50°C, at which both carriers were easily dissolved but model drugs remained in solid form. The physicochemical properties of the hot-melt extrudates, including differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR), were measured. Content uniformity of the drugs was also checked by HPLC. CLSM imaging showed that model drugs were well distributed throughout the hot-melt extrudate, giving better content uniformity with low batch-to-batch variations compared with simple physical mixtures. DSC, PXRD and FT-IR data showed that there was no interaction or interference between model drugs and thermosensitive polymers. The current HME methods could be used to prepare uniformly distributed and reproducible solid dosage forms containing very low dose drugs for further pharmaceutical applications. PMID:24157343

Park, Jun-Bom; Kang, Chin-Yang; Kang, Wie-Soo; Choi, Han-Gon; Han, Hyo-Kyung; Lee, Beom-Jin

2013-12-31

173

ADVANCED TOOLS FOR ASSESSING SELECTED PRESCRIPTION AND ILLICIT DRUGS IN TREATED SEWAGE EFFLUENTS AND SOURCE WATERS  

EPA Science Inventory

The purpose of this poster is to present the application and assessment of advanced state-of-the-art technologies in a real-world environment - wastewater effluent and source waters - for detecting six drugs [azithromycin, fluoxetine, omeprazole, levothyroxine, methamphetamine, m...

174

USE OF CASE REPORTS IN ASSESSING ADVERSE OUTCOMES OF HUMAN PRENATAL DRUG EXPOSURES: AN APPROACH  

EPA Science Inventory

The use of case reports for assessing the developmental consequences of prenatal drug exposure is limited by the inability to determine the incidence of adverse outcomes and by the high likelihood for bias. Yet, because it is impossible to conduct clinical trials for the assessme...

175

Development and validation of a survey instrument for assessing prescribers' perception of computerized drug-drug interaction alerts  

PubMed Central

Objective To develop a theoretically informed and empirically validated survey instrument for assessing prescribers' perception of computerized drug–drug interaction (DDI) alerts. Materials and methods The survey is grounded in the unified theory of acceptance and use of technology and an adapted accident causation model. Development of the instrument was also informed by a review of the extant literature on prescribers' attitude toward computerized medication safety alerts and common prescriber-provided reasons for overriding. To refine and validate the survey, we conducted a two-stage empirical validation study consisting of a pretest with a panel of domain experts followed by a field test among all eligible prescribers at our institution. Results The resulting survey instrument contains 28 questionnaire items assessing six theoretical dimensions: performance expectancy, effort expectancy, social influence, facilitating conditions, perceived fatigue, and perceived use behavior. Satisfactory results were obtained from the field validation; however, a few potential issues were also identified. We analyzed these issues accordingly and the results led to the final survey instrument as well as usage recommendations. Discussion High override rates of computerized medication safety alerts have been a prevalent problem. They are usually caused by, or manifested in, issues of poor end user acceptance. However, standardized research tools for assessing and understanding end users' perception are currently lacking, which inhibits knowledge accumulation and consequently forgoes improvement opportunities. The survey instrument presented in this paper may help fill this methodological gap. Conclusion We developed and empirically validated a survey instrument that may be useful for future research on DDI alerts and other types of computerized medication safety alerts more generally.

Fear, Kathleen; Chaffee, Bruce W; Zimmerman, Christopher R; Karls, Edward M; Gatwood, Justin D; Stevenson, James G; Pearlman, Mark D

2011-01-01

176

Towards spatially distributed quantitative assessment of tsunami inundation models  

NASA Astrophysics Data System (ADS)

This paper presents a framework and data for spatially distributed assessment of tsunami inundation models. Our associated validation test is based upon the 2004 Indian Ocean tsunami, which affords a uniquely large amount of observational data for events of this kind. Specifically, we use eyewitness accounts to assess onshore flow depths and speeds as well as a detailed inundation survey of Patong City, Thailand to compare modelled and observed inundation. Model predictions matched well the detailed inundation survey as well as altimetry data from the JASON satellite, eyewitness accounts of wave front arrival times and onshore flow speeds. Important buildings and other structures were incorporated into the underlying elevation model and are shown to have a large influence on inundation extent.

Jakeman, John Davis; Nielsen, Ole M.; Putten, Kristy Van; Mleczko, Richard; Burbidge, David; Horspool, Nick

2010-10-01

177

Assessing the distribution of the Argentine ant using physiological data  

NASA Astrophysics Data System (ADS)

To address the lack of physiological approaches in current models assessing the potential distribution of the Argentine ant, we used data on brood development from distinct sources to evaluate a series of degree-day models for Catalonia (NE Iberian Peninsula), and data on the brood survival and oviposition rates to develop a worker production model. The degree-day model generated using data from Newell and Barber (1913) and Benois (1973) indicated that the number of degree-days required for the complete development from egg to adult worker was 445.4 degree-days above a threshold of 15.9 °C, while the model calibrated using data from Abril et al. (2008, in press) suggested 599.5 degree-days above 18.4 °C. Comparisons between the degree-day model predictions and the currently known distribution of the Argentine ant suggested that the one generated using data from Newell and Barber (1913) and Benois (1973) overestimated the presence of the species, while the one calibrated using data from Abril et al. (2008; in press) underestimated it. On the other hand, the predicted daily net production of Argentine ant workers generated by the worker production model predicted more accurately the distribution of the Argentine ant than the degree-day models. Our results show the utility of incorporating physiological data in models to assess the distribution limits of the Argentine ant, which up to date have taken little account of the physiological needs of the species in terms of its establishment and dispersion in its introduced ranges.

Abril, Sílvia; Roura-Pascual, Núria; Oliveras, Jordi; Gómez, Crisanto

2009-09-01

178

Development of a cell-based assay system considering drug metabolism and immune- and inflammatory-related factors for the risk assessment of drug-induced liver injury.  

PubMed

Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical pharmacotherapy. However, prediction of DILI is difficult because the underlying mechanisms are not fully understood. To establish a novel cell-based screening system to suggest drugs with hepatotoxic potential in preclinical drug development, comprehensive gene expression analyses during in vivo DILI are necessary. Using in vivo mouse DILI models and 4 sets of hepatotoxic positive and non-hepatotoxic drugs, we found that the hepatic mRNA levels of S100A8; S100A9; "NATCH, LRR, and pyrin domain-containing protein 3" (NALP3); interleukin (IL)-1?; and the receptor for advanced glycation endproducts (RAGE) were commonly increased in hepatotoxic drug-administered mice compared to non-hepatotoxic drug-administered mice. To clarify whether these 5 in vivo biomarkers can be applied to a cell-based screening system, we adapted human liver microsomes (HLM) in the presence of NADPH to assess the metabolic activation reaction, and we also adapted human monocytic leukemia cells HL-60, K562, KG-1 and THP-1 to assess the effects on mRNA expression of immune- and inflammatory-related factors. We investigated 30 clinical drugs with different safety profiles with regard to DILI and found that the total sum score of gene expression levels of S100A8, S100A9, RAGE, NALP3 and IL-1? mRNA in HL-60 or K562 cells incubated with HLM, could identify drugs at high risk for hepatotoxicity. We proposed the use of the total sum score of gene expression level for assessing metabolic activation by drug-metabolizing enzymes and immune- and inflammatory-related factors for the risk assessment of DILI in preclinical drug development. PMID:24747151

Yano, Azusa; Oda, Shingo; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

2014-07-01

179

Penetration and Distribution of Thiocolchicoside through Human Skin: Comparison Between a Commercial Foam (Miotens®) and a Drug Solution  

PubMed Central

Penetration and distribution of thiocolchicoside from a commercially available foam (Miotens® 0.25%, w/v) through human excised full-thickness skin were evaluated using two different in vitro apparatus: a Franz diffusion cell and a Saarbruecken penetration model-based cell. In order to evaluate the intrinsic capability of the drug to penetrate into the skin, a simple drug aqueous solution prepared at the same drug concentration as Miotens® was also tested. Results showed that both apparatus were suitable to study thiocolchicoside penetration into human skin. Penetrated drug amounts were comparable using the two apparatus, probably because skin acts as “sink” for the drug. Miotens® was found to significantly promote thiocolchicoside accumulation into full human skin thickness in comparison with the simple drug solution. The mixture of propylene glycol and propylene glycol diperlargonate contained into Miotens® foam has been proven to be effective to promote penetration of thiocolchicoside into human skin.

Aguzzi, Carola; Rossi, Silvia; Bagnasco, Michela; Lanata, Luigi; Sandri, Giuseppina; Bona, Fosca; Ferrari, Franca; Bonferoni, Maria Cristina

2008-01-01

180

In vivo assessment of the teratogenic potential of drugs in humans.  

PubMed

The difficulties in assessing the teratogenic potential of drugs used during pregnancy have been made evident by experiences with thalidomide and diethylstilbestrol (DES). In the case of thalidomide, the drug's ability to cause phocomelia tended to be species specific, and thus animal studies were unreliable indicators of teratogenicity in humans. With DES, the delayed appearance of injury, almost a generation after birth, indicates that short-term studies may fail to reveal serious effects. In both cases only the otherwise rare occurrence of the condition led to the suspicion of a cause-and-effect relationship. Although wide-spread use of drugs such as LSD, heroin, and marijuana has necessitated assessment of their teratogenic potential, a controlled investigation of their effects has so far been impossible to conduct. Both tobacco and alcohol have been associated with adverse effects on the fetus and neonate, but the precise mechanisms by which these effects occur are as yet unclear. There is also reason for concern about the teratogenic potential of environmental pollutants such as organic mercury compounds, lead, and radiation. Furthermore, the fetus may potentially be harmed if a particular drug is not administered (eg, insulin for diabetes during pregnancy). In the final analysis, any potential benefits of therapy for the mother must be weighed against known and unknown risks to the infant. Rational management requires an understanding of the physiologic and pharmacologic principles involved in each case and careful and judicious selection of drug therapy. PMID:7031539

Stern, L

1981-11-01

181

Arrhythmic risk biomarkers for the assessment of drug cardiotoxicity: from experiments to computer simulations  

PubMed Central

In this paper, we illustrate how advanced computational modelling and simulation can be used to investigate drug-induced effects on cardiac electrophysiology and on specific biomarkers of pro-arrhythmic risk. To do so, we first perform a thorough literature review of proposed arrhythmic risk biomarkers from the ionic to the electrocardiogram levels. The review highlights the variety of proposed biomarkers, the complexity of the mechanisms of drug-induced pro-arrhythmia and the existence of significant animal species differences in drug-induced effects on cardiac electrophysiology. Predicting drug-induced pro-arrhythmic risk solely using experiments is challenging both preclinically and clinically, as attested by the rise in the cost of releasing new compounds to the market. Computational modelling and simulation has significantly contributed to the understanding of cardiac electrophysiology and arrhythmias over the last 40 years. In the second part of this paper, we illustrate how state-of-the-art open source computational modelling and simulation tools can be used to simulate multi-scale effects of drug-induced ion channel block in ventricular electrophysiology at the cellular, tissue and whole ventricular levels for different animal species. We believe that the use of computational modelling and simulation in combination with experimental techniques could be a powerful tool for the assessment of drug safety pharmacology.

Corrias, A.; Jie, X.; Romero, L.; Bishop, M. J.; Bernabeu, M.; Pueyo, E.; Rodriguez, B.

2010-01-01

182

An interventional study on intensive care unit drug therapy assessment in a rural district hospital in India  

PubMed Central

Background: Intensive care unit is a potential area for drug-related problems. As many of the patients treated are complex patients, clinical pharmacy intervention could find drug therapy problems. Materials and Methods: Drug information liaisons daily attended ward rounds with intensivists and screened the patient for drug therapy assessment using the American Society for Health-System Pharmacists clinical skills competition DTA format. This was a prospective study done for 6 months from August 2012 to January 2013. Simple statistics were used to tabulate the drug-related problems assessed. Results: A total of 72 patients were screened for drug therapy problems, for which 947 drug doses were prescribed in the study period. The total number of prescriptions was 148. The average number of drugs per prescription was 6.39 and the average number of drugs per patient was 13.15. A total of 243 problems were identified; on an average, 1.67 problems were present per prescription. The total number of drug interactions identified was N = 192 (78.2%); majority of them (61.4%) were of type C (not serious). So, 55.73% of them were monitored and not stopped or substituted. The second type of problem was a correlation between drug therapy and medical problem (7.4%). Appropriate drug selection and drug regimen was the third problem, and the adverse drug reactions and therapeutic duplications accounted for approximately 2% of the drug-related problems identified. Conclusion: Drug interactions constituted the major problem of ICUs, but not many were serious or significant. Consensus in assessment of drug-related problems and convincing intensivists with good quality evidences are required for better acceptance of interventions.

Pichala, Priyanka Tejashwani; Kumar, Bharani Mukkillapati; Zachariah, Seeba; Thomas, Dixon; Saunchez, Laura; Gerardo, Alvarez-Uria

2013-01-01

183

A Marginal Structural Modeling Approach to Assess the Cumulative Effect of Drug Treatment on Later Drug Use Abstinence  

Microsoft Academic Search

In this article, we applied a marginal structural model (MSM) to estimate the effect on later drug use of drug treatments occurring over 10 years following first use of the primary drug. The study was based on the longitudinal data that were collected in three projects among 421 subjects and covered 15 years since first use of their primary drug.

Libo Li; Elizabeth Evans; Yih-Ing Hser

2010-01-01

184

Subcellular Distribution of Basic Drugs Accumulated in the Isolated Perfused Lung  

Microsoft Academic Search

To clarify the mechanism by which basic drugs accumulate in the lung, the binding selectivity of drugs to different subcellular structures of the perfused rat lung was examined. Imipramine, quinine, and metoclopramide were used as examples of basic drugs. The accumulation of basic drugs was highest in the mitochondrial fraction. The drug accumulation in the lung mitochondrial fraction increased with

Hisahiro Yoshida; Katsuhiko Okumura; Ryohei Hori

1987-01-01

185

Chemical and structural investigation of lipid nanoparticles: drug-lipid interaction and molecular distribution.  

PubMed

Lipid nanoparticles are a promising alternative to existing carriers in chemical or drug delivery systems. A key challenge is to determine how chemicals are incorporated and distributed inside nanoparticles, which assists in controlling chemical retention and release characteristics. This study reports the chemical and structural investigation of gamma-oryzanol loading inside a model lipid nanoparticle drug delivery system composed of cetyl palmitate as solid lipid and Miglyol 812 as liquid lipid. The lipid nanoparticles were prepared by high pressure homogenization at varying liquid lipid content, in comparison with the gamma-oryzanol free systems. The size of the lipid nanoparticles, as measured by the photon correlation spectroscopy, was found to decrease with increased liquid lipid content from 200 to 160 nm. High-resolution proton nuclear magnetic resonance ((1)H-NMR) measurements of the medium chain triglyceride of the liquid lipid has confirmed successful incorporation of the liquid lipid in the lipid nanoparticles. Differential scanning calorimetric and powder x-ray diffraction measurements provide complementary results to the (1)H-NMR, whereby the crystallinity of the lipid nanoparticles diminishes with an increase in the liquid lipid content. For the distribution of gamma-oryzanol inside the lipid nanoparticles, the (1)H-NMR revealed that the chemical shifts of the liquid lipid in gamma-oryzanol loaded systems were found at rather higher field than those in gamma-oryzanol free systems, suggesting incorporation of gamma-oryzanol in the liquid lipid. In addition, the phase-separated structure was observed by atomic force microscopy for lipid nanoparticles with 0% liquid lipid, but not for lipid nanoparticles with 5 and 10% liquid lipid. Raman spectroscopic and mapping measurements further revealed preferential incorporation of gamma-oryzanol in the liquid part rather than the solid part of in the lipid nanoparticles. Simple models representing the distribution of gamma-oryzanol and lipids (solid and liquid) inside the lipid nanoparticle systems are proposed. PMID:20182010

Anantachaisilp, Suranan; Smith, Siwaporn Meejoo; Treetong, Alongkot; Pratontep, Sirapat; Puttipipatkhachorn, Satit; Ruktanonchai, Uracha Rungsardthong

2010-03-26

186

The use of formulation technology to assess regional gastrointestinal drug absorption in humans.  

PubMed

The aim of this study was to assess the feasibility of using oral modified-release formulations for the purposes of site-specific targeting and regional drug absorption assessment in man. An immediate release pellet formulation containing ranitidine as the model drug of choice for the study was fabricated by extrusion-spheronisation, and then film coated with either the enteric polymer polyvinyl acetate phthalate or the bacteria-degradable polymer amylose, in combination with ethylcellulose, to effect drug release within the small intestine and colon, respectively. Optimised formulations were evaluated in vivo in ten healthy volunteers, who each received, on four separate occasions, the immediate release, small intestinal release and colonic release formulations (each equivalent to 150mg ranitidine), and an intravenous injection of ranitidine (equivalent to 50mg ranitidine). Blood samples were collected and assessed for ranitidine concentration, and radiolabelled placebo pellets were co-administered with the coated ranitidine pellets to monitor their gastrointestinal transit using a gamma camera. Ranitidine was rapidly released and absorbed from the immediate release formulation, whereas the enteric formulation (10% coat weight gain) delayed drug release until some or all of the pellets had emptied into the small intestine. The amylose-ethylcellulose coated formulation (coat ratio 1:3, coat weight gain 25%) retarded ranitidine release until the pellets had reached the colon. The mean absolute bioavailability of ranitidine from the immediate release, small intestinal release and colonic release formulations were 50.6, 46.1 and 5.5%, respectively. These data are in general agreement to those obtained from a previous regional intubation study. The present study therefore demonstrates the practical potential of utilising a non-invasive, formulation-based approach to assess drug absorption from different regions of the human gastrointestinal tract. PMID:14757489

Basit, Abdul W; Podczeck, Fridrun; Newton, J Michael; Waddington, Wendy A; Ell, Peter J; Lacey, Larry F

2004-02-01

187

A framework establishing clear decision criteria for the assessment of drug efficacy.  

PubMed

Much has been published on various aspects of data analysis and reporting from clinical trials within the biopharmaceutical environment. This ranges from regulatory guidelines on the format and content of registration dossiers to recommendations on data presentation and the statistical methodologies that are appropriate for the diverse types of data one observes in clinical trials. Little has been written about designing a clinical trial analysis and reporting package that focuses on the decisions that must be made throughout the drug development process. Pharmaceutical companies today are under enormous pressure to develop drugs quickly and (cost-) efficiently. Because of this, drugs often move into the later phases of drug development before evidence from prior phases is completely understood. This provides a challenge to clinical trialists to design and execute a clinical trial programme which can expedite drug development. The statistician, as a clinical trialist, must strive to determine the optimum analytical methodology that facilitates decision making for this clinical trial programme. This paper proposes a new framework for the assessment of efficacy in drug development called the 'one programme, one p-value' framework. This framework will accelerate drug development by providing clear criteria for the decisions which must be made along the way. The 'one programme, one p-value' framework is based on the notion that the clinical trial programme comprises exploratory and confirmatory phases. The use of the likelihood function in the exploratory phase facilitates the decision whether (or when) to move into the confirmatory phase. The confirmatory phase consists of one confirmatory trial with a single hypothesis test of the drug's efficacy; hence 'one p-value'. Sponsor interaction with regulatory agencies is necessary at each decision point. Finally, the paper considers how analysis and reporting of efficacy data can be accomplished from a clinical trial programme as described. PMID:9749450

Huster, W J; Enas, G G

188

In silico assessment of drug safety in human heart applied to late sodium current blockers  

PubMed Central

Drug-induced action potential (AP) prolongation leading to Torsade de Pointes is a major concern for the development of anti-arrhythmic drugs. Nevertheless the development of improved anti-arrhythmic agents, some of which may block different channels, remains an important opportunity. Partial block of the late sodium current (INaL) has emerged as a novel anti-arrhythmic mechanism. It can be effective in the settings of free radical challenge or hypoxia. In addition, this approach can attenuate pro-arrhythmic effects of blocking the rapid delayed rectifying K+ current (IKr). The main goal of our computational work was to develop an in-silico tool for preclinical anti-arrhythmic drug safety assessment, by illustrating the impact of IKr/INaL ratio of steady-state block of drug candidates on “torsadogenic” biomarkers. The O’Hara et al. AP model for human ventricular myocytes was used. Biomarkers for arrhythmic risk, i.e., AP duration, triangulation, reverse rate-dependence, transmural dispersion of repolarization and electrocardiogram QT intervals, were calculated using single myocyte and one-dimensional strand simulations. Predetermined amounts of block of INaL and IKr were evaluated. “Safety plots” were developed to illustrate the value of the specific biomarker for selected combinations of IC50s for IKr and INaL of potential drugs. The reference biomarkers at baseline changed depending on the “drug” specificity for these two ion channel targets. Ranolazine and GS967 (a novel potent inhibitor of INaL) yielded a biomarker data set that is considered safe by standard regulatory criteria. This novel in-silico approach is useful for evaluating pro-arrhythmic potential of drugs and drug candidates in the human ventricle.

Trenor, Beatriz; Gomis-Tena, Julio; Cardona, Karen; Romero, Lucia; Rajamani, Sridharan; Belardinelli, Luiz; Giles, Wayne R; Saiz, Javier

2013-01-01

189

In silico assessment of drug safety in human heart applied to late sodium current blockers.  

PubMed

Drug-induced action potential (AP) prolongation leading to Torsade de Pointes is a major concern for the development of anti-arrhythmic drugs. Nevertheless the development of improved anti-arrhythmic agents, some of which may block different channels, remains an important opportunity. Partial block of the late sodium current (INaL) has emerged as a novel anti-arrhythmic mechanism. It can be effective in the settings of free radical challenge or hypoxia. In addition, this approach can attenuate pro-arrhythmic effects of blocking the rapid delayed rectifying K (+) current (IKr). The main goal of our computational work was to develop an in-silico tool for preclinical anti-arrhythmic drug safety assessment, by illustrating the impact of IKr/INaL ratio of steady-state block of drug candidates on "torsadogenic" biomarkers. The O'Hara et al. AP model for human ventricular myocytes was used. Biomarkers for arrhythmic risk, i.e., AP duration, triangulation, reverse rate-dependence, transmural dispersion of repolarization and electrocardiogram QT intervals, were calculated using single myocyte and one-dimensional strand simulations. Predetermined amounts of block of INaL and IKr were evaluated. "Safety plots" were developed to illustrate the value of the specific biomarker for selected combinations of IC 50s for IKr and INaL of potential drugs. The reference biomarkers at baseline changed depending on the "drug" specificity for these two ion channel targets. Ranolazine and GS967 (a novel potent inhibitor of INaL) yielded a biomarker data set that is considered safe by standard regulatory criteria. This novel in-silico approach is useful for evaluating pro-arrhythmic potential of drugs and drug candidates in the human ventricle. PMID:23696033

Trenor, Beatriz; Gomis-Tena, Julio; Cardona, Karen; Romero, Lucia; Rajamani, Sridharan; Belardinelli, Luiz; Giles, Wayne R; Saiz, Javier

2013-05-21

190

Rapid, Serial, Non-invasive Assessment of Drug Efficacy in Mice with Autoluminescent Mycobacterium ulcerans Infection  

PubMed Central

Background Buruli ulcer (BU) caused by Mycobacterium ulcerans is the world's third most common mycobacterial infection. There is no vaccine against BU and surgery is needed for patients with large ulcers. Although recent experience indicates combination chemotherapy with streptomycin and rifampin improves cure rates, the utility of this regimen is limited by the 2-month duration of therapy, potential toxicity and required parenteral administration of streptomycin, and drug-drug interactions caused by rifampin. Discovery and development of drugs for BU is greatly hampered by the slow growth rate of M. ulcerans, requiring up to 3 months of incubation on solid media to produce colonies. Surrogate markers for evaluating antimicrobial activity in real-time which can be measured serially and non-invasively in infected footpads of live mice would accelerate pre-clinical evaluation of new drugs to treat BU. Previously, we developed bioluminescent M. ulcerans strains, demonstrating proof of concept for measuring luminescence as a surrogate marker for viable M. ulcerans in vitro and in vivo. However, the requirement of exogenous substrate limited the utility of such strains, especially for in vivo experiments. Methodology/Principal Finding For this study, we engineered M. ulcerans strains that express the entire luxCDABE operon and therefore are autoluminescent due to endogenous substrate production. The selected reporter strain displayed a growth rate and virulence similar to the wild-type parent strain and enabled rapid, real-time monitoring of in vitro and in vivo drug activity, including serial, non-invasive assessments in live mice, producing results which correlated closely with colony-forming unit (CFU) counts for a panel of drugs with various mechanisms of action. Conclusions/Significance Our results indicate that autoluminescent reporter strains of M. ulcerans are exceptional tools for pre-clinical evaluation of new drugs to treat BU due to their potential to drastically reduce the time, effort, animals, compound, and costs required to evaluate drug activity.

Zhang, Tianyu; Li, Si-Yang; Converse, Paul J.; Grosset, Jacques H.; Nuermberger, Eric L.

2013-01-01

191

Understanding pharmacokinetics using realistic computational models of fluid dynamics: biosimulation of drug distribution within the CSF space for intrathecal drugs  

Microsoft Academic Search

We introduce how biophysical modeling in pharmaceutical research and development, combining physiological observations at\\u000a the tissue, organ and system level with selected drug physiochemical properties, may contribute to a greater and non-intuitive\\u000a understanding of drug pharmacokinetics and therapeutic design. Based on rich first-principle knowledge combined with experimental\\u000a data at both conception and calibration stages, and leveraging our insights on disease

Andreas Kuttler; Thomas Dimke; Steven Kern; Gabriel Helmlinger; Donald Stanski; Luca A. Finelli

2010-01-01

192

Reliability of the Roussel Uclaf Causality Assessment Method for Assessing Causality in Drug-Induced Liver Injury*  

PubMed Central

The Roussel Uclaf Causality Assessment Method (RUCAM) was developed to quantify the strength of association between a liver injury and the medication implicated as causing the injury. However, its reliability in a research setting has never been fully explored. The aim of this study was to determine test-retest and interrater reliabilities of RUCAM in retrospectively-identified cases of drug induced liver injury. The Drug-Induced Liver Injury Network is enrolling well-defined cases of hepatotoxicity caused by isoniazid, phenytoin, clavulanate/amoxicillin, or valproate occurring since 1994. Each case was adjudicated by three reviewers working independently; after an interval of at least 5 months, cases were readjudicated by the same reviewers. A total of 40 drug-induced liver injury cases were enrolled including individuals treated with isoniazid (nine), phenytoin (five), clavulanate/amoxicillin (15), and valproate (11). Mean ± standard deviation age at protocol-defined onset was 44.8 ± 19.5 years; patients were 68% female and 78% Caucasian. Cases were classified as hepatocellular (44%), mixed (28%), or cholestatic (28%). Test-retest differences ranged from ?7 to +8 with complete agreement in only 26% of cases. On average, the maximum absolute difference among the three reviewers was 3.1 on the first adjudication and 2.7 on the second, although much of this variability could be attributed to differences between the enrolling investigator and the external reviewers. The test-retest reliability by the same assessors was 0.54 (upper 95% confidence limit = 0.77); the interrater reliability was 0.45 (upper 95% confidence limit = 0.58). Categorizing the RUCAM to a five-category scale improved these reliabilities but only marginally. Conclusion The mediocre reliability of the RUCAM is problematic for future studies of drug-induced liver injury. Alternative methods, including modifying the RUCAM, developing drug-specific instruments, or causality assessment based on expert opinion, may be more appropriate.

Rochon, James; Protiva, Petr; Seeff, Leonard B.; Fontana, Robert J.; Liangpunsakul, Suthat; Watkins, Paul B.; Davern, Timothy; McHutchison, John G.

2013-01-01

193

77 FR 20025 - Draft Guidance for Industry on Compliance Policy for Reporting Drug Sample Distribution...  

Federal Register 2010, 2011, 2012, 2013

...and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. FOR FURTHER INFORMATION CONTACT: Donovan F. Duggan, Jr., Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51,...

2012-04-03

194

Novel nanocarriers for topical drug delivery: investigating delivery efficiency and distribution in skin using two-photon microscopy  

NASA Astrophysics Data System (ADS)

The complex structure of skin represents an effective barrier against external environmental factors, as for example, different chemical and biochemical compounds, yeast, bacterial and viral infections. However, this impermeability prevents efficient transdermal drug delivery which limits the number of drugs that are able to penetrate the skin efficiently. Current trends in drug application through skin focus on the design and use of nanocarriers for transport of active compounds. The transport systems applied so far have several drawbacks, as they often have low payload, high toxicity, a limited variability of inclusion molecules, or long degradation times. The aim of these current studies is to investigate novel topical drug delivery systems, e.g. nanocarriers based on cyclic oligosaccharides - cyclodextrins (CD) or iron (III)-based metal-organic frameworks (MOF). Earlier studies on cell cultures imply that these drug nanocarriers show promising characteristics compared to other drug delivery systems. In our studies, we use two-photon microscopy to investigate the ability of the nanocarriers to deliver compounds through ex-vivo skin samples. Using near infrared light for excitation in the so called optical window of skin allows deep-tissue visualization of drug distribution and localization. In addition, it is possible to employ two-photon based fluorescence correlation spectroscopy for quantitative analysis of drug distribution and concentrations in different cell layers.

Kirejev, Vladimir; Guldbrand, Stina; Bauer, Brigitte; Smedh, Maria; Ericson, Marica B.

2011-02-01

195

Evaluation of a novel in vitro assay for assessing drug penetration into avascular regions of tumours.  

PubMed Central

The poor blood supply to solid tumours introduces many factors that affect the outcome of chemotherapy, one of which is the problem of drug delivery to poorly vascularized regions of tumours. Whereas poor drug penetration has been recognized as a contributing factor to the poor response of many solid tumours, the question of drug penetration through multicell layers has not been thoroughly addressed, largely because of restrictions imposed upon these studies by the requirement for either radiolabelled or naturally fluorescent compounds. The aim of this study is to describe modifications made to a recently published assay that broadens the scope for assessing drug penetration during the early stages of drug development and to characterize the ability of various drugs to penetrate multicell layers. DLD-1 human colon carcinoma cells were cultured on Transwell-COL plastic inserts placed into 24-well culture plates so that a top and bottom chamber were established, the two chambers being separated by a microporous membrane. Drugs were added to the top chamber at doses equivalent to peak plasma concentrations in vivo and the rate of appearance of drugs in the bottom chamber determined by high-performance liquid chromatography (HPLC). Both 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine) and 7-[4'-(2-nitroimidazol-1-yl)-butyl]-theophylline (NITP) rapidly penetrated DLD-1 multicell layers (50.9 +/- 12.1 microm thick) with t(1/2) values of 1.36 and 2.38 h respectively, whereas the rate of penetration of 5-aziridino-3-hydroxymethyl-1-methyl-2-[1H-indole-4,7-dione] prop-beta-en-alpha-ol (EO9) and doxorubicin through multicell layers was significantly slower (t(1/2) = 4.62 and 13.1 h respectively). Inclusion of dicoumarol increases the rate of EO9 penetration, whereas reducing the oxygen tension to 5% causes a reduction in tirapazamine penetration through multicell layers, suggesting that the extent of drug metabolism is one factor that determines the rate at which drugs penetrate multicell layers. The fact that EO9 does not readily penetrate a multicell layer, in conjunction with its rapid elimination in vivo (t(1/2) < 10 min), suggests that EO9 is unlikely to penetrate more than a few microm from a blood vessel within its pharmacokinetic lifespan. These results suggest that the failure of EO9 in the clinic is due to a combination of poor drug penetration and rapid elimination in vivo. Images Figure 3

Phillips, R. M.; Loadman, P. M.; Cronin, B. P.

1998-01-01

196

Evaluation of a novel in vitro assay for assessing drug penetration into avascular regions of tumours.  

PubMed

The poor blood supply to solid tumours introduces many factors that affect the outcome of chemotherapy, one of which is the problem of drug delivery to poorly vascularized regions of tumours. Whereas poor drug penetration has been recognized as a contributing factor to the poor response of many solid tumours, the question of drug penetration through multicell layers has not been thoroughly addressed, largely because of restrictions imposed upon these studies by the requirement for either radiolabelled or naturally fluorescent compounds. The aim of this study is to describe modifications made to a recently published assay that broadens the scope for assessing drug penetration during the early stages of drug development and to characterize the ability of various drugs to penetrate multicell layers. DLD-1 human colon carcinoma cells were cultured on Transwell-COL plastic inserts placed into 24-well culture plates so that a top and bottom chamber were established, the two chambers being separated by a microporous membrane. Drugs were added to the top chamber at doses equivalent to peak plasma concentrations in vivo and the rate of appearance of drugs in the bottom chamber determined by high-performance liquid chromatography (HPLC). Both 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine) and 7-[4'-(2-nitroimidazol-1-yl)-butyl]-theophylline (NITP) rapidly penetrated DLD-1 multicell layers (50.9 +/- 12.1 microm thick) with t(1/2) values of 1.36 and 2.38 h respectively, whereas the rate of penetration of 5-aziridino-3-hydroxymethyl-1-methyl-2-[1H-indole-4,7-dione] prop-beta-en-alpha-ol (EO9) and doxorubicin through multicell layers was significantly slower (t(1/2) = 4.62 and 13.1 h respectively). Inclusion of dicoumarol increases the rate of EO9 penetration, whereas reducing the oxygen tension to 5% causes a reduction in tirapazamine penetration through multicell layers, suggesting that the extent of drug metabolism is one factor that determines the rate at which drugs penetrate multicell layers. The fact that EO9 does not readily penetrate a multicell layer, in conjunction with its rapid elimination in vivo (t(1/2) < 10 min), suggests that EO9 is unlikely to penetrate more than a few microm from a blood vessel within its pharmacokinetic lifespan. These results suggest that the failure of EO9 in the clinic is due to a combination of poor drug penetration and rapid elimination in vivo. PMID:9649122

Phillips, R M; Loadman, P M; Cronin, B P

1998-06-01

197

Distribution and drug susceptibilities of Candida species causing candidemia from a medical center in central Taiwan.  

PubMed

Invasive fungal infections have increased significantly in the past few decades because of the increase in high-risk populations. To investigate the distribution and drug susceptibilities of such infections, we analyzed all 152 Candida isolates causing candidemia from 2004 to 2006 at the China Medical University Hospital, a medical center in central Taiwan. Candida albicans was the most common species, accounting for 52.6% of the isolates, followed by C. tropicalis (19.7%), C. parapsilosis (14.5%), C. glabrata (8.6%), C. guilliermondii (3.9%), and C. pelliculosa (0.7%). All isolates were susceptible to amphotericin B, anidulafungin, micafungin, and voriconazole according to minimum inhibitory concentrations (MICs) after a 24-h incubation; 0.7%, 6.6%, and 7.9% of isolates were resistant to amphotericin B, fluconazole, and voriconazole, respectively, after 48-h incubation. Both C. albicans and C. parapsilosis had high degrees of agreement for azoles between 24- and 48-h incubation periods, whereas C. glabrata (38.5-46.2%) and C. tropicalis (56.7-63.3%) did not. The majority of the isolates with high azole MICs displayed a trailing growth phenotype. Hence, the MICs of different drugs after 24-h incubation may be considered for prognosis of candidemia. PMID:23732308

Chang, Te-Pin; Ho, Mao-Wang; Yang, Yun-Liang; Lo, Pai-Chang; Lin, Pei-Sheng; Wang, An-Huei; Lo, Hsiu-Jung

2013-12-01

198

Assessment of the Role of Renal Organic Anion Transporters in Drug-Induced Nephrotoxicity  

PubMed Central

In the present review we have attempted to assess the involvement of the organic anion transporters OAT1, OAT2, OAT3, and OAT4, belonging to the SLC22 family of polyspecific carriers, in drug-induced renal damage in humans. We have focused on drugs with widely recognized nephrotoxic potential, which have previously been reported to interact with OAT family members, and whose underlying pathogenic mechanism suggests the participation of tubular transport. Thus, only compounds generally believed to cause kidney injury either by means of direct tubular toxicity or crystal nephropathy have been considered. For each drug, or class of agents, the evidence for actual transport mediated by individual OATs under in vivo conditions is discussed. We have then examined their role in the context of other carriers present in the renal proximal tubule sharing certain substrates with OATs, as these are critical determinants of the overall contribution of OAT-dependent transport to intracellular accumulation and transepithelial drug secretion, and thus the impact it may have in drug-induced nephrotoxicity.

Hagos, Yohannes; Wolff, Natascha A.

2010-01-01

199

Assessing the quality of pharmacist answers to telephone drug information questions.  

PubMed

A quality assurance (QA) program is described in which frontline pharmacists were asked test drug information questions via anonymous telephone calls. The program was instituted at a university hospital that began providing decentralized pharmaceutical services in 1985. Questions were developed on the basis of a pilot study conducted to determine the types and complexity of drug information questions received by frontline pharmacists at the hospital. Data on departmental clinical productivity were used to determine the number of questions that would be posed during each shift in the various service areas. The questions were posed during a 10-day period; the pharmacists were aware of the program, but the callers did not identify their affiliation with it. In response to 105 questions asked, 86 were judged to have been answered correctly, 13 answers were deemed incomplete, and 6 were judged incorrect. Pharmacists were more likely to respond incorrectly to complex questions and questions posed during the night shift. As a result of the audit, staff members with advanced clinical knowledge were asked to help less experienced pharmacists, the position of assistant director for drug information and staff development was created, and educational programs were instituted. The QA audit has been repeated twice. Posing test drug information questions via anonymous telephone calls is effective in assessing the quality of drug information provided by pharmacists in patient-care areas. PMID:2321656

Woodward, C T; Stevenson, J G; Poremba, A

1990-04-01

200

In Vitro Release Kinetics of Antituberculosis Drugs from Nanoparticles Assessed Using a Modified Dissolution Apparatus  

PubMed Central

The aim of this study was to assess the in vitro release kinetics of antituberculosis drug-loaded nanoparticles (NPs) using a “modified” cylindrical apparatus fitted with a regenerated cellulose membrane attached to a standard dissolution apparatus (modifiedcylinder method). The model drugs that were used were rifampicin (RIF) and moxifloxacin hydrochloride (MX). Gelatin and polybutyl cyanoacrylate (PBCA) NPs were evaluated as the nanocarriers, respectively. The dissolution and release kinetics of the drugs from loaded NPs were studied in different media using the modified cylinder method and dialysis bag technique was used as the control technique. The results showed that use of the modified cylinder method resulted in different release profiles associated with unique release mechanisms for the nanocarrier systems investigated. The modified cylinder method also permitted discrimination between forced and normal in vitro release of the model drugs from gelatin NPs in the presence or absence of enzymatic degradation. The use of dialysis bag technique resulted in an inability to differentiate between the mechanisms of drug release from the NPs in these cases. This approach offers an effective tool to investigate in vitro release of RIF and MX from NPs, which further indicate that this technique can be used for performance testing of nanosized carrier systems.

Gao, Yuan; Zuo, Jieyu; Bou-Chacra, Nadia; Pinto, Terezinha de Jesus Andreoli; Clas, Sophie-Dorothee; Walker, Roderick B.; Lobenberg, Raimar

2013-01-01

201

Performance Assessment of OVERFLOW on Distributed Computing Environment  

NASA Technical Reports Server (NTRS)

The aerodynamic computer code, OVERFLOW, with a multi-zone overset grid feature, has been parallelized to enhance its performance on distributed and shared memory paradigms. Practical application benchmarks have been set to assess the efficiency of code's parallelism on high-performance architectures. The code's performance has also been experimented with in the context of the distributed computing paradigm on distant computer resources using the Information Power Grid (IPG) toolkit, Globus. Two parallel versions of the code, namely OVERFLOW-MPI and -MLP, have developed around the natural coarse grained parallelism inherent in a multi-zonal domain decomposition paradigm. The algorithm invokes a strategy that forms a number of groups, each consisting of a zone, a cluster of zones and/or a partition of a large zone. Each group can be thought of as a process with one or multithreads assigned to it and that all groups run in parallel. The -MPI version of the code uses explicit message-passing based on the standard MPI library for sending and receiving interzonal boundary data across processors. The -MLP version employs no message-passing paradigm; the boundary data is transferred through the shared memory. The -MPI code is suited for both distributed and shared memory architectures, while the -MLP code can only be used on shared memory platforms. The IPG applications are implemented by the -MPI code using the Globus toolkit. While a computational task is distributed across multiple computer resources, the parallelism can be explored on each resource alone. Performance studies are achieved with some practical aerodynamic problems with complex geometries, consisting of 2.5 up to 33 million grid points and a large number of zonal blocks. The computations were executed primarily on SGI Origin 2000 multiprocessors and on the Cray T3E. OVERFLOW's IPG applications are carried out on NASA homogeneous metacomputing machines located at three sites, Ames, Langley and Glenn. Plans for the future will exploit the distributed parallel computing capability on various homogeneous and heterogeneous resources and large scale benchmarks. Alternative IPG toolkits will be used along with sophisticated zonal grouping strategies to minimize the communication time across the computer resources.

Djomehri, M. Jahed; Rizk, Yehia M.

2000-01-01

202

Penetration and Distribution of Thiocolchicoside through Human Skin: Comparison Between a Commercial Foam (Miotens ® ) and a Drug Solution  

Microsoft Academic Search

Penetration and distribution of thiocolchicoside from a commercially available foam (Miotens® 0.25%, w\\/v) through human excised full-thickness skin were evaluated using two different in vitro apparatus: a Franz diffusion cell and a Saarbruecken penetration model-based cell. In order to evaluate the intrinsic capability\\u000a of the drug to penetrate into the skin, a simple drug aqueous solution prepared at the same

Carola Aguzzi; Silvia Rossi; Michela Bagnasco; Luigi Lanata; Giuseppina Sandri; Fosca Bona; Franca Ferrari; Maria Cristina Bonferoni; Carla Caramella

2008-01-01

203

[Counterfeit drugs in Israel and worldwide. Part II: distribution profile and anti-counterfeiting strategies and actions].  

PubMed

Counterfeit drugs are a major threat to public health and safety around the world. This review describes the various distribution methods and channels of counterfeit drugs, including the growing use of the internet. National, regional and international efforts to confront this problem are presented, as well as a wide range of technologies that may assist in detection and enforcement. Finally, the Israeli perspective and actions are illustrated. PMID:21465764

Furman-Assaf, Sharon; Tamir, Orly; Marom, Eli; Arieli, Mickey; Shemer, Joshua

2010-07-01

204

Quantitative assessment of tear production: A review of methods and utility in dry eye drug discovery  

Microsoft Academic Search

The successful development of a therapeutic agent targeting treatment of dry eye syndrome necessitates the demonstration of\\u000a drug efficacy for both sign and symptom endpoints. As numerous therapeutic strategies incorporate a secretagogue function\\u000a into their overall mechanism of action, the quantitative assessment of tear production serves as a logical endpoint to anchor\\u000a “sign” efficacy. Although several methods including the Schirmer,

Michelle Senchyna; Martin B Wax

2008-01-01

205

Assessing Drug Use in the Workplace: A Comparison of Self Report, Urinalysis, and Hair Analysis  

Microsoft Academic Search

A random sample of 1,200 employees of a steel plant in the western United States was randomly assigned to four different self-report methods of assessing illicit drug use: individual interview in the workplace, group-administered questionnaire in the workplace, telephone interview, and individual interview off the worksite. Urine specimens were collected and analyzed on all 928 subjects participating in the study,

Royer F. Cook; Alan D. Bernstein; Christine M. Andrews

206

In Vivo Assessment of Drug Efficacy against Plasmodium falciparum Malaria: Duration of Follow-Up  

Microsoft Academic Search

To determine the optimum duration of follow-up for the assessment of drug efficacy against Plasmodium falciparum malaria, 96 trial arms from randomized controlled trials (RCTs) with follow-up of 28 days or longer that were conducted between 1990 and 2003 were analyzed. These trials enrolled 13,772 patients, and partic- ipating patients comprised 23% of all patients enrolled in RCTs over the

Kasia Stepniewska; Walter R. J. Taylor; Mayfong Mayxay; Ric Price; Frank Smithuis; Jean-Paul Guthmann; Karen Barnes; Hla Yin Myint; Martin Adjuik; Piero Olliaro; Sasithon Pukrittayakamee; Sornchai Looareesuwan; Tran Tinh Hien; Jeremy Farrar; Francois Nosten; Nicholas P. J. Day; Nicholas J. White

2004-01-01

207

Parameter uncertainty assessment for distributed water quality models  

NASA Astrophysics Data System (ADS)

A new method is developed by the authors that assess the parameter uncertainty in distributed water quality models for multiple outputs in an efficient and effective way. Distributed water quality models have a high number of parameters, high parameter correlations, several output variables and a complex structure leading to multiple minima in the objective function. General uncertainty/optimization methods based on random sampling as GLUE or local methods such as PEST are often not applicable for theoretical or practical reasons. Therefore, the method "ParaSol" (Parameter Solutions) is developed to perform optimization and model parameter uncertainty analysis for complex models such as distributed (water quality) models. Optimization is achieved by adapting the SCE-UA to enable it to account for multi-objective problems while not being trapped in a localized minimum. The simulations performed by the SCE-UA are further used for uncertainty analysis. Two methods have been developed that select "good" parameter solutions out of the SCE-UA simulations based on an objective threshold. The first method is based on chi-squared statistics to delineate the confidence regions around the optimum/optima. The second method uses Bayesian statistics to define high probability regions whereby it accounts for the fact that the high probability regions are likely to be sampled more densely. The application of ParaSol on the flow and sediments simulations for Honey creek (Ohio) showed that, when 2 years of daily data are used, the confidence regions are very small when the chi -squared statistics are used and even smaller when using the Bayesian statistics. The results were also used to validate the suitability of SCE-UA sampling for uncertainty analysis by comparing to 500000 Monte Carlo samples. It was shown that the SCE-UA sampling was more effective and efficient as none of the Monte Carlo samples were close to the minimum or within the confidence region defined by ParaSol.

van Griensven, A.; Meixner, T.

2003-12-01

208

Lack of Effect of Experimental Hypovolemia on Imipenem Muscle Distribution in Rats Assessed by Microdialysis  

Microsoft Academic Search

The aim of this study was to investigate the influence of hypovolemia on the distribution of imipenem in muscle extracellular fluid determined by microdialysis in awake rats. Microdialysis probes were inserted into the jugular vein and hind leg muscle. Imipenem recoveries in muscle and blood were determined in each rat by retrodialysis by drug before drug administration. Hypovolemia was induced

Sandrine Marchand; Claire Dahyot; Isabelle Lamarche; Elodie Plan; Olivier Mimoz; William Couet

2005-01-01

209

Neighborhood History as a Factor Shaping Syringe Distribution Networks Among Drug Users at a U.S. Syringe Exchange1  

PubMed Central

Throughout the US, high-visibility drug markets are concentrated in neighborhoods with few economic opportunities, while drug buyers/users are widely dispersed. A study of Pittsburgh Syringe Exchange participants provides data on travel between and network linkages across neighborhoods with different levels of drug activity. There are distinct racial patterns to syringe distribution activity within networks and across neighborhoods. Pittsburgh’s history suggests these patterns emerge from historical patterns of social and economic development. Study data demonstrate the ability of IDUs to form long term social ties across racial and geographic boundaries and use them to reduce the risk of HIV transmission.

Braine, Naomi; Acker, Caroline; Goldblatt, Cullen; Yi, Huso; Friedman, Samuel; DesJarlais, Don C.

2008-01-01

210

Adverse Drug Reactions in Clinical Practice: a Causality Assessment of a Case of Drug-Induced Pancreatitis  

Microsoft Academic Search

Modern therapy has changed the way diseases are controlled and has brought significant benefits. In spite of all the benefits, adverse drug reactions are a common, often preventable, cause of illness, disability and even death. Besides the intrinsic danger associated with the drug, patients might have a particular, unpredictable hypersensitivity to certain drugs, which requires careful monitoring. Different studies have

Andreea Farcas; Marius Bojita

211

Investigation of drug-cyclodextrin complexes by a phase-distribution method: some theoretical and practical considerations.  

PubMed

The purpose of the study was to evaluate an octanol-water phase distribution method for investigation of drug/cyclodextrin (D/CD) complexes and to compare stability constant values obtained by this method to values obtained by the phase solubility method. A general equation for determination of 1 : 1 D/CD complex stability constant (K1 : 1) from the slope of a phase-distribution diagram (a diagram of the reciprocal of the apparent partition coefficient vs. the total CD concentration) was derived. The equation accounted for the possible inclusion of the organic solvent in the CD cavity and the gradual saturation of the CD binding with increasing concentration of the guest compound. This method was used to determine K1 : 1 for 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) complexes of hydrocortisone, prednisolone, diazepam, beta-estradiol and diethylstilbestrol. These values were comparable to K1 : 1 values determined by the phase-solubility method. The phase-distribution method could also be applied to determine stability constants for the neutral and ionic forms of the weakly acidic drugs, naproxen and triclosan and the weakly basic drug lidocaine. The phase-distribution method is a very versatile and fast method and has the advantage, compared to the phase-solubility method, that it only requires very small drug samples. Thus, this method would be suitable for screening of new drug candidates. PMID:16079528

Másson, Már; Sigurdardóttir, Birna Vigdís; Matthíasson, Kristján; Loftsson, Thorsteinn

2005-08-01

212

The effect of roxatidine acetate and cimetidine on hepatic drug clearance assessed by simultaneous administration of three model substrates.  

PubMed Central

The effect of pretreatment for 7 days with either roxatidine acetate 75 mg twice daily or cimetidine 200 mg four times daily on the kinetics of antipyrine (AP), trimethadione (TMO) and indocyanine green (ICG) was studied in seven healthy, male, nonsmoking subjects. After pretreatment with cimetidine, the plasma clearances (CL) of AP and TMO were significantly lower and the elimination half-life (t1/2) of AP was significantly increased. The volumes of distribution (V) of AP and TMO were not affected. After roxatidine acetate, the pharmacokinetics of AP and TMO were unchanged. The cumulative renal excretion (% dose) and formation clearance of 3-hydroxymethyl-3-nor-antipyrine (NORA) were lowered by cimetidine treatment, but not following the administration of roxatidine acetate. ICG clearance was not changed significantly by either pretreatment. The results of this study show that roxatidine acetate does not impair the metabolism of three model substrates used to assess hepatic drug clearance.

Tanaka, E; Nakamura, K

1989-01-01

213

Microbial degradation of illicit drugs, their precursors, and manufacturing by-products: implications for clandestine drug laboratory investigation and environmental assessment.  

PubMed

Chemicals associated with clandestine drug laboratories are often disposed of covertly into soil, sewerage systems, or public waste management facilities. There are two significant issues relating to such dumps of materials; they might contain valuable evidence as to drug manufacture, and they might be a source of pollution. This study presents initial findings in relation to the impact microorganisms from environmental sources have upon drugs, their precursors, and manufacturing by-products. The aim of this study was to identify which chemicals associated with clandestine drug laboratories persist in the environment in order to allow forensic drug chemists to link discarded residues with the method of manufacture, and to allow the environmental impact of clandestine drug laboratories to be assessed accurately. When exposed to soil microorganisms, phenyl-2-propanone (P2P) was rapidly metabolized into mixtures of 1-phenyl-2-propanol, 1-phenyl-1,2-propanedione, 1-hydroxy-1-phenyl-2-propanone, 2-hydroxy-1-phenyl-1-propanone, and the two diastereoisomers of 1-phenyl-1,2-propanediol. On the other hand, when exposed under the same conditions, methylamphetamine sulphate (MAS) remained virtually unchanged. Implications relating to evidence gathering for forensic purposes and to environmental assessment of clandestine drug laboratories are discussed. PMID:12842360

Janusz, A; Kirkbride, K P; Scott, T L; Naidu, R; Perkins, M V; Megharaj, M

2003-06-24

214

Hepatocyte-based in vitro model for assessment of drug-induced cholestasis.  

PubMed

Early detection of drug-induced cholestasis remains a challenge during drug development. We have developed and validated a biorelevant sandwich-cultured hepatocytes- (SCH) based model that can identify compounds causing cholestasis by altering bile acid disposition. Human and rat SCH were exposed (24-48h) to known cholestatic and/or hepatotoxic compounds, in the presence or in the absence of a concentrated mixture of bile acids (BAs). Urea assay was used to assess (compromised) hepatocyte functionality at the end of the incubations. The cholestatic potential of the compounds was expressed by calculating a drug-induced cholestasis index (DICI), reflecting the relative residual urea formation by hepatocytes co-incubated with BAs and test compound as compared to hepatocytes treated with test compound alone. Compounds with clinical reports of cholestasis, including cyclosporin A, troglitazone, chlorpromazine, bosentan, ticlopidine, ritonavir, and midecamycin showed enhanced toxicity in the presence of BAs (DICI?0.8) for at least one of the tested concentrations. In contrast, the in vitro toxicity of compounds causing hepatotoxicity by other mechanisms (including diclofenac, valproic acid, amiodarone and acetaminophen), remained unchanged in the presence of BAs. A safety margin (SM) for drug-induced cholestasis was calculated as the ratio of lowest in vitro concentration for which was DICI?0.8, to the reported mean peak therapeutic plasma concentration. SM values obtained in human SCH correlated well with reported % incidence of clinical drug-induced cholestasis, while no correlation was observed in rat SCH. This in vitro model enables early identification of drug candidates causing cholestasis by disturbed BA handling. PMID:24211272

Chatterjee, Sagnik; Richert, Lysiane; Augustijns, Patrick; Annaert, Pieter

2014-01-01

215

Environmental assessment of avermectins by the US Food and Drug Administration.  

PubMed

The Center of Veterinary Medicine (CVM) of the Food and Drug Administration (FDA) is required under the National Environmental Policy Act (NEPA) to include in its decision making, an objective consideration of the potential environmental impacts associated with each contemplated action. As part of the application process for new animal drugs, detailed data must be submitted in order to develop a prediction of the environmental fate and effects of the drug and/or its active metabolites. Ivermectin (22,23-dihydroavermectin B1) is a highly active antiparasitic animal drug utilized in a variety of injectable, oral and topical formulations. Residues of this drug may reach the environment through manufacturing and animal wastes and may potentially have effects on terrestrial and aquatic organisms. A comprehensive data base has been submitted to the FDA in support of the environmental assessments for ivermectin drug products. Detailed information has been submitted on the physical and chemical properties, introduction, fate and effects of the ivermectins in the environment. These data indicate that ivermectin binds tightly to soil and is subject to photodegradation and biotransformation to less active compounds. In contrast, ivermectin is highly toxic to certain aquatic organisms but would not be expected to partition into the aquatic environment. Much lower toxicity has been demonstrated toward bacteria, fungi, earthworms, plants and birds. CVM evaluated ivermectin products based on the use pattern of the product, the metabolism pattern in target animals, calculations of potential ivermectin residue concentrations in the environment and data on persistence, soil sorption and acute toxicity in aquatic and terrestrial environments. PMID:8346641

Bloom, R A; Matheson, J C

1993-06-01

216

Applicability Domain Analysis (ADAN): A Robust Method for Assessing the Reliability of Drug Property Predictions.  

PubMed

We report a novel method called ADAN (Applicability Domain ANalysis) for assessing the reliability of drug property predictions obtained by in silico methods. The assessment provided by ADAN is based on the comparison of the query compound with the training set, using six diverse similarity criteria. For every criterion, the query compound is considered out of range when the similarity value obtained is larger than the 95th percentile of the values obtained for the training set. The final outcome is a number in the range of 0-6 that expresses the number of unmet similarity criteria and allows classifying the query compound within seven reliability categories. Such categories can be further exploited to assign simpler reliability classes using a traffic light schema, to assign approximate confidence intervals or to mark the predictions as unreliable. The entire methodology has been validated simulating realistic conditions, where query compounds are structurally diverse from those in the training set. The validation exercise involved the construction of more than 1000 models. These models were built using a combination of training set, molecular descriptors, and modeling methods representative of the real predictive tasks performed in the eTOX project (a project whose objective is to predict in vivo toxicological end points in drug development). Validation results confirm the robustness of the proposed assessment methodology, which compares favorably with other classical methods based solely on the structural similarity of the compounds. ADAN characteristics make the method well-suited for estimate the quality of drug predictions obtained in extremely unfavorable conditions, like the prediction of drug toxicity end points. PMID:24821140

Carrió, Pau; Pinto, Marta; Ecker, Gerhard; Sanz, Ferran; Pastor, Manuel

2014-05-27

217

Evaluation of higher distribution and/or utilization voltages. Fourth interim report (August 1980): assessment of optimum distribution configuration  

SciTech Connect

This interim report provides documentation on the fourth task, Assessment of Optimum Distribution Configuration, of DOE Contract No. ET-78-C-01-2866, Evaluation of Higher Distribution and/or Utilization Voltages. The work performed under this task includes the development of a computer model for assessment of life cycle costs for the distribution and utilization systems, the development of an optimization algorithm to enable distribution system configuration optimization and a net energy analysis to determine potential net energy savings. Input data for this task derive from Task 3. The major output of this task is a documented computer code.

Not Available

1981-04-01

218

An assessment of reactive power\\/voltage control devices in distribution networks  

Microsoft Academic Search

This paper provides an assessment of candidate voltage\\/reactive power control devices for distribution systems. The recent trend toward distributed energy resources (DERs), and distributed generation (DG), in particular, is often based on the rationale to support voltage and compensate for reactive power closer to the end users. This situation calls for a systematic approach to assessing alternatives for voltage control,

Anupam A. Thatte; Marija D. Ilic

2006-01-01

219

The practice of pre-marketing safety assessment in drug development.  

PubMed

The last 15 years have seen a substantial increase in efforts devoted to safety assessment by statisticians in the pharmaceutical industry. While some of these efforts were driven by regulations and public demand for safer products, much of the motivation came from the realization that there is a strong need for a systematic approach to safety planning, evaluation, and reporting at the program level throughout the drug development life cycle. An efficient process can help us identify safety signals early and afford us the opportunity to develop effective risk minimization plan early in the development cycle. This awareness has led many pharmaceutical sponsors to set up internal systems and structures to effectively conduct safety assessment at all levels (patient, study, and program). In addition to process, tools have emerged that are designed to enhance data review and pattern recognition. In this paper, we describe advancements in the practice of safety assessment during the premarketing phase of drug development. In particular, we share examples of safety assessment practice at our respective companies, some of which are based on recommendations from industry-initiated working groups on best practice in recent years. PMID:23331218

Chuang-Stein, Christy; Xia, H Amy

2013-01-01

220

Statistical and regulatory considerations in assessments of interchangeability of biological drug products.  

PubMed

When the patent of a brand-name, marketed drug expires, new, generic products are usually offered. Small-molecule generic and originator drug products are expected to be chemically identical. Their pharmaceutical similarity can be typically assessed by simple regulatory criteria such as the expectation that the 90% confidence interval for the ratio of geometric means of some pharmacokinetic parameters be between 0.80 and 1.25. When such criteria are satisfied, the drug products are generally considered to exhibit therapeutic equivalence. They are then usually interchanged freely within individual patients. Biological drugs are complex proteins, for instance, because of their large size, intricate structure, sensitivity to environmental conditions, difficult manufacturing procedures, and the possibility of immunogenicity. Generic and brand-name biologic products can be expected to show only similarity but not identity in their various features and clinical effects. Consequently, the determination of biosimilarity is also a complicated process which involves assessment of the totality of the evidence for the close similarity of the two products. Moreover, even when biosimilarity has been established, it may not be assumed that the two biosimilar products can be automatically substituted by pharmacists. This generally requires additional, careful considerations. Without declaring interchangeability, a new product could be prescribed, i.e. it is prescribable. However, two products can be automatically substituted only if they are interchangeable. Interchangeability is a statistical term and it means that products can be used in any order in the same patient without considering the treatment history. The concepts of interchangeability and prescribability have been widely discussed in the past but only in relation to small molecule generics. In this paper we apply these concepts to biosimilars and we discuss: definitions of prescribability and interchangeability and their statistical implementation; the relation between bioequivalence and interchangeability for small-molecule drug products; regulatory requirements and expectations of biosimilar products in various jurisdictions; possible statistical approaches to establish the similarity and interchangeability of biologic drug products; definition of other technical terms such as switchability and automatic substitution. The paper will be concluded with a discussion of the anticipated future use of interchangeability of biological drug products. PMID:24832831

Tóthfalusi, Lászlo; Endrényi, László; Chow, Shein-Chung

2014-05-01

221

Assessments of pharmacokinetic drug interactions and tolerability of albendazole, praziquantel and ivermectin combinations.  

PubMed

The pharmacokinetic interactions and tolerability of albendazole, praziquantel and ivermectin combinations were assessed in 23 healthy Thai volunteers (12 males and 11 females). The study was an open, randomised, three-way crossover design in which each subject attended the study on three separate occasions (Phases I, II and III), of 4 d or 8 d each, with at least 1 or 2 weeks (but not longer than 2 months) between each phase. All subjects received the three study drug regimens as follows: regimen I, oral praziquantel (40 mg/kg body weight); regimen II, oral ivermectin (200 microg/kg body weight) given concurrently with an oral dose of albendazole (400 mg); and regimen III, oral ivermectin given concurrently with albendazole and praziquantel. All treatment regimens showed acceptable tolerability profiles. The incidence of overall drug-related adverse events was significantly higher following regimens I (12/23) and III (7/23) compared with that following regimen II (0/23). Six statistically significant changes in the pharmacokinetic parameters of albendazole sulphoxide (Cmax, AUC0-infinity, Vz/F, CL/F), praziquantel (Vz/F) and ivermectin (AUC0-infinity) were observed when the three drugs were given concurrently. However, based on US Food and Drug Administration criteria, these changes were not considered of clinical relevance. PMID:16271272

Na-Bangchang, K; Kietinun, S; Pawa, K K; Hanpitakpong, W; Na-Bangchang, C; Lazdins, J

2006-04-01

222

Principles of laboratory assessment of drug abuse liability and implications for clinical development.  

PubMed

Abuse liability testing plays an important role in informing drug development, regulatory processes, and clinical practice. This paper describes the current "gold standard" methodologies that are used for laboratory assessments of abuse liability in non-human and human subjects. Particular emphasis is given to procedures such as non-human drug discrimination, self-administration, and physical dependence testing, and human dose-effect abuse liability studies that are commonly used in regulatory submissions to governmental agencies. The potential benefits and risks associated with the inclusion of measures of abuse liability in industry-sponsored clinical trials is discussed. Lastly, it is noted that many factors contribute to patterns of drug abuse and dependence outside of the laboratory setting and positive or negative signals in abuse liability studies do not always translate to high or low levels of actual abuse or dependence. Well-designed patient and physician education, pharmacovigilance, and postmarketing surveillance can reduce the diversion and misuse of drugs with abuse liability and can effectively foster the protection and promotion of public health. PMID:19443137

Carter, Lawrence P; Griffiths, Roland R

2009-12-01

223

Evaluation of stability and size distribution of sunflower oil-coated micro bubbles for localized drug delivery  

PubMed Central

Background Micro bubbles were initially introduced as contrast agents for ultrasound examinations as they are able to modify the signal-to-noise ratio in imaging, thus improving the assessment of clinical information on human tissue. Recent developments have demonstrated the feasibility of using these bubbles as drug carriers in localized delivery. In micro fluidics devices for generation of micro bubbles, the bubbles are formed at interface of liquid gas through a strangulation process. A device that uses these features can produce micro bubbles with small size dispersion in a single step. Methods A T-junction micro fluidic device constructed using 3D prototyping was made for the production of mono dispersed micro bubbles. These micro bubbles use sunflower oil as a lipid layer. Stability studies for micro bubbles with diameters different generated from a liquid phase of the same viscosity were conducted to evaluate whether micro bubbles can be used as drug carriers. The biocompatibility of coating layer, the ability to withstand environmental pressure variations combined with echogenicity, are key factors that they can safely play the role of drug transporters. Results The normal distribution curve with small dispersion of the diameter of bubbles validates the process of generating micro bubbles with low value of variation coefficient, i.e., 0.381 at 1.90%. The results also showed the feasibility of using sunflower oil as the lipid matrix with stable population of bubbles over 217 minutes for micro bubbles with an average diameter of 313.04 ?m and 121 minutes for micro bubbles with an average diameter of 73.74 ?m, considering bubbles with air as gaseous phase. Conclusion The results indicate that the micro fluidic device designed can be used for producing micro bubbles with low variation coefficient using sunflower oil as a coating of micro bubbles. These carriers were stable for periods of time that are long enough for clinical applications even when regular air is used as the gas phase. Improved stability can be achieved when biocompatible gas with lower permeability is used.

2012-01-01

224

Understanding the Assessment of Psychotropic Drug Harms in Clinical Trials to Improve Social Workers' Role in Medication Monitoring  

ERIC Educational Resources Information Center

The purpose of this integrative review is to facilitate social work practitioners' understanding of how psychotropic drug harms are assessed in clinical trials and to make specific suggestions for social workers' increased involvement in detecting drug harms in their clients. The authors undertook a comprehensive review of interdisciplinary…

Hughes, Shannon; Cohen, David

2010-01-01

225

Validation of quantitative real-time PCR for the in vitro assessment of antileishmanial drug activity.  

PubMed

In vitro assays play an important role in the discovery and development of new antileishmanial drugs. The classic macrophage-amastigote models using murine peritoneal macrophages or human-monocyte derived macrophages as host cells are useful for drug screening. A major limitation of these models is the dependence on microscopic counting, a time-consuming and subjective method of analysis. The present study describes a detailed protocol for applying quantitative real-time PCR (qPCR) as an accurate and sensitive tool to assess parasite load in an amastigote-macrophage model. This assay can be performed in a standardized medium-to-high throughput procedure, replacing traditional readout of number of amastigote per macrophages by DNA load measurement. PMID:22475774

Gomes, Luciana I; Gonzaga, Felipe M; de Morais-Teixeira, Eliane; de Souza-Lima, Bruna S; Freire, Verônica V; Rabello, Ana

2012-06-01

226

Kidney function assessment and its role in drug development, review and utilization.  

PubMed

A key regulatory requirement pertaining to drug development is characterization of the role of kidney function in drug disposition and response, along with provision of corresponding renal dose adjustment recommendations. Traditionally, this information has been derived from Phase I pharmacokinetic studies in which regulatory guidance exists for pharmaceutical manufacturers on the design, conduct, analysis, and interpretation of data. Categorization and stratification of subjects into kidney function groups and dosing recommendations have historically been based on creatinine clearance estimates using the Cockcroft-Gault equation. As new estimating equations have emerged, the choice of equation for assessment of kidney function has become an area of debate. This review highlights these equations and provides recent examples of the use of quantitative models, incorporating efficacy and safety to make rational dose recommendations in subjects with impaired kidney function. PMID:24875237

Tortorici, Michael A; Nolin, Thomas D

2014-07-01

227

Adhesion forces in interactive powder mixtures of a micronized drug and carrier particles of various particle size distributions  

Microsoft Academic Search

The adhesion force between micronized drug particles (Salmeterol Xinafoate) and lactose monohydrate carrier particles in interactive powder mixtures has been determined. Artificial particle size distributions of the carrier powder were produced from fine (< 20 ?m), medium ( 20 ?m to < 70 ?m), and coarse ( 70 ?m) carrier particle fractions. Using three different grades of lactose monohydrate, in

F. Podczeck

1998-01-01

228

COMPARATIVE ASSESSMENT OF TWO DISTRIBUTED WATERSHED MODELS WITH APPLICATION TO A SMALL WATERSHED  

EPA Science Inventory

Distributed watershed models are beneficial tools for assessment of management practices on runoff and water-induced erosion. This paper evaluates, by application to an experimental watershed, two promising distributed watershed-scale sediment models in detail: The Kinematic Runo...

229

A novel gamma-fitting statistical method for anti-drug antibody assays to establish assay cut points for data with non-normal distribution.  

PubMed

In recent years there has been growing recognition of the impact of anti-drug or anti-therapeutic antibodies (ADAs, ATAs) on the pharmacokinetic and pharmacodynamic behavior of the drug, which ultimately affects drug exposure and activity. These anti-drug antibodies can also impact safety of the therapeutic by inducing a range of reactions from hypersensitivity to neutralization of the activity of an endogenous protein. Assessments of immunogenicity, therefore, are critically dependent on the bioanalytical method used to test samples, in which a positive versus negative reactivity is determined by a statistically derived cut point based on the distribution of drug naïve samples. For non-normally distributed data, a novel gamma-fitting method for obtaining assay cut points is presented. Non-normal immunogenicity data distributions, which tend to be unimodal and positively skewed, can often be modeled by 3-parameter gamma fits. Under a gamma regime, gamma based cut points were found to be more accurate (closer to their targeted false positive rates) compared to normal or log-normal methods and more precise (smaller standard errors of cut point estimators) compared with the nonparametric percentile method. Under a gamma regime, normal theory based methods for estimating cut points targeting a 5% false positive rate were found in computer simulation experiments to have, on average, false positive rates ranging from 6.2 to 8.3% (or positive biases between +1.2 and +3.3%) with bias decreasing with the magnitude of the gamma shape parameter. The log-normal fits tended, on average, to underestimate false positive rates with negative biases as large a -2.3% with absolute bias decreasing with the shape parameter. These results were consistent with the well known fact that gamma distributions become less skewed and closer to a normal distribution as their shape parameters increase. Inflated false positive rates, especially in a screening assay, shifts the emphasis to confirm test results in a subsequent test (confirmatory assay). On the other hand, deflated false positive rates in the case of screening immunogenicity assays will not meet the minimum 5% false positive target as proposed in the immunogenicity assay guidance white papers. PMID:19891969

Schlain, Brian; Amaravadi, Lakshmi; Donley, Jean; Wickramasekera, Ananda; Bennett, Donald; Subramanyam, Meena

2010-01-31

230

A comprehensive approach to benefit-risk assessment in drug development.  

PubMed

Major regulatory agencies, for example, FDA and EMA, have started to request comprehensive benefit-risk analyses of pharmaceutical products prior to approval or labelling expansion. The purpose of this study is to develop a generally applicable and reliable data-driven benefit-risk assessment method, where two or more drugs/doses can be compared. Our aim is to formulate an approach that is simple to apply, allows direct comparison of different types of risks and benefits, and is tailored for application in different disease areas both during clinical development and in the marketing approval phase. The proposed benefit-risk assessment method involves eight successive steps: (1) establishment of the decision context, (2) identification of benefit and risk criteria, (3) weighting, (4) scoring, (5) evaluation of uncertainty, (6) calculation of weighted scores, (7) visualization, and (8) discussion and formulation of an overall conclusion. To reduce the impact of subjective judgements, scores are assigned to each criterion on the basis of objective information (data) wherever possible. The proposed benefit-risk evaluation approach offers comprehensive, data-driven assessments that can facilitate decision processes. It employs descriptive statistical methods to highlight the clinically significant differences between drugs in clinical trials. The approach can be used in single as well as in multiple trials and provides clear diagrams as the basis for presentation and discussion of the results. PMID:22356197

Sarac, Sinan B; Rasmussen, Christian H; Rasmussen, Morten A; Hallgreen, Christine E; Søeborg, Tue; Colding-Jørgensen, Morten; Christensen, Per K; Thirstrup, Steffen; Mosekilde, Erik

2012-07-01

231

Validating CHARMM parameters and exploring charge distribution rules in structure-based drug design  

PubMed Central

Using an extensive series of TIBO compounds that are non-nucleoside inhibitors of HIV-1 reverse transcriptase, we have systematically evaluated the quality of recently developed ligand parameters that are consistent with the CHARMM22 force field. Thermodynamic integration simulations for 44 pairs of TIBO compounds achieve a high level of success with an overall average unsigned error (AUE) in the relative binding affinities of 1.3 kcal/mol; however, the accuracy is strongly dependent on the size differential between the substituents sampled as well as the class of functional group. Low errors are observed among the alkyl, allyl, aldehyde, nitrile, trifluorinated methyl, and halide TIBO derivatives and large systematic errors among thioether derivatives. We have also investigated how different charge assignment schemes for small molecules impact the quality of computed binding affinities for a subset of this series. This study demonstrates the advantage of using model compounds to derive physically meaningful charge distributions and bond-charge increments for rapidly expanding fragment libraries for drug development applications. Specifically, in the absence of a bond-charge increment for a given pair of atom types, the strategy of adopting CHELPG charges from localized regions of model compounds provides reliable results when modeling with the CHARMM force field.

Knight, Jennifer L.; Brooks, Charles L.

2009-01-01

232

Landslide Probability Assessment by the Derived Distributions Technique  

NASA Astrophysics Data System (ADS)

Landslides are potentially disastrous events that bring along human and economic losses; especially in cities where an accelerated and unorganized growth leads to settlements on steep and potentially unstable areas. Among the main causes of landslides are geological, geomorphological, geotechnical, climatological, hydrological conditions and anthropic intervention. This paper studies landslides detonated by rain, commonly known as "soil-slip", which characterize by having a superficial failure surface (Typically between 1 and 1.5 m deep) parallel to the slope face and being triggered by intense and/or sustained periods of rain. This type of landslides is caused by changes on the pore pressure produced by a decrease in the suction when a humid front enters, as a consequence of the infiltration initiated by rain and ruled by the hydraulic characteristics of the soil. Failure occurs when this front reaches a critical depth and the shear strength of the soil in not enough to guarantee the stability of the mass. Critical rainfall thresholds in combination with a slope stability model are widely used for assessing landslide probability. In this paper we present a model for the estimation of the occurrence of landslides based on the derived distributions technique. Since the works of Eagleson in the 1970s the derived distributions technique has been widely used in hydrology to estimate the probability of occurrence of extreme flows. The model estimates the probability density function (pdf) of the Factor of Safety (FOS) from the statistical behavior of the rainfall process and some slope parameters. The stochastic character of the rainfall is transformed by means of a deterministic failure model into FOS pdf. Exceedance probability and return period estimation is then straightforward. The rainfall process is modeled as a Rectangular Pulses Poisson Process (RPPP) with independent exponential pdf for mean intensity and duration of the storms. The Philip infiltration model is used along with the soil characteristic curve (suction vs. moisture) and the Mohr-Coulomb failure criteria in order to calculate the FOS of the slope. Data from two slopes located on steep tropical regions of the cities of Medellín (Colombia) and Rio de Janeiro (Brazil) where used to verify the model's performance. The results indicated significant differences between the obtained FOS values and the behavior observed on the field. The model shows relatively high values of FOS that do not reflect the instability of the analyzed slopes. For the two cases studied, the application of a more simple reliability concept (as the Probability of Failure - PR and Reliability Index - ?), instead of a FOS could lead to more realistic results.

Muñoz, E.; Ochoa, A.; Martínez, H.

2012-12-01

233

Assessment of flood frequency models using empirical distribution function statistics  

Microsoft Academic Search

Tests of goodness of fit of the generalized extreme value (GEV) and the generalized logistic (GL) distribution based on the empirical distribution function are described. Significance points for the Anderson-Darling (Anderson and Darling, 1952, 1954) and a recently introduced modified Anderson- Darling (Sinclair et al., 1987) test statistic are obtained by simulation. For each of these distributions the unknown parameters

M. I. Ahmad; C. D. Sinclair; B. D. Spurr

1988-01-01

234

The mastermind approach to CNS drug therapy: translational prediction of human brain distribution, target site kinetics, and therapeutic effects  

PubMed Central

Despite enormous advances in CNS research, CNS disorders remain the world’s leading cause of disability. This accounts for more hospitalizations and prolonged care than almost all other diseases combined, and indicates a high unmet need for good CNS drugs and drug therapies. Following dosing, not only the chemical properties of the drug and blood–brain barrier (BBB) transport, but also many other processes will ultimately determine brain target site kinetics and consequently the CNS effects. The rate and extent of all these processes are regulated dynamically, and thus condition dependent. Therefore, heterogenious conditions such as species, gender, genetic background, tissue, age, diet, disease, drug treatment etc., result in considerable inter-individual and intra-individual variation, often encountered in CNS drug therapy. For effective therapy, drugs should access the CNS “at the right place, at the right time, and at the right concentration”. To improve CNS therapies and drug development, details of inter-species and inter-condition variations are needed to enable target site pharmacokinetics and associated CNS effects to be translated between species and between disease states. Specifically, such studies need to include information about unbound drug concentrations which drive the effects. To date the only technique that can obtain unbound drug concentrations in brain is microdialysis. This (minimally) invasive technique cannot be readily applied to humans, and we need to rely on translational approaches to predict human brain distribution, target site kinetics, and therapeutic effects of CNS drugs. In this review the term “Mastermind approach” is introduced, for strategic and systematic CNS drug research using advanced preclinical experimental designs and mathematical modeling. In this way, knowledge can be obtained about the contributions and variability of individual processes on the causal path between drug dosing and CNS effect in animals that can be translated to the human situation. On the basis of a few advanced preclinical microdialysis based investigations it will be shown that the “Mastermind approach” has a high potential for the prediction of human CNS drug effects.

2013-01-01

235

Drug-specific quality indicators assessing outpatient antibiotic use among French general practitioners.  

PubMed

Quality indicators assessing the use of antibiotics among general practitioners (GPs) would be useful to target antibiotic stewardship interventions. We adapted to an individual GP level a set of 12 drug-specific quality indicators of outpatient antibiotic use in Europe developed by the European surveillance of antimicrobial consumption project. We performed a cross-sectional study analysing reimbursement data on outpatient antibiotic prescriptions in adults in south-eastern France in 2009. Substantial heterogeneity in antibiotic prescribing among French GPs was observed, and opportunity to improve antibiotic prescribing can be identified. PMID:22843612

Pulcini, Céline; Lions, Caroline; Ventelou, Bruno; Verger, Pierre

2013-04-01

236

Methods for the assessment of the effects of drugs on coronary blood flow in man.  

PubMed Central

The methods currently available for measurement of coronary blood flow in man are reviewed and their advantages and limitations discussed. Most of the techniques are invasive and involve cardiac catheterization. The least invasive isotope techniques are either not quantitative or involve expensive equipment not available in many centres. Two of the most suitable methods for assessing the effects of drugs on coronary flow are coronary sinus thermodilution and isotope washout curves using 133xenon or [125I]-iodo-antipyrine. The ideal technique for measuring coronary blood flow has yet to be developed.

Swanton, R H; Coltart, D J

1978-01-01

237

The Washington Needle Depot: fitting healthcare to injection drug users rather than injection drug users to healthcare: moving from a syringe exchange to syringe distribution model  

PubMed Central

Needle exchange programs chase political as well as epidemiological dragons, carrying within them both implicit moral and political goals. In the exchange model of syringe distribution, injection drug users (IDUs) must provide used needles in order to receive new needles. Distribution and retrieval are co-existent in the exchange model. Likewise, limitations on how many needles can be received at a time compel addicts to have multiple points of contact with professionals where the virtues of treatment and detox are impressed upon them. The centre of gravity for syringe distribution programs needs to shift from needle exchange to needle distribution, which provides unlimited access to syringes. This paper provides a case study of the Washington Needle Depot, a program operating under the syringe distribution model, showing that the distribution and retrieval of syringes can be separated with effective results. Further, the experience of IDUs is utilized, through paid employment, to provide a vulnerable population of people with clean syringes to prevent HIV and HCV.

2010-01-01

238

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

PubMed Central

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

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

2012-01-01

239

Literature based drug interaction prediction with clinical assessment using electronic medical records: novel myopathy associated drug interactions.  

PubMed

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

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

2012-01-01

240

Are Drug Companies Living Up to Their Human Rights Responsibilities? Moving Toward Assessment  

PubMed Central

Background to the debate The human rights responsibilities of drug companies have been considered for years by nongovernmental organizations, but were most sharply defined in a report by the UN Special Rapporteur on the right to health, submitted to the United Nations General Assembly in August 2008. The “Human Rights Guidelines for Pharmaceutical Companies in relation to Access to Medicines” include responsibilities for transparency, management, monitoring and accountability, pricing, and ethical marketing, and against lobbying for more protection in intellectual property laws, applying for patents for trivial modifications of existing medicines, inappropriate drug promotion, and excessive pricing. Two years after the release of the Guidelines, the PLoS Medicine Debate asks whether drug companies are living up to their human rights responsibilities. Sofia Gruskin and Zyde Raad from the Harvard School of Public Health say more assessment is needed of such responsibilities; Geralyn Ritter, Vice President of Global Public Policy and Corporate Responsibility at Merck & Co. argues that multiple stakeholders could do more to help States deliver the right to health; and Paul Hunt and Rajat Khosla introduce Mr. Hunt's work as the UN Special Rapporteur on the right to the highest attainable standard of health, regarding the human rights responsibilities of pharmaceutical companies and access to medicines.

Gruskin, Sofia; Raad, Zyde

2010-01-01

241

Evaluation of pre-analysis loss of dependent drugs in wastewater: stability and binding assessments.  

PubMed

Wastewater analysis has the potential to provide objective and timely data on population drug consumption, but some crucial factors such as pre-analysis drug loss during sample storage and filtration could affect the accuracy and reliability of the method, and these uncertainties have yet to be fully assessed. This study was designed to evaluate analyte stability in wastewater stored under different conditions with the aim of optimizing the sample storage procedures for future studies. It also investigated whether there is significant analyte loss during filtration before sample extraction and storage after that. The studied substances and metabolites were: cotinine, cocaine and its metabolite benzoylecgonine, phenethylamines amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), opioids including codeine, methadone, 6-monoacetylmorphine (MAM) and morphine. In most situations, storing samples at 4?°C is sufficient to stabilize analytes for at least 2?weeks, and refrigeration is unnecessary during sample transportation within 3?days. However, additional measures need to be taken if unstable analytes such as cocaine and MAM are to be analyzed. No significant analyte loss was observed in the filtration process or in reconstituted extract stored at 4?°C or -20?°C for 2?weeks. By choosing stable analytes and proper storage conditions, wastewater analysis has the potential to provide accurate data for estimation of community drug use. PMID:23047767

Chen, Chang; Kostakis, Chris; Irvine, Rodney J; Felgate, Peter D; White, Jason M

2013-08-01

242

Drug-resistant primary headache patients undergoing surgical therapies: how should we assess outcomes?  

PubMed

The introduction of neurostimulation procedures for chronic drug-resistant primary headaches has offered new hope to patients, but has also introduced new problems. The methods to be used in assessing clinical outcomes and monitoring treatment efficacy need careful attention. The International Headache Society guidelines recommend that treatment efficacy should be monitored by getting patients to report the number of attacks per day, in a headache diary. The headache diary is a fundamental instrument for objectively assessing subjective pain in terms of headache frequency, intensity and duration and analgesic consumption. The huge discrepancy sometimes reported between patient satisfaction and headache improvement suggests that patient satisfaction should not be a primary efficacy endpoint, and more importantly should not be put forward as an argument in establishing the efficacy of highly experimental neurostimulation procedures. PMID:20464593

Leone, Massimo; Franzini, Angelo; Cecchini, Alberto Proietti; Mea, Eliana; Peccarisi, Cesare; Tullo, Vincenzo; Broggi, Giovanni; Bussone, Gennaro

2010-06-01

243

How the Medicare Part D Drug Benefit Changed the Distribution of Out-of-Pocket Pharmacy Spending Among Older Beneficiaries  

PubMed Central

Objective. To examine the impact of the Medicare drug benefit (Part D) on the distribution of out-of-pocket pharmacy spending among older adults. Methods. We used a pre-post-with-comparison-group design to compare four groups of beneficiaries continuously enrolled in a Medicare Advantage plan between 2004 and 2007: three intervention groups with no or limited (quarterly caps of $150 or $350) prior coverage that obtained Part D benefits in 2006 and a comparison group with stable drug coverage from 2004 to 2007. Results. The comparison group’s out-of-pocket drug spending was stable throughout 2004–2007, whereas Part D reduced out-of-pocket spending 13.4% among those without prior coverage (95% confidence interval [CI] ?17.1% to ?9.1%) and 15.9% among those with $150 quarterly caps (95% CI ?19.1% to ?12.8%) relative to the comparison group. Individuals in the top decile of drug spending paid a greater share of their costs out-of-pocket than others in the top 5 deciles. Discussion. Although Part D reduced out-of-pocket expenditures for older adults, those with the highest drug spending still pay a substantial share of their drug costs out-of-pocket. Thus, the Part D benefit does not achieve a primary purpose of insurance—to offer the greatest financial protection to those at the highest risk.

Lave, Judith R.; Newhouse, Joseph P.; Donohue, Julie M.

2010-01-01

244

Further assessment of Mirazid as antischistosomal drug in experimental schistosomiasis hematobium.  

PubMed

Conflicting reports are found in the literature about the efficacy of Mirazid (MZ), which is a special formulation of myrrh obtained from the stem of Commiphora molmol (Nees), Engl. tree (Burseraceae), as an antischistosomal drug. This initiated the present study to further assess this drug in experimental schistosomiasis hematobium. The drug was administered orally to hamsters infected with Schistosoma hematobium ( Bilharz, 1852 ) using 500 mg/kg body weight for six successive days on an empty stomach. The drug effect was examined after three periods: 4, 8 and 12 weeks post-treatment. Emphasis was given to certain parameters such as change in worm load, number of ova/mg tissue, oogram pattern and number of ova/g stool, and tegumental changes in the worms by electron microscopy after prolonged observation periods. The results showed very slight 3.4% worm reduction by MZ after the longest evaluation period (12 weeks), versus very high reduction (100%) by the reference drug praziquantel (PZQ). In comparison with the untreated control no change was found in the number of ova/mg tissue in MZ-treated hamsters regardless of the date of observation (4-12 weeks), versus significantly high reduction (99.6%) observed in the case of PZQ treatment. However, a significant decrease (22%) in the ratio of immature and increase in dead ova in tissues of MZ-treated hamsters was obvious at 12 weeks post treatment. In MZ-treated animals, a slight reduction (18.3%) in the number of stool eggs versus absence of eggs in PZQ-treated animals 12 weeks after treatment. Scanning electron microscopic examination of S. hematobium worms revealed intact tubercles, spines and sensory bulbs and no effect of the ventral side after MZ treatment. Meanwhile, PZQ treatment revealed extensive disruption of the tegument worm. Therefore, this experimental study gives extra support to previously reported negative evaluation about the effectiveness of this drug in the treatment of schistosomiasis against many other published positive results. This controversy about the efficacy of MZ may be attributed to inconsistency of its material which is obtained from natural origin. PMID:20645776

Ramzy, Fatem; Mahmoud, Soheir; William, Samia

2010-07-01

245

Assessment of Azithromycin in Combination with Other Antimalarial Drugs against Plasmodium falciparum In Vitro  

PubMed Central

Initial field malaria prophylaxis trials with azithromycin revealed insufficient efficacy against falciparum malaria to develop azithromycin as a single agent. The objective of this in vitro study was to determine the best drug combination(s) to evaluate for future malaria treatment and prophylaxis field trials. In vitro, azithromycin was tested in combination with chloroquine against 10 representative Plasmodium falciparum isolates. Azithromycin was also assessed in combination with eight additional antimalarial agents against two or three multidrug-resistant P. falciparum isolates. Parasite susceptibility testing was carried out with a modification of the semiautomated microdilution technique. The incubation period was extended from the usual 48 h to 68 h. Fifty percent inhibitory concentrations (IC50s) were calculated for each drug alone and for drugs in fixed combinations of their respective IC50s (1:1, 3:1, 1:3, 4:1, 1:4, and 5:1). These data were used to calculate fractional inhibitory concentrations and isobolograms. Chloroquine-azithromycin studies revealed a range of activity from additive to synergistic interactions for the eight chloroquine-resistant isolates tested, while an additive response was seen for the two chloroquine-sensitive isolates. Quinine, tafenoquine, and primaquine were additive to synergistic with azithromycin, while dihydroartemisinin was additive with a trend toward antagonism. The remaining interactions appeared to be additive. These results suggest that a chloroquine-azithromycin combination should be evaluated for malaria prophylaxis and that a quinine-azithromycin combination should be evaluated for malaria treatment in areas of drug resistance.

Ohrt, Colin; Willingmyre, George D.; Lee, Patricia; Knirsch, Charles; Milhous, Wilbur

2002-01-01

246

Personalized Risk Assessment of Drug-Related Harm Is Associated with Health Outcomes  

PubMed Central

Background The Independent Scientific Committee on Drugs (ISCD) assigned quantitative scores for harm to 20 drugs. We hypothesized that a personalized, ISCD-based Composite Harm Score (CHS) would be associated with poor health outcomes in polysubstance users. Methods A prospective community sample (n=293) of adults living in marginal housing was assessed for substance use. The CHS was calculated based on the ISCD index, and the personal substance use characteristics over four weeks. Regression models estimated the association between CHS and physical, psychological, and social health outcomes. Results Polysubstance use was pervasive (95.8%), as was multimorbid illness (median 3, possible range 0–12). The median CHS was 2845 (interquartile range 1865–3977). Adjusting for age and sex, every 1000-unit CHS increase was associated with greater mortality (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.07–2.01, p = 0.02), and persistent hepatitis C infection (OR 1.29, 95% CI 1.02–1.67, p = 0.04). The likelihood of substance-induced psychosis increased 1.39-fold (95% CI 1.13–1.67, p = 0.001). The amount spent on drugs increased 1.51-fold (1.40–1.62, p < 0.001) and the odds of having committed a crime increased 1.74-fold (1.46–2.10, p < 0.001). Multimorbid illness increased 1.43-fold (95% CI 1.26–1.63, p < 0.001). Conclusions Greater CHS predicts poorer physical, psychological, and social health, and may be a useful quantitative, personalized measure of risk for drug-related harm.

Jones, Andrea A.; Vila-Rodriguez, Fidel; Panenka, William J.; Leonova, Olga; Strehlau, Verena; Lang, Donna J.; Thornton, Allen E.; Wong, Hubert; Barr, Alasdair M.; Procyshyn, Ric M.; Smith, Geoffrey N.; Buchanan, Tari; Krajden, Mel; Krausz, Michael; Montaner, Julio S.; MacEwan, G. William; Nutt, David J.; Honer, William G.

2013-01-01

247

In vitro assessment of drug release rates from oil depot formulations intended for intra-articular administration.  

PubMed

In vitro drug release rates from oil depot formulations intended for intra-articular injection have been investigated by using the rotating dialysis cell. The rate of drug appearance in the acceptor phase after instillation of sesame oil solutions of naproxen and lidocaine into the small aqueous donor compartment applied to first-order kinetics. In the present three-compartment model oil-aqueous phase distribution equilibrium was maintained at all times in the donor phase and thus drug efflux from the donor compartment was dictated by the distribution coefficient. A mathematical description of the rate of drug release into the acceptor phase and the interdependence of the observed apparent first-order rate constants and the drug oil-water distribution coefficients is provided. The in vitro model may constitute a valuable tool in formulation design and development allowing comparison of drug release rates originating from alteration of the oil vehicle composition, the drug compound or the composition of the release media to be performed. PMID:16920337

Larsen, Susan Weng; Østergaard, Jesper; Friberg-Johansen, Henrik; Jessen, Marit N B; Larsen, Claus

2006-12-01

248

Independent Orbiter Assessment (IOA): Assessment of the electrical power distribution and control subsystem, volume 3  

NASA Technical Reports Server (NTRS)

The results of the Independent Orbiter Assessment (IOA) of the Failure Modes and Effects Analysis (FMEA) and Critical Items List (CIL) are presented. The IOA first completed an analysis of the Electrical Power Distribution and Control (EPD and C) hardware, generating draft failure modes and potential critical items. To preserve independence, this analysis was accomplished without reliance upon the results contained within the NASA FMEA/CIL documentation. The IOA results were then compared to the NASA FMEA/CIL baseline with proposed Post 51-L updates included. A resolution of each discrepancy from the comparison is provided through additional analysis as required. This report documents the results of that comparison for the Orbiter EPD and C hardware. Volume 3 continues the presentation of IOA worksheets and contains the potential critical items list and the NASA FMEA to IOA worksheet cross reference and recommendations.

Schmeckpeper, K. R.

1988-01-01

249

Independent Orbiter Assessment (IOA): Assessment of the Electrical Power Distribution and Control Subsystem, Volume 2  

NASA Technical Reports Server (NTRS)

The results of the Independent Orbiter Assessment (IOA) of the Failure Modes and Effects Analysis (FMEA) and Critical Items List (CIL) are presented. The IOA first completed an analysis of the Electrical Power Distribution and Control (EPD and C) hardware, generating draft failure modes and potential critical items. To preserve independence, this analysis was accomplished without reliance upon the results contained within the NASA FMEA/CIL documentation. The IOA results were then compared to the NASA FMEA/CIL baseline with proposed Post 51-L updates included. A resolution of each discrepancy from the comparison is provided through additional analysis as required. This report documents the results of that comparison for the Orbiter EPD and C hardware. Volume 2 continues the presentation of IOA worksheets.

Schmeckpeper, K. R.

1988-01-01

250

Comparison of equilibrium and non-equilibrium distribution coefficients for the human drug carbamazepine in soil.  

PubMed

The distribution coefficient (KD) for the human drug carbamazepine was measured using a non-equilibrium technique. Repacked soil columns were prepared using an Airport silt loam (Typic Natrustalf) with an average organic matter content of 2.45%. Carbamazepine solutions were then leached through the columns at 0.5, 1.0 and 1.5 mL min(-1) representing average linear velocities of 1.8, 3.5 and 5.3 cm h(-1) respectively. Each flow rate was replicated three times and three carbamazepine pulses were applied to each column resulting in a total of 9 columns with 27 total carbamazepine pulses. Breakthrough curves were used to determine KD using the parameter fitting software CXTFIT. Results indicate that as flow rate decreased from 5.3 to 1.8 cm h(-1), KD increased an average of 21%. Additionally, KD determined by column leaching (14.7-22.7 L kg(-1)) was greater than KD determined by a 2h batch equilibrium adsorption (12.6 L kg(-1)). Based on these KD's carbamazepine would be generally characterized as non-mobile in the soil investigated. However, repeated carbamazepine applications resulted in an average 22% decrease in KD between the first and third applications. Decreasing KD is attributed to differences in sorption site kinetics and carbamazepine residence time in contact with the soil. This would indicate that the repeated use of reclaimed wastewater at high application rates for long-term irrigation or groundwater recharge has the potential to lead to greater transport of carbamazepine than KD determined by batch equilibrium would predict. PMID:24050717

Williams, C F; Watson, J E; Nelson, S D

2014-01-01

251

An integrated approach to improved toxicity prediction for the safety assessment during preclinical drug development using Hep G2 cells  

Microsoft Academic Search

Efficient and accurate safety assessment of compounds is extremely important in the preclinical development of drugs especially when hepatotoxicty is in question. Multiparameter and time resolved assays are expected to greatly improve the prediction of toxicity by assessing complex mechanisms of toxicity. An integrated approach is presented in which Hep G2 cells and primary rat hepatocytes are compared in frequently

Fozia Noor; Jens Niklas; Ursula Mueller-Vieira; Elmar Heinzle

2009-01-01

252

Drug quality in South Africa: perceptions of key players involved in medicines distribution  

Microsoft Academic Search

Purpose – Substandard medicines contribute to poor public health and affect development, especially in the developing world. However knowledge of how manufacturers, distributors and providers understand the concept of drug quality and what strategies they adopt to ensure drug quality is limited, particularly in the developing world. The purpose of this paper is to explore pharmaceutical manufacturers', distributors' and providers'

Aarti Patel; Pauline Norris; Robin Gauld; Thomas Rades

2009-01-01

253

Supply Adequacy Assessment of Distribution System Including Wind-Based DG During Different Modes of Operation  

Microsoft Academic Search

Keen interest in the development and utilization of wind-based distributed generation (DG) has been currently observed worldwide. The reliability impact of this highly variable energy source is an important aspect that needs to be assessed as wind power penetration becomes increasingly significant. Distribution system adequacy assessment including wind-based DG units during different modes of operation is described in this paper.

Y. M. Atwa; E. F. El-Saadany; Anne-Claire Guise

2010-01-01

254

The use of 2D fingerprint methods to support the assessment of structural similarity in orphan drug legislation  

PubMed Central

Background In the European Union, medicines are authorised for some rare disease only if they are judged to be dissimilar to authorised orphan drugs for that disease. This paper describes the use of 2D fingerprints to show the extent of the relationship between computed levels of structural similarity for pairs of molecules and expert judgments of the similarities of those pairs. The resulting relationship can be used to provide input to the assessment of new active compounds for which orphan drug authorisation is being sought. Results 143 experts provided judgments of the similarity or dissimilarity of 100 pairs of drug-like molecules from the DrugBank 3.0 database. The similarities of these pairs were also computed using BCI, Daylight, ECFC4, ECFP4, MDL and Unity 2D fingerprints. Logistic regression analyses demonstrated a strong relationship between the human and computed similarity assessments, with the resulting regression models having significant predictive power in experiments using data from submissions of orphan drug medicines to the European Medicines Agency. The BCI fingerprints performed best overall on the DrugBank dataset while the BCI, Daylight, ECFP4 and Unity fingerprints performed comparably on the European Medicines Agency dataset. Conclusions Measures of structural similarity based on 2D fingerprints can provide a useful source of information for the assessment of orphan drug status by regulatory authorities.

2014-01-01

255

Assessing the spatial distribution of nitrogen dioxide in London, Ontario  

Microsoft Academic Search

Land Use Regression (LUR) models have been widely used to characterize the spatial distribution of urban air pollution and estimate exposure in epidemiologic studies. However, spatial patterns of air pollution vary greatly between cities due to local source type and distribution. London is a medium sized city with relatively few and isolated industrial point sources, which allowed the study to

Tor H. Oiamo; Isaac N. Luginaah; Michael Buzzelli; Kathy Tang; Xiaohong Xu; Jeffrey R. Brook; Markey Johnson

2012-01-01

256

On the assessment of adverse drug reactions from spontaneous reporting systems: the influence of under-reporting on odds ratios.  

PubMed

A well-known problem in spontaneous reporting systems (SRSs) for adverse drug reactions (ADRs) is under-reporting, that is, the problem that not all occurrences of ADRs are reported to the SRS. We look at the question of how to draw statistical conclusions from analyses of SRS data using reporting odds ratios. We will show that certain under-reporting problems play no role in assessing ADRs from SRSs: the results from the analyses turn out to be biased by some specific under-reporting problems, but not by others. SRS data can be particularly useful for the assessment of drug-drug interactions. If the assumption holds that there is an under-reporting problem for a first drug, and an under-reporting problem for a second drug, but that these two under-reporting problems do not influence each other, then reporting odds ratios estimated from SRSs are useful for signalling drug-drug interactions in the ADR-experiencing population. Similar results hold for covariate-drug interactions. We illustrate our results using two examples. PMID:12111885

van der Heijden, Peter G M; van Puijenbroek, Eugène P; van Buuren, Stef; van der Hofstede, Jacques W

2002-07-30

257

Development and assessment of conventional and targeted drug combinations for use in the treatment of aggressive breast cancers.  

PubMed

Combination chemotherapy has been at the forefront of cancer treatment for over 40 years. However, the rationale for selecting drug combinations and the process used to demonstrate clinical effectiveness has primarily followed trial and error methodology. Typically, the selection and assessment of combined drug therapies has been based on the effectiveness of each agent as monotherapy in treating the neoplasm and avoiding overlapping toxicities, followed by clinical trials to establish dose scheduling, toxicity, and efficacy. Unfortunately, this scheme is inefficient in terms of the time required to complete and revise these clinical trials based on the outcome to optimize the drug combination. A more rational approach for the development of combination oncology products should consider (i) in vitro assays for assessing therapeutic effects of drug combinations (antagonistic, additive or synergistic interactions) when added simultaneously; (ii) methods for measuring these interactions in vivo; (iii) the importance of understanding pharmacokinetic and biodistribution parameters when using drug combinations; (iv) the need to assess pathways known to contribute to cancer cell survival as well as metastasis; and (iv) the need to assess the fate of different cell populations (cancer and stroma) contributing to the development of cancer. Therefore, the goal of this article is to provide a road map for the preclinical development of drug combination products that will have improved therapeutic activity and a high likelihood of providing beneficial therapeutic outcomes in patients with aggressive cancers with a specific focus on patients with breast cancer. PMID:17017873

Waterhouse, D N; Gelmon, K A; Klasa, R; Chi, K; Huntsman, D; Ramsay, E; Wasan, E; Edwards, L; Tucker, C; Zastre, J; Wang, Y Z; Zhang, Y Z; Yapp, D; Dragowska, W; Dunn, S; Dedhar, S; Bally, M B

2006-09-01

258

Pervasive Technology in Distributed Healthcare: Simultaneous Assessment of Multiple Individuals  

Microsoft Academic Search

The current paradigm of clinic-focused healthcare is challenged by growing numbers of aging baby boomers and the concomitant cost of managing chronic health conditions. We have begun investigating an alternative to clinic-based health assessments, in which pervasive technologies are used to enable continuous monitoring and assessment of patients in a variety of settings outside of hospitals. There are many outstanding

Tamara L. Hayes; Misha Pavel; Andre Adami; Nicole Larimer; Ann Tsay

2006-01-01

259

Distribution of acidic and neutral drugs in surface waters near sewage treatment plants in the lower Great Lakes, Canada.  

PubMed

Prescription and nonprescription drugs have been detected in rivers and streams in Europe and the United States. Sewage treatment plants (STPs) are an important source of these contaminants, but few data exist on the spatial distribution of drugs in surface waters near STPs. Samples of surface water were collected in the summer and fall of 2000 at open-water sites in the lower Great Lakes (Lake Ontario and Lake Erie), at sites near the two STPs for the city of Windsor (ON, Canada), and at sites in Hamilton Harbour (ON, Canada), an embayment of western Lake Ontario that receives discharges from several STPs. In a follow-up study in the summer of 2002, samples of surface water and final effluent from adjacent STPs were collected from sites in Hamilton Harbour and Windsor. In addition, surface water and STP effluent samples were collected in Peterborough (ON, Canada). All samples of surface water and STP effluents were analyzed for selected acidic and neutral drugs. In the survey of Hamilton Harbour and Windsor conducted in 2000, acidic drugs and the antiepileptic drug carbamazepine were detected at ng/L concentrations at sites that were up to 500 m away from the STP, but the hydrological conditions of the receiving waters strongly influenced the spatial distribution of these compounds. Drugs were not detected at open-water locations in western Lake Erie or in the Niagara River near the municipality of Niagara-on-the-Lake (ON, Canada). However, clofibric acid, ketoprofen, fenoprofen, and carbamazepine were detected in samples collected in the summer of 2000 at sites in Lake Ontario and at a site in the Niagara River (Fort Erie, ON, Canada) that were relatively remote from STP discharges. Follow-up studies in the summer of 2002 indicated that concentrations of acidic and neutral drugs in surface waters near the point of sewage discharge into the Little River (ON, Canada) STP were approximately equal to the concentrations in the final effluent from the STP. Caffeine and cotinine, a metabolite of nicotine, were generally present in STP effluents and surface waters contaminated by drugs. The antidepressant fluoxetine and the antibiotic trimethoprom were also detected in most STP effluents and some surface water samples. For the first time, the lipid regulating drug atorvastatin was detected in samples of STP effluent and surface water. PMID:14713027

Metcalfe, Chris D; Miao, Xiu-Sheng; Koenig, Brenda G; Struger, John

2003-12-01

260

A secure distributed logistic regression protocol for the detection of rare adverse drug events  

PubMed Central

Background There is limited capacity to assess the comparative risks of medications after they enter the market. For rare adverse events, the pooling of data from multiple sources is necessary to have the power and sufficient population heterogeneity to detect differences in safety and effectiveness in genetic, ethnic and clinically defined subpopulations. However, combining datasets from different data custodians or jurisdictions to perform an analysis on the pooled data creates significant privacy concerns that would need to be addressed. Existing protocols for addressing these concerns can result in reduced analysis accuracy and can allow sensitive information to leak. Objective To develop a secure distributed multi-party computation protocol for logistic regression that provides strong privacy guarantees. Methods We developed a secure distributed logistic regression protocol using a single analysis center with multiple sites providing data. A theoretical security analysis demonstrates that the protocol is robust to plausible collusion attacks and does not allow the parties to gain new information from the data that are exchanged among them. The computational performance and accuracy of the protocol were evaluated on simulated datasets. Results The computational performance scales linearly as the dataset sizes increase. The addition of sites results in an exponential growth in computation time. However, for up to five sites, the time is still short and would not affect practical applications. The model parameters are the same as the results on pooled raw data analyzed in SAS, demonstrating high model accuracy. Conclusion The proposed protocol and prototype system would allow the development of logistic regression models in a secure manner without requiring the sharing of personal health information. This can alleviate one of the key barriers to the establishment of large-scale post-marketing surveillance programs. We extended the secure protocol to account for correlations among patients within sites through generalized estimating equations, and to accommodate other link functions by extending it to generalized linear models.

El Emam, Khaled; Samet, Saeed; Arbuckle, Luk; Tamblyn, Robyn; Earle, Craig; Kantarcioglu, Murat

2013-01-01

261

Artificial Neural Network Modeling Technique for Voltage Stability Assessment of Radial Distribution Systems  

Microsoft Academic Search

This paper presents an artificial neural network (ANN) based modeling technique for predicting the voltage stability of radial distribution systems. The modeling technique is based on a new voltage stability index for assessment of radial distribution systems Lv . The index is implemented to investigate a 33-bus distribution system. An ANN model which has an input layer with two input

M. M. Hamada; M. A. A. Wahab; N. G. A. Hemdan

2006-01-01

262

The effects of atypical antipsychotics on visceral fat distribution in first episode, drug-naive patients with schizophrenia  

Microsoft Academic Search

The aim of this study was to determine the location of antipsychotic-induced weight gain in drug na??ve, first episode patients with schizophrenia. Various fatness and fat distribution parameters (by Computerized Tomography scanning and anthropometry) and 1600 hr plasma cortisol were measured in 19 (15 men and 4 women) subjects with schizophrenia (mean age = 31.0 years; mean body mass index

Martina C. M Ryan; Susan Flanagan; Una Kinsella; Frank Keeling; Jogin H Thakore

2004-01-01

263

Subcellular daunorubicin distribution and its relation to multidrug resistance phenotype in drug-resistant cell line SMMC-7721\\/R  

Microsoft Academic Search

AIM: To investigate the correlation between subcellular daunorubicin distribution and the multidrug resistance phenotype in drug-resistant cell line SMMC-7721\\/R. METHODS: The multidrug resistant cell line SMMC- 7721\\/R, a human hepatocellular carcinoma cell line, was established. Antisense oligonucleotides (AS-ODN) were used to obtain different multidrug resistance phenotypes by inhibiting the expression of mdr1 gene and\\/or multidrug resistance-related protein gene(mrp) using Lipofectamine

Jia-Yin Yang; Hua-You Luo; Qi-Yuan Lin; Zi-Ming Liu; Lu-Nan Yan; Ping Lin; Jie Zhang; Shong Lei

264

45 CFR 156.295 - Prescription drug distribution and cost reporting.  

Code of Federal Regulations, 2013 CFR

...that were provided under the QHP through retail pharmacies compared to mail order pharmacies, and the percentage of prescriptions for which...compared to all drugs dispensed, broken down by pharmacy type, which includes an independent...

2013-10-01

265

Anti-addiction drug ibogaine inhibits voltage-gated ionic currents: A study to assess the drug's cardiac ion channel profile?  

PubMed Central

The plant alkaloid ibogaine has promising anti-addictive properties. Albeit not licenced as a therapeutic drug, and despite hints that ibogaine may perturb the heart rhythm, this alkaloid is used to treat drug addicts. We have recently reported that ibogaine inhibits human ERG (hERG) potassium channels at concentrations similar to the drugs affinity for several of its known brain targets. Thereby the drug may disturb the heart's electrophysiology. Here, to assess the drug's cardiac ion channel profile in more detail, we studied the effects of ibogaine and its congener 18-Methoxycoronaridine (18-MC) on various cardiac voltage-gated ion channels. We confirmed that heterologously expressed hERG currents are reduced by ibogaine in low micromolar concentrations. Moreover, at higher concentrations, the drug also reduced human Nav1.5 sodium and Cav1.2 calcium currents. Ion currents were as well reduced by 18-MC, yet with diminished potency. Unexpectedly, although blocking hERG channels, ibogaine did not prolong the action potential (AP) in guinea pig cardiomyocytes at low micromolar concentrations. Higher concentrations (? 10 ?M) even shortened the AP. These findings can be explained by the drug's calcium channel inhibition, which counteracts the AP-prolonging effect generated by hERG blockade. Implementation of ibogaine's inhibitory effects on human ion channels in a computer model of a ventricular cardiomyocyte, on the other hand, suggested that ibogaine does prolong the AP in the human heart. We conclude that therapeutic concentrations of ibogaine have the propensity to prolong the QT interval of the electrocardiogram in humans. In some cases this may lead to cardiac arrhythmias.

Koenig, Xaver; Kovar, Michael; Rubi, Lena; Mike, Agnes K.; Lukacs, Peter; Gawali, Vaibhavkumar S.; Todt, Hannes; Hilber, Karlheinz; Sandtner, Walter

2013-01-01

266

An assessment of the use of drug and non-drug interventions in the treatment of Ichthyophthirius multifiliis Fouquet, 1876, a protozoan parasite of freshwater fish.  

PubMed

Infection by the ciliate protozoan Ichthyophthirius multifiliis Fouquet, 1876 causes significant economic losses in freshwater aquaculture worldwide. Following the ban on the use of malachite green for treating food fish, there has been extensive research aimed at identifying suitable replacements. In this paper we critically assess drug and non-drug interventions, which have been tested for use or have been employed against this parasite and evaluate possibilities for their application in farm systems. Current treatments include the administration of formaldehyde, sodium chloride (salt), copper sulphate and potassium permanganate. However, purportedly more environmentally friendly drugs such as humic acid, potassium ferrate (VI), bronopol and the peracetic acid-based products have recently been tested and represent promising alternatives. Further investigation, is required to optimize the treatments and to establish precise protocols in order to minimize the quantity of drug employed whilst ensuring the most efficacious performance. At the same time, there needs to be a greater emphasis placed on the non-drug aspects of management strategies, including the use of non-chemical interventions focusing on the removal of free-swimming stages and tomocysts of I. multifiliis from farm culture systems. Use of such strategies provides the hope of more environmentally friendly alternatives for the control of I. multifiliis infections. PMID:22078025

Picón-Camacho, S M; Marcos-Lopez, M; Bron, J E; Shinn, A P

2012-02-01

267

Recent developments in the risk assessment of potentially genotoxic impurities in pharmaceutical drug substances.  

PubMed

Controlling the quality of medicines is just as important as demonstrating efficacy. The International Conference on Harmonisation has published general guidance on the quality and safety assessment of impurities in pharmaceutical drug substances and drug products. More recently, the European Medicines Evaluation Agency has published a guideline focusing on limits for genotoxic impurities. This is based on a Threshold of Toxicological Concern (TTC) derived from animal carcinogenicity data using multiple worst case assumptions to estimate a daily dose (1.5 microg/day) associated with a lifetime cancer risk of 1 in 100,000, a risk level considered acceptable for genotoxic impurities in human medicines. Based on these assumptions, presentation of the TTC as a single figure infers an unwarranted level of precision and supports the adoption of a more flexible approach by regulatory authorities when evaluating new drug products; a range within fivefold of the TTC limit would seem sensible. Furthermore, the limit is based on 70 years continuous daily exposure, a scenario that is uncommon for most medicines and irrelevant to the preregistration clinical development phase. To address this latter point, a staged TTC has been developed that proposes limits based on shorter durations of treatment, e.g., up to 1 year. Based on recent history, this approach has been acceptable to some authorities but not to others, and it is imperative that steps are taken to reach a common agreement between the pharmaceutical industry and regulatory authorities globally in order that new medicines can continue to be developed and delivered to benefit patients in a safe and timely manner. PMID:17656486

Humfrey, Charles D N

2007-11-01

268

Assessment of Dengue virus helicase and methyltransferase as targets for fragment-based drug discovery.  

PubMed

Seasonal and pandemic flaviviruses continue to be leading global health concerns. With the view to help drug discovery against Dengue virus (DENV), a fragment-based experimental approach was applied to identify small molecule ligands targeting two main components of the flavivirus replication complex: the NS3 helicase (Hel) and the NS5 mRNA methyltransferase (MTase) domains. A library of 500 drug-like fragments was first screened by thermal-shift assay (TSA) leading to the identification of 36 and 32 fragment hits binding Hel and MTase from DENV, respectively. In a second stage, we set up a fragment-based X-ray crystallographic screening (FBS-X) in order to provide both validated fragment hits and structural binding information. No fragment hit was confirmed for DENV Hel. In contrast, a total of seven fragments were identified as DENV MTase binders and structures of MTase-fragment hit complexes were solved at resolution at least 2.0Å or better. All fragment hits identified contain either a five- or six-membered aromatic ring or both, and three novel binding sites were located on the MTase. To further characterize the fragment hits identified by TSA and FBS-X, we performed enzymatic assays to assess their inhibition effect on the N7- and 2'-O-MTase enzymatic activities: five of these fragment hits inhibit at least one of the two activities with IC50 ranging from 180?M to 9mM. This work validates the FBS-X strategy for identifying new anti-flaviviral hits targeting MTase, while Hel might not be an amenable target for fragment-based drug discovery (FBDD). This approach proved to be a fast and efficient screening method for FBDD target validation and discovery of starting hits for the development of higher affinity molecules that bind to novel allosteric sites. PMID:24704437

Coutard, Bruno; Decroly, Etienne; Li, Changqing; Sharff, Andrew; Lescar, Julien; Bricogne, Gérard; Barral, Karine

2014-06-01

269

Project Towards No Drug Abuse (TND): Needs Assessment of a Social Service Referral Telephone Program for High Risk Youth  

PubMed Central

The purpose of this study was to conduct a needs assessment of a potential social service resource telephone program component among high risk youth who received the Project Towards No Drug Abuse (TND) classroom-based program (approximately 1 year earlier). Results supported youths’ overwhelming receptiveness of a social service referral program. The vast majority of respondents indicated a strong desire for resource and referral information on vocational, educational, recreational, transportation, and mental health and drug counseling. Further research is needed to investigate the effectiveness of the provision of social service resource information on drug use among emerging adults.

SUSSMAN, STEVE; SKARA, SILVANA; PUMPUANG, PATCHAREEYA

2011-01-01

270

Initial volume of a drug before it reaches the volume of distribution: pharmacokinetics of F(ab')2 antivenoms and other drugs.  

PubMed

Fast disappearance of F(ab')2 antivenoms from the plasma compartment [Sevcik et al., 2004. Modelling Tityus scorpion venom and antivenom pharmacokinetics. Evidence of active immunoglobulin G's F(ab')2 extrusion mechanism from blood to tissues. Toxicon 44, 731-734; Vazquez et al., 2005. Pharmacokinetics of a F(ab')2 scorpion antivenom in healthy human volunteers. Toxicon 46, 797-805] suggests a quick time course to reach its final distribution volume. An equation was developed to describe how the volume occupied by a drug in the body grows with time. As discussed in the paper this equation is free of some shortcomings of an equation developed for the same purpose by Niazi [1976. Volume of distribution as a function of time. J. Pharm. Sci. 65, 452-454]. Fluorescence microscopy showed that the rapid initial decay in plasmatic F(ab')2 concentration may be related to uptake of F(ab')2 by vascular endothelium which, in combination with accumulation in the vascular wall connective tissue, may produce an intermediate plateau in F(ab')2 V(sl)(t), which reached its final value after 10 h. The V(sl)(t) equation predicts that the plasma concentration half-time of decay has little use to estimate how a drug distributes through the body to exert its action, and predicts that, in some instances, intermediate plateaus in the time course of V(sl)(t) exist. Data from the literature showed that the kinetic considerations for V(sl)(t) also apply to clevidipine, digoxin, digitoxin, lidocaine and thiopentone. PMID:17689580

Sevcik, Carlos; Salazar, Victor; Díaz, Patricia; D'Suze, Gina

2007-10-01

271

Using zebrafish to assess the impact of drugs on neural development and function  

PubMed Central

Background Zebrafish is becoming an increasingly attractive model organism for understanding biology and developing therapeutics, because as a vertebrate, it shares considerable similarity with mammals in both genetic compositions and tissue/organ structures, and yet remains accessible to high throughput phenotype-based genetic and small molecule compound screening. Objective/method The focus of this review is on the nervous system, which is arguably the most complex organ and known to be afflicted by more than six hundred disorders in humans. I discuss the past, present, and future of using zebrafish to assess the impact of small molecule drugs on neural development and function, in light of understanding and treating neurodevelopmental disorders such as autism, neurodegenerative disorders including Alzheimer’s, Parkinson’s, and Hungtington’s disease, and neural system dysfunctions such as anxiety/depression and addiction. Conclusion These studies hold promise to reveal fundamental mechanisms governing nervous system development and function, and to facilitate small molecule drug discovery for the many types of neurological disorders.

Guo, Su

2009-01-01

272

Quantitative assessment of cumulative carcinogenic risk for multiple genotoxic impurities in a new drug substance.  

PubMed

In pharmaceutical development, significant effort is made to minimize the carcinogenic potential of new drug substances (NDS). This involves appropriate genotoxicity and carcinogenicity testing of the NDS, and understanding the genotoxic potential of its impurities. Current available guidance recommends the use of the threshold of toxicological concern (TTC) for a single impurity where mutagenicity but no carcinogenicity information exists. Despite best efforts, the presence of more than one genotoxic impurity in an NDS may occur at trace levels. This paper repeats the analysis performed by others for a single genotoxic compound, but also uses statistical simulations to assess the impact on cancer risk for a mixture of genotoxic compounds. In summary, with the addition of multiple impurities all controlled to the TTC, an increase in cancer risk was observed. This increase is relatively small when considering the conservative assumptions of the TTC. If structurally similar compounds had an assumed strong correlation (+/-10-fold from the first randomly selected impurity) in cancer potency, the resulting cancer risk was not negatively impacted. Findings based on probabilistic analysis here can be very useful in making appropriate decisions about risk management of multiple genotoxic impurities measured in the final drug substance. PMID:18550240

Bercu, Joel P; Hoffman, Wherly P; Lee, Cindy; Ness, Daniel K

2008-08-01

273

Assessment of Therapeutic Drug Monitoring of Vancomycin in Elderly Patients According to New Guidelines  

PubMed Central

Background Concerns regarding increasing microbial resistance to vancomycin have resulted in recommendations for a higher trough serum vancomycin concentration. This study aimed to assess the dosage guidelines targeting vancomycin trough concentrations of 15-20 mg/L. Methods About 216 adult patients (age, >60 yr) were treated with intravenous vancomycin. The patients were divided into 2 groups according to their target vancomycin trough concentrations: the previous guideline group (n=108) treated with targeted vancomycin trough concentrations of 5-15 mg/L from Jan 2009 through April 2011 and the new guideline group (n=108) treated with targeted concentrations of 15-20 mg/L from November 2011 through July 2012. Results The 2 groups were not significantly different with respect to age, weight, initial serum creatinine, initial creatinine clearance, predictive trough levels, doses, serum drug concentrations, and area under the curve/minimal inhibitory concentrations. Regarding the proportions of vancomycin trough concentrations, the target range was achieved in 50% in the previous guideline group and in 16% in the new guideline group. In the previous and new guideline groups, the trough concentrations of 10-20 mg/dL were observed in 32.4% and 52.8% patients, respectively, and those of <10 mg/L were observed in 45.4% and 29.6%, respectively. Conclusions Compared to the previous guideline group, the new guideline group showed higher proportions in the therapeutic range of 10-20 mg/L and lower proportions in trough concentrations <10 mg/L. The strictly managed vancomycin therapeutic drug monitoring in the new guideline group was assessed as more effective.

Oh, Se Jin; Lee, Eun Jeong; Choi, Hee Jung; Kong, Kyoung Ae; Lee, Miae; Chung, Wha Soon

2014-01-01

274

Rapid assessment response (RAR) study: drug use and health risk - Pretoria, South Africa  

Microsoft Academic Search

Background  Within a ten year period South Africa has developed a substantial illicit drug market. Data on HIV risk among drug using populations\\u000a clearly indicate high levels of HIV risk behaviour due to the sharing of injecting equipment and\\/or drug-related unprotected\\u000a sex. While there is international evidence on and experience with adequate responses, limited responses addressing drug use\\u000a and drug-use-related HIV

Monika ML dos Santos; Franz Trautmann; John-Peter Kools

2011-01-01

275

ASSESSMENT AND IMPLICATIONS OF BACTERIAL REGROWTH IN WATER DISTRIBUTION SYSTEMS  

EPA Science Inventory

Two water distribution systems were studied over a 1-year period. Temporal fluctuations in a number of physical, chemical and biological parameters were examined. Total and pigmented bacterial counts, total coliforms, and fecal coliforms were determined at four locations within e...

276

Assessing a Tornado Climatology from Global Tornado Intensity Distributions  

Microsoft Academic Search

Recent work demonstrated that the shape of tornado intensity distributions from various regions worldwide is well described by Weibull functions. This statistical modeling revealed a strong correlation between the fit parameters c for shape and b for scale regardless of the data source. In the present work it is shown that the quality of the Weibull fits is optimized if

Bernold Feuerstein; Nikolai Dotzek; Jürgen Grieser

2005-01-01

277

Distributive Fluvial Systems of the Chaco Plain - Satellite Image Assessment of Fluvial Form and Facies Distributions  

Microsoft Academic Search

Distributive fluvial systems (DFS) dominate fluvial deposition inside modern continental sedimentary basins and are particularly extensive in modern foreland basins. The largest of these DFS are found in the Chaco Plain, Andean Foreland Basin, South America. We use published literature, field and satellite data (Landsat, Modis, and SRTM) to construct preliminary hypotheses about the geomorphic form and fluvial facies distributions

G. S. Weissmann; A. J. Hartley; L. Scuderi; P. Bhattacharyya; H. Buehler; S. Leleu; A. Mather

2009-01-01

278

Pathway-dependent inhibition of paclitaxel hydroxylation by kinase inhibitors and assessment of drug-drug interaction potentials.  

PubMed

Paclitaxel is often used in combination with small molecule kinase inhibitors to enhance antitumor efficacy against various malignancies. Because paclitaxel is metabolized by CYP2C8 and CYP3A4, the possibility of drug-drug interactions mediated by enzyme inhibition may exist between the combining agents. In the present study, a total of 12 kinase inhibitors were evaluated for inhibitory potency in human liver microsomes by monitoring the formation of CYP2C8 and CYP3A4 metabolites simultaneously. For reversible inhibition, nilotinib was found to be the most potent inhibitor against both CYP2C8 and CYP3A4, and the inhibition potency could be explained by strong hydrogen binding based on molecular docking simulations and type II binding based on spectral analysis. Comparison of K(i) values revealed that the CYP2C8 pathway was more sensitive toward some kinase inhibitors (such as axitinib), while the CYP3A4 pathway was preferentially inhibited by others (such as bosutinib). Pathway-dependent inactivation (time-dependent inhibition) was also observed for a number of kinase inhibitors against CYP3A4 but not CYP2C8. Further studies showed that axitinib had a K(I) of 0.93 ?M and k(inact) of 0.0137 min(-1), and the observed inactivation toward CYP3A4 was probably due to the formation of reactive intermediate(s). Using a static model, a reasonably accurate prediction of drug-drug interactions was achieved by incorporating parallel pathways and hepatic extraction ratio. The present results suggest that potent and pathway-dependent inhibition of CYP2C8 and/or CYP3A4 pathways by kinase inhibitors may alter the ratio of paclitaxel metabolites in vivo, and that such changes can be clinically relevant as differential metabolism has been linked to paclitaxel-induced neurotoxicity in cancer patients. PMID:24476576

Wang, Yedong; Wang, Meiyu; Qi, Huixin; Pan, Peichen; Hou, Tingjun; Li, Jiajun; He, Guangzhao; Zhang, Hongjian

2014-04-01

279

Condition Assessment Modeling for Distribution Systems Using Shared Frailty Analysis  

EPA Science Inventory

Condition Assessment (CA) modeling is drawing increasing interest as a methodology for managing drinking water infrastructure. This paper develops a Cox Proportional Hazard (PH)/shared frailty model and applies it to the problem of investment in the repair and replacement of dri...

280

Assessing drug use during follow-up: direct comparison of candidate outcome definitions in pooled analyses of addiction treatment studies  

PubMed Central

Background Selection of appropriate outcome measures is important for clinical studies of drug addiction treatment. Researchers use various methods of collecting drug use outcomes and must consider substances to be included in a urine drug screen (UDS); accuracy of self-report; use of various instruments and procedures for collecting self-reported drug use; and timing of outcome assessments. Objectives We sought to define a set of candidate measures to 1) assess their inter-correlation, and 2) identify any differences in results. Methods Data were combined from completed protocols in the National Institute on Drug Abuse Clinical Trials Network (CTN), with a total of 1897 participants. We defined nine outcome measures based on UDS, self-report, or a combination. Multivariable, multilevel GEE models were used to assess subgroup differences in intervention success, controlling for baseline differences and accounting for clustering by CTN protocols. Results There were high correlations among all candidate outcomes. All outcomes showed consistent overall results with no significant intervention impact on drug use during follow-up. However, with most UDS variables, but not with self-report or “corrected self-report”, we observed a significant gender-ethnicity interaction with benefit shown in African American women, white women, and Hispanic men. Conclusion Despite strong associations between candidate measures, we found some important differences in results. Scientific Significance In this study, we demonstrated the potential utility and impact of combining UDS and self-report data for drug use assessment. Our results suggest possible differences in intervention efficacy by gender and ethnicity, but highlight the need to cautiously interpret observed interactions.

Korte, Jeffrey E.; Magruder, Kathy M.; Chiuzan, Cody; Logan, Sarah; Killeen, Therese; Bandyopadhyay, Dipankar; Brady, Kathleen T.

2011-01-01

281

Assessment of Distributed Generation Potential in JapaneseBuildings  

SciTech Connect

To meet growing energy demands, energy efficiency, renewable energy, and on-site generation coupled with effective utilization of exhaust heat will all be required. Additional benefit can be achieved by integrating these distributed technologies into distributed energy resource (DER) systems (or microgrids). This research investigates a method of choosing economically optimal DER, expanding on prior studies at the Berkeley Lab using the DER design optimization program, the Distributed Energy Resources Customer Adoption Model (DER-CAM). DER-CAM finds the optimal combination of installed equipment from available DER technologies, given prevailing utility tariffs, site electrical and thermal loads, and a menu of available equipment. It provides a global optimization, albeit idealized, that shows how the site energy loads can be served at minimum cost by selection and operation of on-site generation, heat recovery, and cooling. Five prototype Japanese commercial buildings are examined and DER-CAM applied to select the economically optimal DER system for each. The five building types are office, hospital, hotel, retail, and sports facility. Based on the optimization results, energy and emission reductions are evaluated. Furthermore, a Japan-U.S. comparison study of policy, technology, and utility tariffs relevant to DER installation is presented. Significant decreases in fuel consumption, carbon emissions, and energy costs were seen in the DER-CAM results. Savings were most noticeable in the sports facility (a very favourable CHP site), followed by the hospital, hotel, and office building.

Zhou, Nan; Marnay, Chris; Firestone, Ryan; Gao, Weijun; Nishida,Masaru

2005-05-25

282

A novel flow through diffusion cell for assessing drug transport across the buccal mucosa in vitro.  

PubMed

A novel flow through (FT) diffusion cell for assessing the permeability of compounds across the buccal mucosa was designed. Porcine buccal mucosa was mounted between two chambers with flow through capacity in both the donor and receptor chambers. The permeability of caffeine (CAF), triamcinolone acetonide (TAC), and estradiol (E(2)) was determined over 4 h and flux values were compared to those obtained using a modified Ussing chamber (MUC). No significant differences in the flux of each probe compound were observed using either the MUC or the novel FT cell. The design of the FT cell allowed for monitoring appearance of receptor solution within the donor chamber during the initial equilibration period, allowing for visual inspection of tissue integrity. These permeability studies demonstrate that this FT cell is a suitable alternative model for assessing drug permeability across the buccal mucosa, without the limitations associated with the static MUC. This novel model was then utilized to determine whether salmeterol xinafoate (SX) could permeate the buccal mucosa at concentrations expected in the oral cavity following inhalation. Concentration-dependent studies demonstrated that SX permeates the buccal mucosa via passive diffusion and that oral mucosal absorption may contribute significantly to the overall systemic exposure of inhaled SX. PMID:19408309

Lestari, Maria L A D; Nicolazzo, Joseph A; Finnin, Barrie C

2009-12-01

283

Hazard analysis and risk assessment in the development of biomedical drug formulation equipment.  

PubMed

Hazard analysis and risk assessment techniques are utilized within many private sector industries and government agencies, including the medical device and pharmaceutical industry, within a structured process to control human injuries and environmental and property damage. In the U.S. the Federal Drug Administration (FDA) requires a hazard analysis be performed on all medical devices. While there are biomedical engineering applications reported which deal with human hazards in clinical, patient care environment, no previous studies extend these traditional techniques to a university-based, research environment. This study applies a tiered approach to hazard analysis and risk assessment to a biomedical, university-based, research environment in the design of a high throughput platform that screens chemical excipients (additives) for their ability to increase protein solubility. Each design stage (conceptual, preliminary, system, and detailed) requires a unique hazard analysis technique based on available information. The analysis techniques applied here are evaluated for their use in a biomedical research environment where experiment accuracy is a primary concern. PMID:22068884

Johnson, David H; Bidez, Martha W; Delucas, Lawrence J

2012-04-01

284

Development of novel, 384-well high-throughput assay panels for human drug transporters: drug interaction and safety assessment in support of discovery research.  

PubMed

Transporter proteins are known to play a critical role in affecting the overall absorption, distribution, metabolism, and excretion characteristics of drug candidates. In addition to efflux transporters (P-gp, BCRP, MRP2, etc.) that limit absorption, there has been a renewed interest in influx transporters at the renal (OATs, OCTs) and hepatic (OATPs, BSEP, NTCP, etc.) organ level that can cause significant clinical drug-drug interactions (DDIs). Several of these transporters are also critical for hepatobiliary disposition of bilirubin and bile acid/salts, and their inhibition is directly implicated in hepatic toxicities. Regulatory agencies took action to address transporter-mediated DDI with the goal of ensuring drug safety in the clinic and on the market. To meet regulatory requirements, advanced bioassay technology and automation solutions were implemented for high-throughput transporter screening to provide structure-activity relationship within lead optimization. To enhance capacity, several functional assay formats were miniaturized to 384-well throughput including novel fluorescence-based uptake and efflux inhibition assays using high-content image analysis as well as cell-based radioactive uptake and vesicle-based efflux inhibition assays. This high-throughput capability enabled a paradigm shift from studying transporter-related issues in the development space to identifying and dialing out these concerns early on in discovery for enhanced mechanism-based efficacy while circumventing DDIs and transporter toxicities. PMID:24062352

Tang, Huaping; Shen, Ding Ren; Han, Yong-Hae; Kong, Yan; Balimane, Praveen; Marino, Anthony; Gao, Mian; Wu, Sophie; Xie, Dianlin; Soars, Matthew G; O'Connell, Jonathan C; Rodrigues, A David; Zhang, Litao; Cvijic, Mary Ellen

2013-10-01

285

Pollution Prevention Opportunity Assessment, United States Postal Service Stamp Distribution Center, Kansas City, Missouri.  

National Technical Information Service (NTIS)

In this report, the findings of the Pollution Prevention Opportunity Assessment of the United States Postal Service, Stamp Distribution Network (SDN), located in Kansas City, Missouri are described. This report describes the mission of each of the functio...

C. O. Bell M. Hoel H. Huppert S. Rolander

1996-01-01

286

Pollution Prevention Opportunity Assessment, United States Postal Service Materials Distribution Center, Topeka, Kansas.  

National Technical Information Service (NTIS)

In this report, the findings of the Pollution Prevention Opportunity Assessment of the United States Postal Service, Materials Distribution Center, Central Repair Facility, and Label Printing Center located in Topeka, Kansas are described. The report desc...

C. O. Bell M. Hoel H. Huppert S. Rolander

1996-01-01

287

Economic Assessment of Guided Extended-Range Boring Systems for Installing Gas Distribution Pipe.  

National Technical Information Service (NTIS)

Applications and economic value of guided extended-range boring systems (EBS) for installing gas distribution pipe is assessed. The system is comprised of surface drilling frame, pipe-mounted mechanical boring and steering hardware and electronic guidance...

G. T. Pittard

1986-01-01

288

Assessment of drug release from oil depot formulations using an in vitro model -- potential applicability in accelerated release testing.  

PubMed

In vitro drug release and transport rates from oil depot formulations under nonsink conditions have been investigated in the rotating dialysis cell model. Eight model drug compounds and eight oil vehicle compositions were used for the releaseexperiments. The experimentally obtained apparent first-order rate constants related to the drug appearance in the acceptor phase after initial instillation of a drug-containing oil solution were found to be in excellent agreement with the rate constants obtained from a theoretically derived expression. It was observed that the drug oil-water distribution coefficient was the key parameter influencing the release characteristics. As compared with ketoprofen, flurbiprofen exhibited a higher affinity for the oil, resulting in a significantly lower and more slowly decreasing drug concentrations in the aqueous donor compartment. Release profiles for prilocaine and the more lipophilic agent bupivacaine after incorporation of both drugs in fractionated coconut oil were characterized by a fast release of prilocaine, whereas bupivacaine was liberated much slower to the acceptor phase. The high oil-buffer interfacial area generated in vitro by rotation of the donor cell tends to overestimate release rates in comparison to those expected in vivo, for example, after intra-articular administration of oil solutions. The present in vitro method may constitute a valuable tool in accelerated in vitro release testing of parenteral oil depot formulations in areas comprising formulation design and product quality control. PMID:18363145

Larsen, Susan Weng; Jessen, Marit N B; Ostergaard, Jesper; Larsen, Claus

2008-03-01

289

Can Brazil play a more important role in global tuberculosis drug production? An assessment of current capacity and challenges  

PubMed Central

Background Despite the existence of effective treatment, tuberculosis is still a global public health issue. The World Health Organization recommends a six-month four-drug regimen in fixed-dose combination formulation to treat drug sensitive tuberculosis, and long course regimens with several second-line drugs to treat multi-drug resistant tuberculosis. To achieve the projected tuberculosis elimination goal by 2050, it will be essential to ensure a non-interrupted supply of quality-assured tuberculosis drugs. However, quality and affordable tuberculosis drug supply is still a significant challenge for National Tuberculosis Programs. Discussion Quality drug production requires a combination of complex steps. The first challenge is to guarantee the quality of tuberculosis active pharmaceutical ingredients, then ensure an adequate manufacturing process, according to international standards, to guarantee final product´s safety, efficacy and quality. Good practices for storage, transport, distribution and quality control procedures must follow. In contrast to other high-burden countries, Brazil produces tuberculosis drugs through a strong network of public sector drug manufacturers regulated by a World Health Organization-certified national sanitary authority. The installed capacity for production surpasses the 71,000 needed treatments in the country. However, in order to be prepared to act as a global supplier, important bottlenecks are to be overcome. This article presents an in-depth analysis of the current status of production of tuberculosis drugs in Brazil and the bottlenecks and opportunities for the country to sustain national demand and play a role as a potential global supplier. Raw material and drug production, quality control, international certification and pre-qualification, political commitment and regulatory aspects are discussed, as well recommendations for tackling these bottlenecks. This discussion becomes more important as new drugs and regimens to treat tuberculosis are expected in a close future. Summary International manufacturers of raw material for tuberculosis treatment should undergo certification and pre-qualify their active pharmaceutical ingredients as a first step to ensure quality of tuberculosis drugs. At the country level, Brazilian public manufacturers should apply for international certification and tuberculosis drugs should be pre-qualified by international organisms. Finally, only with political commitment and large-scale production will Brazilian public sector manufacturers be able to partially supply the global market.

2013-01-01

290

Assessing the spatial distribution of nitrogen dioxide in London, Ontario.  

PubMed

Land use regression (LUR) models have been widely used to characterize the spatial distribution of urban air pollution and estimate exposure in epidemiologic studies. However, spatial patterns of air pollution vary greatly between cities due to local source type and distribution. London, Ontario, Canada, is a medium-sized city with relatively few and isolated industrial point sources, which allowed the study to focus on the contribution of different transportation sectors to urban air pollution. This study used LUR models to estimate the spatial distribution of nitrogen dioxide (NO2) and to identify local sources influencing NO2 concentrations in London, ON. Passive air sampling was conducted at 50 locations throughout London over a 2-week period in May-June 2010. NO2 concentrations at the monitored locations ranged from 2.8 to 8.9 ppb, with a median of 5.2 ppb. Industrial land use, dwelling density, distance to highway, traffic density, and length of railways were significant predictors of NO2 concentrations in the final LUR model, which explained 78% of NO2 variability in London. Traffic and dwelling density explained most of the variation in NO2 concentrations, which is consistent with LUR models developed in other Canadian cities. We also observed the importance of local characteristics. Specifically, 17% of the variation was explained by distance to highways, which included the impacts of heavily traveled corridors transecting the southern periphery of the city. Two large railway yards and railway lines throughout central areas of the city explained 9% of NO2 variability. These results confirm the importance of traditional LUR variables and highlight the importance of including a broader array of local sources in LUR modeling. Finally, future analyses will use the model developed in this study to investigate the association between ambient air pollution and cardiovascular disease outcomes, including plaque burden, cholesterol, and hypertension. PMID:23210225

Oiamo, Tor H; Luginaah, Isaac N; Buzzelli, Michael; Tang, Kathy; Xu, Xiaohong; Brook, Jeffrey R; Johnson, Markey

2012-11-01

291

Assessing human vulnerability: Daytime residential distribution as a vulnerability indicator  

NASA Astrophysics Data System (ADS)

Natural hazard risk management is based on detailed information on potential impacts of natural hazards. Especially concerning fast onset hazards such as flash floods, earthquakes but also debris flows and landslides, knowing potential hotspots of impact to both, assets and human lives is essential. This information is important for emergency management and decision making in the response phase of the disaster management cycle. Emergency managers are in need of information regarding not only the number of humans being potentially affected but also the respective vulnerability of the group affected based on characteristics such as age, income, health condition, mobility, etc. regarding a certain hazard. The analysis presented focuses on the distribution of the population, assuming a certain pattern of people in a certain radius of action. The method applied is based on a regular pattern of movement of different groups of people and a pattern of presence in certain units, e.g. schools, businesses or residential buildings. The distribution is calculated on a minimum of available data including the average household size, as well as information on building types. The study area is located in the Southwest of Lower Austria, Austria. The city of Waidhofen/Ybbs can be regarded as a regional center providing basic infrastructure, shops and schools. The high concentration of buildings combining shops and residential units leads to a high damage potential throughout the whole study area. The presented results indicate the population distribution within the study area on an average working day. It is clear that explicitly high numbers of people are located in specific buildings (e.g. schools and hospitals) which also include highly vulnerable groups especially to fast onset hazards. The results provide emergency services with the information that they need in order to intervene directly where large numbers of victims or people that need to be evacuated are located. In this way, emergency services can focus and prioritize their actions in order to save lives and reduce the number of potential victims.

Gokesch, Karin; Promper, Catrin; Papathoma-Köhle, Maria; Glade, Thomas

2014-05-01

292

Biotransformation and in vitro assessment of metabolism-associated drug-drug interaction for CRx-102, a novel combination drug candidate.  

PubMed

CRx-102 is an oral synergistic combination drug which contains the cardiovascular agent, dipyridamole (DP) and a very low dose of the glucocorticoid, prednisolone (PRED). CRx-102 works through a novel mechanism of action in which DP selectively amplifies the anti-inflammatory activity of PRED without replicating its side effects. CRx-102 is in clinical trials for the treatment of osteoarthritis. Here we delineate the in vitro metabolism and explore the potential for a drug-drug interaction between the active agents in CRx-102. Our study using human hepatocyte suspensions showed that both DP and PRED were metabolized by CYP3A4 isozymes, resulting in the formation of diverse arrays of both oxidative and oxidative-reduced metabolites. Within phase 1 biotransformation, CYP3A4 was one of the pathways responsible for the metabolism of PRED, while phase 2 biotransformation played a significant role in the metabolism of DP. Glucuronidation of DP was substantial and was catalyzed by many UGT members, specifically those in the UGT1A subfamily. Based on the tandem mass (MS/MS) product ion spectra (PIS) acquired, the major metabolites of both agents, namely, monooxygenated, mono-N-deethanolaminated, dehydrogenated and O-glucuronidated metabolites of DP and the monooxygenated (e.g., 6-hydroxyl), dehydrogenated (prednisone) and reduced (20-hydroxyl) metabolites of PRED, were identified and elucidated. The affinities for DP biotransformation, including CYP3A4-mediated oxidative pathways and UGT-mediated O-glucuronidation, appeared high (K(m)<10 microM), as compared with the modest affinities of PRED biotransformation catalyzed by CYP3A4 (K(m) approximately 40-170 microM). DP, but not PRED, exerted a minimal inhibitory effect on the drug-metabolizing CYP isoforms, including CYP3A4, which was determined using a panel of CYP isoform-preferred substrate activities in pooled human liver microsomal (HLM) preparations and microsomal preparations containing the recombinant enzymes (K(i) approximately 2-12 microM). Using the DP maximal plasma concentration (C(max)) observed in the clinic and a predictive mathematical model for metabolism-associated drug-drug interaction (DDI), we have demonstrated that there is little likelihood of a pharmacokinetic interaction between the two active agents in CRx-102. PMID:19467820

Zhang, Zhi-Yi; Chen, Mei; Chen, Jennifer; Padval, Mahesh V; Kansra, Vikram V

2009-09-01

293

A distributed, collaborative intelligent agent system approach for proactive postmarketing drug safety surveillance.  

PubMed

Discovering unknown adverse drug reactions (ADRs) in postmarketing surveillance as early as possible is of great importance. The current approach to postmarketing surveillance primarily relies on spontaneous reporting. It is a passive surveillance system and limited by gross underreporting (<10% reporting rate), latency, and inconsistent reporting. We propose a novel team-based intelligent agent software system approach for proactively monitoring and detecting potential ADRs of interest using electronic patient records. We designed such a system and named it ADRMonitor. The intelligent agents, operating on computers located in different places, are capable of continuously and autonomously collaborating with each other and assisting the human users (e.g., the food and drug administration (FDA), drug safety professionals, and physicians). The agents should enhance current systems and accelerate early ADR identification. To evaluate the performance of the ADRMonitor with respect to the current spontaneous reporting approach, we conducted simulation experiments on identification of ADR signal pairs (i.e., potential links between drugs and apparent adverse reactions) under various conditions. The experiments involved over 275,000 simulated patients created on the basis of more than 1000 real patients treated by the drug cisapride that was on the market for seven years until its withdrawal by the FDA in 2000 due to serious ADRs. Healthcare professionals utilizing the spontaneous reporting approach and the ADRMonitor were separately simulated by decision-making models derived from a general cognitive decision model called fuzzy recognition-primed decision (RPD) model that we recently developed. The quantitative simulation results show that 1) the number of true ADR signal pairs detected by the ADRMonitor is 6.6 times higher than that by the spontaneous reporting strategy; 2) the ADR detection rate of the ADRMonitor agents with even moderate decision-making skills is five times higher than that of spontaneous reporting; and 3) as the number of patient cases increases, ADRs could be detected significantly earlier by the ADRMonitor. PMID:20007038

Ji, Yanqing; Ying, Hao; Farber, Margo S; Yen, John; Dews, Peter; Miller, Richard E; Massanari, R Michael

2010-05-01

294

A Distributed, Collaborative Intelligent Agent System Approach for Proactive Postmarketing Drug Safety Surveillance  

PubMed Central

Discovering unknown adverse drug reactions (ADRs) in postmarketing surveillance as early as possible is of great importance. The current approach to postmarketing surveillance primarily relies on spontaneous reporting. It is a passive surveillance system and limited by gross underreporting (<10% reporting rate), latency, and inconsistent reporting. We propose a novel team-based intelligent agent software system approach for proactively monitoring and detecting potential ADRs of interest using electronic patient records. We designed such a system and named it ADRMonitor. The intelligent agents, operating on computers located in different places, are capable of continuously and autonomously collaborating with each other and assisting the human users (e.g., the food and drug administration (FDA), drug safety professionals, and physicians). The agents should enhance current systems and accelerate early ADR identification. To evaluate the performance of the ADRMonitor with respect to the current spontaneous reporting approach, we conducted simulation experiments on identification of ADR signal pairs (i.e., potential links between drugs and apparent adverse reactions) under various conditions. The experiments involved over 275 000 simulated patients created on the basis of more than 1000 real patients treated by the drug cisapride that was on the market for seven years until its withdrawal by the FDA in 2000 due to serious ADRs. Healthcare professionals utilizing the spontaneous reporting approach and the ADRMonitor were separately simulated by decision-making models derived from a general cognitive decision model called fuzzy recognition-primed decision (RPD) model that we recently developed. The quantitative simulation results show that 1) the number of true ADR signal pairs detected by the ADRMonitor is 6.6 times higher than that by the spontaneous reporting strategy; 2) the ADR detection rate of the ADRMonitor agents with even moderate decision-making skills is five times higher than that of spontaneous reporting; and 3) as the number of patient cases increases, ADRs could be detected significantly earlier by the ADRMonitor.

Ji, Yanqing; Ying, Hao; Farber, Margo S.; Yen, John; Dews, Peter; Miller, Richard E.; Massanari, R. Michael

2014-01-01

295

Development of an Adverse Drug Reaction Risk Assessment Score among Hospitalized Patients with Chronic Kidney Disease  

PubMed Central

Background Adverse drug reactions (ADRs) represent a major burden on the healthcare system. Chronic kidney disease (CKD) patients are particularly vulnerable to ADRs because they are usually on multiple drug regimens, have multiple comorbidities, and because of alteration in their pharmacokinetics and pharmacodynamic parameters. Therefore, one step towards reducing this burden is to identify patients who are at increased risk of an ADR. Objective To develop a method of identifying CKD patients who are at increased risk for experiencing ADRs during hospitalisation. Materials and Methods Factors associated with ADRs were identified by using demographic, clinical and laboratory variables of patients with CKD stages 3 to 5 (estimated glomerular filtration rate, 10–59 ml/min/1.73 m2) who were admitted between January 1, 2012, and December 31, 2012, to the renal unit of Dubai Hospital. An ADR risk score was developed by constructing a series of logistic regression models. The overall model performance for sequential models was evaluated using Akaike Information Criterion for goodness of fit. Odd ratios of the variables retained in the best model were used to compute the risk scores. Results Of 512 patients (mean [SD] age, 60 [16] years), 62 (12.1%) experienced an ADR during their hospitalisation. An ADR risk score included age 65 years or more, female sex, conservatively managed end-stage renal disease, vascular disease, serum level of C-reactive protein more than 10 mg/L, serum level of albumin less than 3.5 g/dL, and the use of 8 medications or more during hospitalization. The C statistic, which assesses the ability of the risk score to predict ADRs, was 0.838; 95% CI, 0.784–0.892). Conclusion A score using routinely available patient data can be used to identify CKD patients who are at increased risk of ADRs.

Saheb Sharif-Askari, Fatemeh; Syed Sulaiman, Syed Azhar; Saheb Sharif-Askari, Narjes; Al Sayed Hussain, Ali

2014-01-01

296

Transmission Assessment Surveys (TAS) to Define Endpoints for Lymphatic Filariasis Mass Drug Administration: A Multicenter Evaluation  

PubMed Central

Background Lymphatic filariasis (LF) is targeted for global elimination through treatment of entire at-risk populations with repeated annual mass drug administration (MDA). Essential for program success is defining and confirming the appropriate endpoint for MDA when transmission is presumed to have reached a level low enough that it cannot be sustained even in the absence of drug intervention. Guidelines advanced by WHO call for a transmission assessment survey (TAS) to determine if MDA can be stopped within an LF evaluation unit (EU) after at least five effective rounds of annual treatment. To test the value and practicality of these guidelines, a multicenter operational research trial was undertaken in 11 countries covering various geographic and epidemiological settings. Methodology The TAS was conducted twice in each EU with TAS-1 and TAS-2 approximately 24 months apart. Lot quality assurance sampling (LQAS) formed the basis of the TAS survey design but specific EU characteristics defined the survey site (school or community), eligible population (6–7 year olds or 1st–2nd graders), survey type (systematic or cluster-sampling), target sample size, and critical cutoff (a statistically powered threshold below which transmission is expected to be no longer sustainable). The primary diagnostic tools were the immunochromatographic (ICT) test for W. bancrofti EUs and the BmR1 test (Brugia Rapid or PanLF) for Brugia spp. EUs. Principal Findings/Conclusions In 10 of 11 EUs, the number of TAS-1 positive cases was below the critical cutoff, indicating that MDA could be stopped. The same results were found in the follow-up TAS-2, therefore, confirming the previous decision outcome. Sample sizes were highly sex and age-representative and closely matched the target value after factoring in estimates of non-participation. The TAS was determined to be a practical and effective evaluation tool for stopping MDA although its validity for longer-term post-MDA surveillance requires further investigation.

Chu, Brian K.; Deming, Michael; Biritwum, Nana-Kwadwo; Bougma, Windtare R.; Dorkenoo, Ameyo M.; El-Setouhy, Maged; Fischer, Peter U.; Gass, Katherine; Gonzalez de Pena, Manuel; Mercado-Hernandez, Leda; Kyelem, Dominique; Lammie, Patrick J.; Flueckiger, Rebecca M.; Mwingira, Upendo J.; Noordin, Rahmah; Offei Owusu, Irene; Ottesen, Eric A.; Pavluck, Alexandre; Pilotte, Nils; Rao, Ramakrishna U.; Samarasekera, Dilhani; Schmaedick, Mark A.; Settinayake, Sunil; Simonsen, Paul E.; Supali, Taniawati; Taleo, Fasihah; Torres, Melissa; Weil, Gary J.; Won, Kimberly Y.

2013-01-01

297

Assessing mechanical vulnerability in water distribution networks under multiple failures  

NASA Astrophysics Data System (ADS)

mechanical vulnerability of water distribution networks (WDN) is of direct relevance for water utilities since it entails two different purposes. On the one hand, it might support the identification of severe failure scenarios due to external causes (e.g., natural or intentional events) which result into the most critical consequences on WDN supply capacity. On the other hand, it aims at figure out the WDN portions which are more prone to be affected by asset disruptions. The complexity of such analysis stems from the number of possible scenarios with single and multiple simultaneous shutdowns of asset elements leading to modifications of network topology and insufficient water supply to customers. In this work, the search for the most disruptive combinations of multiple asset failure events is formulated and solved as a multiobjective optimization problem. The higher vulnerability failure scenarios are detected as those causing the lower supplied demand due to the lower number of simultaneous failures. The automatic detection of WDN topology, subsequent to the detachments of failed elements, is combined with pressure-driven analysis. The methodology is demonstrated on a real water distribution network. Results show that, besides the failures causing the detachment of reservoirs, tanks, or pumps, there are other different topological modifications which may cause severe WDN service disruptions. Such information is of direct relevance to support planning asset enhancement works and improve the preparedness to extreme events.

Berardi, Luigi; Ugarelli, Rita; Røstum, Jon; Giustolisi, Orazio

2014-03-01

298

Assessment of 287 Japanese cases of drug induced liver injury by the diagnostic scale of the International Consensus Meeting  

Microsoft Academic Search

Two hundred and eighty seven Japanese cases of drug induced liver injury were assessed by the diagnostic scale of the International Consensus Meeting (ICM). They were classified to the hepatocellular (55%), mixed (24%) and cholestatic (22%) type according to the type of liver injury. Five cases were diagnosed as ‘unrelated’, since the reaction occurred more than 15 days after stopping

Hajime Takikawa; Yoriyuki Takamori; Teru Kumagi; Morikazu Onji; Masaaki Watanabe; Akitaka Shibuya; Akiko Hisamochi; Ryukichi Kumashiro; Tadashi Ito; Yasuhide Mitsumoto; Atsushi Nakamura; Takashi Sakaguchi

2003-01-01

299

Assessment and Continued Validation of the Malaria SYBR Green I-Based Fluorescence Assay for Use in Malaria Drug Screening  

Microsoft Academic Search

Several new fluorescence malaria in vitro drug susceptibility microtiter plate assays that detect the presence of malarial DNA in infected erythrocytes have recently been reported, in contrast to traditional isotopic screens that involve radioactive substrate incorporation to measure in vitro malaria growth inhibition. We have assessed and further characterized the malaria SYBR Green I-based fluorescence (MSF) assay for its ability

Jacob D. Johnson; Richard A. Dennull; Lucia Gerena; Miriam Lopez-Sanchez; Norma E. Roncal; Norman C. Waters

2007-01-01

300

A simple and validated tool for the clinician to assess psychosocial status when conducting anticonvulsant drug trials.  

PubMed

Using 94 people with epilepsy, categorized as either idiopathic or post-traumatic, and subdivided according to the severity of the disorder, the WPSI was tested and found to be a simple and validated tool for the clinician to assess psychosocial status when conducting anticonvulsant drug trials. PMID:3843219

Flanagan, P J; Beran, R G

1985-01-01

301

Health Risk Assessment Practices in the U.S. Food and Drug Administration  

Microsoft Academic Search

The U.S. Food and Drug Administration (FDA) regulates a wide variety of consumer products. Safety issues involve chemical and microbial contaminants in food, biologics, and medical devices; side effects from prescription and nonprescription drugs; residues of animal drugs in food; and radiation from electronic devices. Because of this wide diversity, the legal standards, rules, and policies governing the regulation of

D. W. Gaylor; J. A. Axelrad; R. P. Brown; J. A. Cavagnaro; W. H. Cyr; K. L. Hulebak; R. J. Lorentzen; M. A. Miller; L. T. Mulligan; B. A. Schwetz

1997-01-01

302

Some US Food and Drug Administration perspectives on data mining for pediatric safety Assessment  

Microsoft Academic Search

Background: The US Food and Drug Administration's (FDA's) large spontaneous reporting database contains >110,000 voluntary reports of adverse drug events (ADEs) observed during postmarketing pediatric practice and submitted to the FDA by manufacturers, health care providers, or consumers. These reports may provide evidence about known or unknown harm associated with single or combination drug treatments in pediatric patients. We recently

Robert T. O'Neill; Ana Szarfman

2001-01-01

303

National Institute of Justice Research in Brief: Assessing the Impact of Dade County's Felony Drug Court.  

National Technical Information Service (NTIS)

The extraordinary growth in the drug-related criminal caseload during the 1980's and the perceived impact of illicit drugs on public safety in Dade County prompted Florida's Eleventh Judicial Circuit to implement a court-based drug abuse treatment approac...

D. Weiland J. S. Goldkamp

1993-01-01

304

An Assessment of the Drug Abuse Resistance Education (DARE) Program in Fort Wayne, Indiana.  

ERIC Educational Resources Information Center

DARE is a preventive drug education program intended to combat drug use by students before it commences. The elementary school program is the core curriculum of DARE. It is designed to help those enrolled to develop skills that will allow them to resist the pressures to use substances such as illegal drugs, alcohol and tobacco. Students are taught…

Fife, Brian L.

305

10 CFR 32.21 - Radioactive drug: Manufacture, preparation, or transfer for commercial distribution of capsules...  

Code of Federal Regulations, 2010 CFR

...distribution of capsules containing carbon-14 urea each for âin vivoâ diagnostic use for...distribution of capsules containing carbon-14 urea each for âin vivoâ diagnostic use for...containing 37 kBq (1 µCi) carbon-14 urea (allowing for nominal variation that...

2010-01-01

306

10 CFR 32.21 - Radioactive drug: Manufacture, preparation, or transfer for commercial distribution of capsules...  

Code of Federal Regulations, 2010 CFR

...distribution of capsules containing carbon-14 urea each for âin vivoâ diagnostic use for...distribution of capsules containing carbon-14 urea each for âin vivoâ diagnostic use for...containing 37 kBq (1 µCi) carbon-14 urea (allowing for nominal variation that...

2009-01-01

307

Morphology, drug distribution, and in vitro release profiles of biodegradable polymeric microspheres containing protein fabricated by double-emulsion solvent extraction\\/evaporation method  

Microsoft Academic Search

The surface and internal morphology, drug distribution and release kinetics at 22°C of polyesters such as PCL (polycaprolactone) and PLGA (poly(dl-lactic-co-glycolic acid)) 65:35 microspheres containing BSA (bovine serum albumin) have been investigated in order to understand the relationship amongst morphology, drug distribution and in vitro release profiles and to develop controlled release devices for marine fishes in tropical area. CLSM

Yi-Yan Yang; Tai-Shung Chung; Ngee Ping Ng

2001-01-01

308

Hybrid Method to Assess Sensitive Process Interruption Costs Due to Faults in Electric Power Distribution Networks  

Microsoft Academic Search

This paper shows a new hybrid method for risk assessment regarding interruptions in sensitive processes due to faults in electric power distribution systems. This method determines indices related to long duration interruptions and short duration voltage variations (SDVV), such as voltage sags and swells in each customer supplied by the distribution network. Frequency of such occurrences and their impact on

Juan C. Cebrian; Nelson Kagan

2010-01-01

309

Condition Assessment of Ferrous Water Transmission and Distribution Systems State of Technology Review Report  

EPA Science Inventory

This White Paper was developed to serve as the basis for discussion at a Technology Forum on Condition Assessment of Water Transmission and Distribution Systems that was held on September 9 and 10, 2008, at Edison, NJ. It was distributed to the Forum participants for review in a...

310

A cross sectional pilot study on assessing the knowledge, attitude and behavior of community pharmacists to adverse drug reaction related aspects in the Sultanate of Oman  

PubMed Central

Background and objectives Adverse drug reaction (ADR) monitoring and reporting requires a multidisciplinary approach and pharmacists have a major role to play in it. The present pilot study was conducted to assess the knowledge, attitude and behavior of community pharmacists to ADR related aspects in the Sultanate of Oman. Methods A self-administered questionnaire comprising of 21 questions were distributed to a random sample of pharmacists in two Governorates in the Sultanate of Oman. It assessed the knowledge of pharmacists on some of the selected basic aspects of drug safety. Further, the knowledge and attitude of community pharmacists toward ADR reporting and their behavior on ADR related aspects were assessed. A scoring scheme was used to estimate the median total score of participants for various parameters. Obtained scores were correlated with the demographics of the respondents. Results A total of 107 community pharmacists participated in the survey giving a response rate of 72.3%. The responses of the pharmacists to the questions on the drug safety of individual drugs were incorrect for some important and practical questions. Consequently, total median score corresponding to these questions was 5 (Inter Quartile Range, IQR 2) out of a possible maximum score of 9, which was below the acceptable score. Total median score based on knowledge, attitude and behavior was 38 (IQR 8) out of a possible maximum of 50 which shows a moderate score. Lack of awareness on how to report an ADR and concern that the report may be wrong were the most common factors discouraging pharmacists from reporting ADRs. Qualification as well as years of experience were the only demographic parameters which had an influence on the score obtained by the pharmacists. Conclusions Even though the pharmacists had an acceptable knowledge, attitude and behavior on ADR reporting and related aspects, a good number of them had below than acceptable knowledge on drug safety related aspects of specific drugs. Educational programs have to be continued to generate awareness on how to report ADR and stimulate pharmacists’ more active participation in the pharmacovigilance program. There is a genuine need to have training programs to improve the knowledge of pharmacists on ADR related aspects which are of benefit on a daily basis which could greatly have an impact on patient safety.

Jose, Jimmy; Jimmy, Beena; Al-Ghailani, Aliya Said Hamed; Al Majali, Maryam Abdullah

2013-01-01

311

Assessing the spectral distribution on different tracking confederations  

NASA Astrophysics Data System (ADS)

In this paper we evaluate the local spectral resource of different tracking configurations for low CPV applications, under clear sky conditions. The Spectral Model for Atmospheric Transmission of Sunshine (SMARTS) is employed to compute the solar spectrum of cloud free weather conditions, together with a model that describes the performance of different tracking configurations. The required input data to run the models are gathered for one specific clear sky day at Cabauw, The Netherlans, where the measured radiative fluxes showed a good agreement. We also calculate the spectral indicator Average Photon Energy (APE) of the SMARTS output for the different tracking configurations, to study the spectral variation during the day. Results show that the spectral distribution of a tracking system varies more than a horizontal fixed surface, and also, that the different tracking configurations can have different shifts in the incident spectrum, which provides interesting information for a low CPV systems design.

Gaspar, G.; Pó, J. M.; Magarreiro, C.; Los, A.; Brito, M. C.

2012-10-01

312

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

PubMed

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

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

2014-05-01

313

WS-DREAM: A distributed reliability assessment Mechanism for Web Services  

Microsoft Academic Search

It is critical to guarantee the reliability of service- oriented applications. This is because they may employ remote Web Services as components, which may easily become unavailable in the unpredictable Internet environment. This practical experience report presents a Distribute REliability Assessment Mechanism for Web Services (WS-DREAM), allowing users to carry out Web Services reliability assessment in a collaborative manner. With

Zibin Zheng; Michael R. Lyu

2008-01-01

314

A Modified Marple-Type Cascade Impactor for Assessing Aerosol Particle Size Distributions in Workplaces  

Microsoft Academic Search

Knowledge of the particle size distributions for workplace aerosols is invaluable in the assessment of aerosol-related health effects. Cascade impactors have been widely used for obtaining such information, including a small number that have been developed as personal samplers of the type that can be used for the assessment of the exposures of individual workers. Common limitations for most samplers

Yi-Hsuan Wu; James H. Vincent

2007-01-01

315

Simulating the pharmacokinetics of tabletized ambroxol using the dynamics of drug distribution in saliva  

Microsoft Academic Search

The pharmacokinetics of ambrogexal (generic) and ambroxol (INN) tablets were investigated in 18 healthy volunteers after peroral\\u000a administration in a single dose of 60 mg. The levels of ambroxol hydrochloride in saliva were significantly higher (statistically\\u000a reliable) than those in the blood plasma for the first 1.5 hours after administration due to features of the drug absorption\\u000a in the gastrointestinal

S. N. Kondratenko; A. K. Starodubtsev; I. V. Zolkina; G. A. Belyakova

2009-01-01

316

Geographic distribution of human immunodeficiency virus markers in parenteral drug abusers.  

PubMed

Drug abuse treatment programs in six regions of the United States collaborated in a study aimed at monitoring trends in the seroprevalence of human immunodeficiency virus (HIV) antibodies. The wide disparities in HIV seroprevalence in the face of similarities in drug using behavior have important implications for prevention. In the New York City area (Harlem, Brooklyn), 61 per cent of samples (N = 280) obtained in late 1986 were positive, up from 50 per cent of samples (N = 585) in early 1985. In Baltimore, Maryland, 29 per cent of samples (N = 184) representing 11 programs were positive. In contrast, samples from programs distant from the Northeast corridor had far lower rates: Denver, Colorado 5 per cent (N = 100); San Antonio, Texas 2 per cent (N = 106); Southern California, 1.5 per cent (N = 413); and Tampa, Florida, 0 per cent (N = 102). Contrary to expectations, there was no corresponding difference in reported lifetime needle sharing experiences, which ranged from 70 per cent in New York to 99 per cent in San Antonio. HIV seropositivity was associated only with geographic location and ethnicity; however, because needle sharing is practiced by parenteral drug abusers in areas where seroprevalence is still relatively low, these areas are potentially vulnerable to the same catastrophic spread seen in the Northeast. A window of opportunity exists where prompt, vigorous, and aggressive efforts at prevention could have major impact. PMID:3348473

Lange, W R; Snyder, F R; Lozovsky, D; Kaistha, V; Kaczaniuk, M A; Jaffe, J H

1988-04-01

317

Can vesicle size distributions assess eruption intensity during volcanic activity?  

NASA Astrophysics Data System (ADS)

We studied three-dimensional (3-D) vesicle size distributions by X-ray microtomography in scoria collected during the relatively quiescent Phase II of the April-May 2010 eruption at Eyjafjallajökull volcano, Iceland. Our goal was to compare cumulative vesicle size distributions (VSDs) measured in these samples with those found in Stromboli volcano, Italy. Stromboli was chosen because its VSDs are well-characterized and show a correlation with eruption intensity: typical Strombolian activity produces VSDs with power-law exponents near 1, whereas larger and more energetic vulcanian-type explosions and Plinian eruptions produce VSDs with power-law exponents near 1.5. The first hypothesis to be tested was whether or not the samples studied in this work would contain VSDs similar to normal Strombolian products, display higher power-law exponents, or be described by exponential functions. Before making this comparison, we tested a second hypothesis, which was that the magma-water interactions in the Eyjafjallajökull eruption might have a significant effect on the VSDs. We performed 1 bar bubble-growth experiments in which the samples were inundated with water and compared them to similar control experiments without water inundation. No significant differences between the VSDs of the two sets of experiments were found, and the second hypothesis is not supported by the experimental evidence. The Phase II Eyjafjallajökull VSDs are described by power-law exponents of ~0.8, typical of normal Strombolian eruptions, and support the first hypothesis. The comparable VSDs and behavior of Phase II of the Eyjafjallajökull 2010 eruption to Stromboli are interpreted to be a reflection of similar conduit systems in both volcanoes that are being constantly fed by the ascent of mingled/mixed magma from depth. Such behavior implies that continued activity during Phase II of the Eyjafjallajökull eruption could be expected and would have been predicted, had our VSDs been measured in real time during the eruption. However, the products studied show no peculiar feature that could herald the renewed eruption intensity observed in the following Phase III of the eruption.

LaRue, A.; Baker, D. R.; Polacci, M.; Allard, P.; Sodini, N.

2013-10-01

318

Does mass drug administration for the integrated treatment of neglected tropical diseases really work? Assessing evidence for the control of schistosomiasis and soil-transmitted helminths in Uganda  

PubMed Central

Background Less is known about mass drug administration [MDA] for neglected tropical diseases [NTDs] than is suggested by those so vigorously promoting expansion of the approach. This paper fills an important gap: it draws upon local level research to examine the roll out of treatment for two NTDs, schistosomiasis and soil-transmitted helminths, in Uganda. Methods Ethnographic research was undertaken over a period of four years between 2005-2009 in north-west and south-east Uganda. In addition to participant observation, survey data recording self-reported take-up of drugs for schistosomiasis, soil-transmitted helminths and, where relevant, lymphatic filariasis and onchocerciasis was collected from a random sample of at least 10% of households at study locations. Data recording the take-up of drugs in Ministry of Health registers for NTDs were analysed in the light of these ethnographic and social survey data. Results The comparative analysis of the take-up of drugs among adults revealed that although most long term residents have been offered treatment at least once since 2004, the actual take up of drugs for schistosomiasis and soil-transmitted helminths varies considerably from one district to another and often also within districts. The specific reasons why MDA succeeds in some locations and falters in others relates to local dynamics. Issues such as population movement across borders, changing food supply, relations between drug distributors and targeted groups, rumours and conspiracy theories about the 'real' purpose of treatment, subjective experiences of side effects from treatment, alternative understandings of affliction, responses to social control measures and historical experiences of public health control measures, can all make a huge difference. The paper highlights the need to adapt MDA to local circumstances. It also points to specific generalisable issues, notably with respect to health education, drug distribution and more effective use of existing public health legislation. Conclusion While it has been an achievement to have offered free drugs to so many adults, current standard practices of monitoring, evaluation and delivery of MDA for NTDs are inconsistent and inadequate. Efforts to integrate programmes have exacerbated the difficulties. Improved assessment of what is really happening on the ground will be an essential step in achieving long-term overall reduction of the NTD burden for impoverished communities.

2011-01-01

319

Assessment of insulin resistance and metabolic syndrome in drug naive patients of bipolar disorder.  

PubMed

The levels of fasting glucose, fasting insulin, insulin resistance (IR) and the prevalence of metabolic syndrome (MS) in a sample population of bipolar disorder (BPD) patients who were newly diagnosed and psychotropically naïve were assessed and compared with an age, sex and racially matched control population. 55 BPD-I patients (15-65 years) who were non-diabetic, nonpregnant, and drug naïve for a period of at least 6 months were included in the study. Diagnosis was made using the structured clinical interview for DSM-IV axis I disorders (SCID IV). IR was assessed using homeostasis model of insulin resistance (HOMA-IR); MS was defined according to National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III). Data were compared with 25 healthy controls. BPD patients had significantly higher mean levels of fasting plasma insulin (13.2 ± 9.2 vs. 4.68 ± 3.1 ?IU/ml, p < 0.05), postprandial plasma insulin (27.2 ± 14.5 vs. 18.1 ± 9.3 ?IU/ml, p < 0.05) and a higher value of HOMA-IR (3.16 ± 2.2 vs. 1.19 ± 0.8, p < 0.05) when compared to the controls. A significantly higher proportion of patients of BPD compared to controls were manifesting levels of fasting plasma glucose, serum triglyceride and blood pressure higher than the cut off while waist circumference and serum HDL cholesterol failed to show any significant difference in the proportion. There was a significantly higher proportion of prevalence of IR between BPD cases and controls (26/55 vs. 2/25, z value 9.97, p < 0.05) while there was no significant difference in proportion of prevalence of MS between these two groups. Within BPD patients, logistic regression analysis showed that age, sex or current mood status (depressed/manic) were not significantly predictive of presence or absence of MS or increased IR. PMID:24478549

Guha, Prathama; Bhowmick, Kaushik; Mazumder, Piyanku; Ghosal, Malay; Chakraborty, Indranil; Burman, Prabir

2014-01-01

320

Predicted Drug Concentration Distribution Using a Validated Finite Element Model in Locally Advanced Breast Cancer.  

National Technical Information Service (NTIS)

The long-term objective of this study is to develop methods to predict the concentration-distribution of liposomally encapsulated doxorubicin in locally advanced breast cancer. Chemotherapy is frequently ineffective in shrinking these tumors to the point ...

B. Viglianti M. W. Dewhirst

2004-01-01

321

Assessment of surface concentrations in resorbable ocular implants: controlled drug delivery devices for 5-fluorouracil (5-FU)  

NASA Astrophysics Data System (ADS)

The antineoplastic drug 5-fluorouracil (5-fluoro- 2,4,(1H,3H)-pyrimidinedione; 5-FU) has been used to control proliferation of penetrating fibroblasts and to prevent channel closure following glaucoma filtration surgery (trabeculectomy) or laser sclerectomy. Because of the toxicity of the drug, administration of low dosages slowly over time, at the site of the desired treatment, is indicated for optimum efficacy. Repeated injections of low dosages of the drug represent an undesirable intervention and may also result in unwanted toxicity to the corneal epithelium. A suitable biocompatible and resorbable polymer matrix composed of a poly (D,L-lactic-co-glycolic acid: PLGA) has been admixed with varying amounts of 5-FU and cast as shapes suitable for intracorneal implantation. Slow biodegradation of this polymer over a one to two week period has been shown to result in an acceptably slow drug release mechanism. An issue arising during the clinical evaluation of the efficacy of this drug delivery system was how best to quantify the concentration of 5-FU and its distribution spatially in the solid implant. FT-IR and FT-Raman spectroscopies distinguishes between the drug and the polymer matrix and were used to differentiate and quantitate the 5-FU concentration of the implants.

Milne, Peter J.; Gautier, Sandrine; Parel, Jean-Marie A.; Jallet, Valerie

1997-05-01

322

On the Use of the Beta Distribution in Probabilistic Resource Assessments  

SciTech Connect

The triangular distribution is a popular choice when it comes to modeling bounded continuous random variables. Its wide acceptance derives mostly from its simple analytic properties and the ease with which modelers can specify its three parameters through the extremes and the mode. On the negative side, hardly any real process follows a triangular distribution, which from the outset puts at a disadvantage any model employing triangular distributions. At a time when numerical techniques such as the Monte Carlo method are displacing analytic approaches in stochastic resource assessments, easy specification remains the most attractive characteristic of the triangular distribution. The beta distribution is another continuous distribution defined within a finite interval offering wider flexibility in style of variation, thus allowing consideration of models in which the random variables closely follow the observed or expected styles of variation. Despite its more complex definition, generation of values following a beta distribution is as straightforward as generating values following a triangular distribution, leaving the selection of parameters as the main impediment to practically considering beta distributions. This contribution intends to promote the acceptance of the beta distribution by explaining its properties and offering several suggestions to facilitate the specification of its two shape parameters. In general, given the same distributional parameters, use of the beta distributions in stochastic modeling may yield significantly different results, yet better estimates, than the triangular distribution.

Olea, Ricardo A., E-mail: olea@usgs.gov [U.S. Geological Survey (United States)

2011-12-15

323

The Effect of Antihypertensive Drugs on Endothelial Function as Assessed by Flow-Mediated Vasodilation in Hypertensive Patients  

PubMed Central

Endothelial dysfunction is found in hypertensive patients and may serve as a prognostic marker of future cardiovascular events. Endothelial function can be assessed noninvasively by flow-mediated vasodilation (FMD). The goal of this paper is to summarize comprehensively the clinical trials that investigated the effects of antihypertensive drugs on endothelial function assessed by FMD in hypertensive patients. A PubMed-based search found 38 clinical trial papers published from January 1999 to June 2011. Significant improvement of FMD after antihypertensive treatment was shown in 43 of 71 interventions (among 38 clinical trial papers). Angiotensin II receptor blockers and angiotensin converting enzyme inhibitors appeared to improve FMD more than other drug types. Antihypertensive treatment can improve endothelial dysfunction when assessed by FMD, although there are conflicting data that require further research.

Miyamoto, Michiaki; Kotani, Kazuhiko; Ishibashi, Shun; Taniguchi, Nobuyuki

2012-01-01

324

Toward a model of drug relapse: An assessment of the validity of the reinstatement procedure  

PubMed Central

Background and Rationale The reinstatement model is widely used animal model of relapse to drug addiction. However, the model’s validity is open to question. Objective We assess the reinstatement model in terms of criterion and construct validity. Research highlights and Conclusions We find that the reinstatement model has adequate criterion validity in the broad sense of the term, as evidenced by the fact that reinstatement in laboratory animals is induced by conditions reported to provoke relapse in humans. The model’s criterion validity in the narrower sense, as a medication screen, seems promising for relapse to heroin, nicotine, and alcohol. For relapse to cocaine, criterion validity has not yet established, primarily because clinical studies have examined medication’s effects on reductions in cocaine intake rather than relapse during abstinence. The model’s construct validity faces more substantial challenges and is yet to be established, but we argue that some of the criticisms of the model in this regard may have been overstated.

Epstein, David H.; Preston, Kenzie L.; Stewart, Jane; Shaham, Yavin

2006-01-01

325

The relevance of polymeric synthetic membranes in topical formulation assessment and drug diffusion study.  

PubMed

Synthetic membranes are composed of thin sheets of polymeric macromolecules that can control the passage of components through them. Generally, synthetic membranes used in drug diffusion studies have one of two functions: skin simulation or quality control. Synthetic membranes for skin simulation, such as the silicone-based membranes polydimethylsiloxane and Carbosil, are generally hydrophobic and rate limiting, imitating the stratum corneum. In contrast, synthetic membranes for quality control, such as cellulose esters and polysulfone, are required to act as a support rather than a barrier. These synthetic membranes also often contain pores; hence, they are called porous membranes. The significance of Franz diffusion studies and synthetic membranes in quality control studies involves an understanding of the fundamentals of synthetic membranes. This article provides a general overview of synthetic membranes, including a brief background of the history and the common applications of synthetic membranes. This review then explores the types of synthetic membranes, the transport mechanisms across them, and their relevance in choosing a synthetic membrane in Franz diffusion cell studies for formulation assessment purposes. PMID:22553050

Ng, Shiow-Fern; Rouse, Jennifer J; Sanderson, Francis D; Eccleston, Gillian M

2012-03-01

326

Distributional Assumptions in Educational Assessments Analysis: Normal Distributions versus Generalized Beta Distribution in Modeling the Phenomenon of Learning  

ERIC Educational Resources Information Center

This paper introduces the generalized beta (GB) model as a new modeling tool in the educational assessment area and evaluation analysis, specifically. Unlike normal model, GB model allows us to capture some real characteristics of data and it is an important tool for understanding the phenomenon of learning. This paper develops a contrast with the…

Campos, Jose Alejandro Gonzalez; Moraga, Paulina Saavedra; Del Pozo, Manuel Freire

2013-01-01

327

Computational assessment of drug-induced effects on the electrocardiogram: from ion channel to body surface potentials  

PubMed Central

Background and Purpose Understanding drug effects on the heart is key to safety pharmacology assessment and anti-arrhythmic therapy development. Here our goal is to demonstrate the ability of computational models to simulate the effect of drug action on the electrical activity of the heart, at the level of the ion-channel, cell, heart and ECG body surface potential. Experimental Approach We use the state-of-the-art mathematical models governing the electrical activity of the heart. A drug model is introduced using an ion channel conductance block for the hERG and fast sodium channels, depending on the IC50 value and the drug dose. We simulate the ECG measurements at the body surface and compare biomarkers under different drug actions. Key Results Introducing a 50% hERG-channel current block results in 8% prolongation of the APD90 and 6% QT interval prolongation, hERG block does not affect the QRS interval. Introducing 50% fast sodium current block prolongs the QRS and the QT intervals by 12% and 5% respectively, and delays activation times, whereas APD90 is not affected. Conclusions and Implications Both potassium and sodium blocks prolong the QT interval, but the underlying mechanism is different: for potassium it is due to APD prolongation; while for sodium it is due to a reduction of electrical wave velocity. This study shows the applicability of in silico models for the investigation of drug effects on the heart, from the ion channel to the ECG-based biomarkers.

Zemzemi, Nejib; Bernabeu, Miguel O; Saiz, Javier; Cooper, Jonathan; Pathmanathan, Pras; Mirams, Gary R; Pitt-Francis, Joe; Rodriguez, Blanca

2013-01-01

328

Hepatitis C genotype distribution and homology among geographically disparate injecting drug users in Afghanistan.  

PubMed

Hepatitis C virus (HCV) prevalence is high among injecting drug users in Afghanistan, but transmission dynamics are poorly understood. Samples from HCV-infected injecting drug users were sequenced to determine circulating genotypes and potential transmission linkages. Serum samples were obtained from injecting drug user participants in Hirat, Jalalabad, and Mazar-i-Sharif between 2006 and 2008 with reactive anti-HCV rapid tests. Specimens with detected HCV viremia were amplified and underwent sequence analysis. Of 113 samples evaluated, 25 samples (35.2%) were only typeable in NS5B, nine samples (12.7%) were only typeable in CE1, and 37 samples (52.1%) were genotyped in both regions. Of those with typeable HCV, all were Afghan males with a mean age of 31.1 (standard deviation [SD]?±?8.0) years and mean duration of injecting of 3.9 (SD?±?4.3) years. Most reported residence outside Afghanistan in the last decade (90.1%) and prior incarceration (76.8%). HCV genotypes detected were: 1a, (35.2%, n?=?25), 3a (62.0%, n?=?44), and 1b (2.8%, n?=?2). Cluster formation was detected in NS5B and CE1 and were generally from within the same city. All participants within clusters reported being a refugee in Iran compared to 93.5% of those outside clusters. Only 22.2% (4/11) of those within clusters had been refugees in Pakistan and these four individuals had also been refugees in Iran. Predominance of genotype 3a and the association between HCV viremia and having been a refugee in Iran potentially reflects migration between Afghanistan and Iran among IDUs from Mazar-i-Sharif and Hirat and carry implications for harm reduction programs for this migratory population. PMID:23918535

Sanders-Buell, Eric; Rutvisuttinunt, Wiriya; Todd, Catherine S; Nasir, Abdul; Bradfield, Andrea; Lei, Esther; Poltavee, Kultida; Savadsuk, Hathairat; Kim, Jerome H; Scott, Paul T; de Souza, Mark; Tovanabutra, Sodsai

2013-07-01

329

Measuring topology of low-intensity DNA methylation sites for high-throughput assessment of epigenetic drug-induced effects in cancer cells  

SciTech Connect

Epigenetic anti-cancer drugs with demethylating effects have shown to alter genome organization in mammalian cell nuclei. The interest in the development of novel epigenetic drugs has increased the demand for cell-based assays to evaluate drug performance in pre-clinical studies. An imaging-based cytometrical approach that can measure demethylation effects as changes in the spatial nuclear distributions of methylated cytosine and global DNA in cancer cells is introduced in this paper. The cells were studied by immunofluorescence with a specific antibody against 5-methylcytosine (MeC), and 4,6-diamidino-2-phenylindole (DAPI) for delineation of methylated sites and global DNA in nuclei. In the preprocessing step the segmentation of nuclei in three-dimensional images (3-D) is followed by an automated assessment of nuclear DAPI/MeC patterns to exclude dissimilar entities. Next, low-intensity MeC (LIM) and low-intensity DNA (LID) sites of similar nuclei are localized and processed to obtain specific nuclear density profiles. These profiles sampled at half of the total nuclear volume yielded two parameters: LIM{sub 0.5} and LID{sub 0.5}. The analysis shows that zebularine and 5-azacytidine-the two tested epigenetic drugs introduce changes in the spatial distribution of low-intensity DNA and MeC signals. LIM{sub 0.5} and LID{sub 0.5} were significantly different (p < 0.001) in 5-azacytidine treated (n = 660) and zebularine treated (n = 496) vs. untreated (n = 649) DU145 human prostate cancer cells. In the latter case the LIM sites were predominantly found at the nuclear border, whereas treated populations showed different degrees of increase in LIMs towards the interior nuclear space, in which a large portion of heterochromatin is located. The cell-by-cell evaluation of changes in the spatial reorganization of MeC/DAPI signals revealed that zebularine is a more gentle demethylating agent than 5-azacytidine. Measuring changes in the topology of low-intensity sites can potentially be a valuable component in the high-throughput assessment of demethylation and risk of chromatin reorganization in epigenetic-drug screening tasks.

Gertych, Arkadiusz, E-mail: gertycha@cshs.org [Translational Cytomics Group, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA (United States) [Translational Cytomics Group, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA (United States); Bioinformatics, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA (United States); Farkas, Daniel L., E-mail: dlfarkas@gmail.com [Translational Cytomics Group, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA (United States); Tajbakhsh, Jian, E-mail: tajbakhshj@cshs.org [Translational Cytomics Group, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA (United States)] [Translational Cytomics Group, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA (United States)

2010-11-15

330

Usefulness of charge–transfer complexation for the assessment of sympathomimetic drugs: Spectroscopic properties of drug ephedrine hydrochloride complexed with some ?-acceptors  

NASA Astrophysics Data System (ADS)

Recently, ephedrine (Eph) assessment in food products, pharmaceutical formulations, human fluids of athletes and detection of drug toxicity and abuse, has gained a growing interest. To provide basic data that can be used to assessment of Eph quantitatively based on charge–transfer (CT) complexation, the CT complexes of Eph with 7?,8,8?-tetracyanoquinodimethane (TCNQ), dichlorodicyanobenzoquinone (DDQ), 1,3-dinitrobenzene (DNB) or tetrabromothiophene (TBT) were synthesized and spectroscopically investigated. The newly synthesized complexes have been characterized via elemental analysis, IR, Raman, 1H NMR, and UV–visible spectroscopy. The formation constant (KCT), molar extinction coefficient (?CT) and other spectroscopic data have been determined using the Benesi–Hildebrand method and its modifications. The sharp, well-defined Bragg reflections at specific 2? angles have been identified from the powder X-ray diffraction patterns. Thermal decomposition behavior of these complexes was also studied, and their kinetic thermodynamic parameters were calculated with Coats–Redfern and Horowitz–Metzger equations.

Refat, Moamen S.; Ibrahim, Omar B.; Saad, Hosam A.; Adam, Abdel Majid A.

2014-05-01

331

Impact of injection drug use on distribution and severity of chronic venous disorders  

PubMed Central

We examined chronic venous disorders (CVD) in persons who injected illicit drugs. The study design was cross-sectional, comparative stratified by age, gender, ethnicity, as well as by three types of drug use (noninjection; arm or upper body injection only; and legs with or without upper body injection). Subjects completed demographic, health, and substances abuse questionnaires and were evaluated using the clinical component of the Clinical-Etiology-Anatomy-Pathophysiology Classification. Seven hundred and thirteen participants were evaluated. Those who injected in the legs ± arms had significantly worse CVD. Thirty-nine percent of leg ± arm injectors vs. 4.2% or noninjectors or arm only injectors had moderate to severe CVD. Persons who injected in the legs ± arms were 9.14 times more likely to develop venous ulcers than those that injected in the arms and upper body only and 34.64 times more likely as those who never injected. CVD was associated with injecting in the groin, legs and feet as compared with other sites. The pattern of disorders associated with leg injection is consistent with the underlying pathology of chronic venous insufficiency.

Pieper, Barbara; Templin, Thomas N.; Kirsner, Robert S.; Birk, Thomas J.

2009-01-01

332

Application and assessment of Chinese arsenic drugs in treating malignant hematopathy in China  

Microsoft Academic Search

Chinese arsenic drugs have been applied in Chinese medicine for several centuries. Beginning from 1970s, arsenic containing\\u000a drugs have been generally used for the treatment of malignant hematologic diseases including acute promyelocytic leukemia,\\u000a myelodysplastic syndrome, and multiple myeloma. No matter what ingredients of arsenic drugs were applied, either arsenic trioxide,\\u000a arsenic disulfide, or arsenic containing Chinese herbal compositions including Qinghuang

Xiao-mei Hu; Feng Liu; Rou Ma

2010-01-01

333

Assessment of Pediatric asthma drug use in three European countries; a TEDDY study  

Microsoft Academic Search

Asthma drugs are amongst the most frequently used drugs in childhood, but international comparisons on type and indication\\u000a of use are lacking. The aim of this study was to describe asthma drug use in children with and without asthma in the Netherlands\\u000a (NL), Italy (IT), and the United Kingdom (UK). We conducted a retrospective analysis of outpatient medical records of

Elif Fatma Sen; Katia M. C. Verhamme; Antje Neubert; Yingfen Hsia; Macey Murray; Mariagrazia Felisi; Carlo Giaquinto; Geert W. ‘t Jong; Gino Picelli; Eugenio Baraldi; Alfredo Nicolosi; Adriana Ceci; Ian C. Wong; Miriam C. J. M. Sturkenboom

2011-01-01

334

Identification of crucial performance dimensions Phase 1 of the systematic process redesign of drug distribution  

Microsoft Academic Search

Background: Worldwide patient safety has become a major social policy problem for healthcare organisations. As in other organisations, the patients in our hospital also suffer from an inadequate distribution process, as becomes clear from incident reports involving medication errors. Medisch Spectrum Twente is a top primary-care, clinical, teaching hospital. The hospital pharmacy takes care of 1070 internal beds and 1120

H. Colen; C. Neef; R. W. Schuring

2003-01-01

335

Rapid assessment of drug response in cancer cells using microwell array and molecular imaging.  

PubMed

Selection of personalized chemotherapy regimen for individual patients has significant potential to improve chemotherapy efficacy and to reduce the deleterious effects of ineffective chemotherapy drugs. In this study, a rapid and high-throughput in vitro drug response assay was developed using a combination of microwell array and molecular imaging. The microwell array provided high-throughput analysis of drug response, which was quantified based on the reduction in intracellular uptake (2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose) (2-NBDG). Using this synergistic approach, the drug response measurement was completed within 4 h, and only a couple thousand cells were needed for quantification. The broader application of this microwell molecular imaging approach was demonstrated by evaluating the drug response of two cancer cell lines, cervical (HeLa) and bladder (5637) cancer cells, to two distinct classes of chemotherapy drugs (cisplatin and paclitaxel). This approach did not require an extended cell culturing period, and the quantification of cellular drug response was 4-16 times faster compared with other cell-microarray drug response studies. Moreover, this molecular imaging approach had comparable sensitivity to traditional cell viability assays, i.e., the MTT assay and propidium iodide labeling of cellular nuclei;and similar throughput results as flow cytometry using only 1,000-2,000 cells. Given the simplicity and robustness of this microwell molecular imaging approach, it is anticipated that the assay can be adapted to quantify drug responses in a wide range of cancer cells and drugs and translated to clinical settings for a rapid in vitro drug response using clinically isolated samples. PMID:24760393

Wang, Min S; Luo, Zhen; Nitin, Nitin

2014-07-01

336

Distributive Fluvial Systems of the Chaco Plain - Satellite Image Assessment of Fluvial Form and Facies Distributions  

NASA Astrophysics Data System (ADS)

Distributive fluvial systems (DFS) dominate fluvial deposition inside modern continental sedimentary basins and are particularly extensive in modern foreland basins. The largest of these DFS are found in the Chaco Plain, Andean Foreland Basin, South America. We use published literature, field and satellite data (Landsat, Modis, and SRTM) to construct preliminary hypotheses about the geomorphic form and fluvial facies distributions on the DFSs in this basin. The Pilcomayo River DFS extends over 700 km from apex to toe. The river enters the DFS apex as a large braided river with a bankfull channel width of 2500 m. Gravels and cobbles occur in terraces cut through the apex. At ~70-km downstream the bankfull channel width is ~2000 m and the channel is dominated by fine sand with cut banks 2-3 m high. The proximal channel belt is surrounded by floodplain sediments, however many sandy abandoned channel belts are present across the DFS, indicating a mobile channel system. Abandoned channels have a similar form to the modern channel, with minor reworking by underfit meandering streams. At ~75-km downfan, the river system diminishes in size (bankfull channel width up to 2 km but generally <1.5 km) and becomes increasingly sinuous in planform. This point appears to serve as a node for a series of recently abandoned meander belts and splays associated with discrete channels surrounded by floodplain material. At 100 km downstream the planform is highly sinuous and bankfull width has decreased to 1500 m or less. Downstream of this area abandoned meander belts dominate along the flanks of the modern channel with oxbow lakes present adjacent to the active channel. At 150 km downstream the bankfull channel belt width is 500 m or less and the river bifurcates into splays and multiple active channels which extend downstream for a further 200 km. Vegetation maps derived from Modis imagery indicate an increase in tree density around the DFS at this elevation (230 m). Along the distal portion of the DFS, a springline at ~150 m elevation separates the upper, well drained, aridisol dominated dry Chaco area of the DFS from the poorly drained wet Chaco at the toe. Channels below this line remain wet, are mud-dominated, and associated soils are hydromorphic. At the termination of the DFS the main Pilcomayo channel has a bankfull width of 120 m with sediments consisting of interbedded fine sand and mudstone. The observations from the Pilcomayo can serve as important analogues for the development of DFS in ancient foreland basin successions, particularly the recognition of the radial distribution of distinct facies types and the downstream changes in soil types associated with the spring line.

Weissmann, G. S.; Hartley, A. J.; Scuderi, L.; Bhattacharyya, P.; Buehler, H.; Leleu, S.; Mather, A.

2009-12-01

337

Establishment of an In Vitro Assay for Assessing the Effects of Drugs on the Liver Stages of Plasmodium vivax Malaria  

PubMed Central

Plasmodium vivax (Pv) is the second most important human malaria parasite. Recent data indicate that the impact of Pv malaria on the health and economies of the developing world has been dramatically underestimated. Pv has a unique feature in its life cycle. Uninucleate sporozoites (spz), after invasion of human hepatocytes, either proceed to develop into tens of thousands of merozoites within the infected hepatocytes or remain as dormant forms called hypnozoites, which cause relapses of malaria months to several years after the primary infection. Elimination of malaria caused by Pv will be facilitated by developing a safe, highly effective drug that eliminates Pv liver stages, including hypnozoites. Identification and development of such a drug would be facilitated by the development of a medium to high throughput assay for screening drugs against Pv liver stages. We undertook the present pilot study to (1) assess the feasibility of producing large quantities of purified, vialed, cryopreserved Pv sporozoites and (2) establish a system for culturing the liver stages of Pv in order to assess the effects of drugs on the liver stages of Pv. We used primaquine (PQ) to establish this assay model, because PQ is the only licensed drug known to clear all Pv hepatocyte stages, including hypnozoites, and the effect of PQ on Pv hepatocyte stage development in vitro has not previously been reported. We report that we have established the capacity to reproducibly infect hepatoma cells with purified, cyropreserved Pv spz from the same lot, quantitate the primary outcome variable of infected hepatoma cells and demonstrate the inhibitory activity of primaquine on the infected hepatoma cells. We have also identified small parasite forms that may be hypnozoites. These data provide the foundation for finalizing a medium throughput, high content assay to identify new drugs for the elimination of all Pv liver stages.

Chattopadhyay, Rana; Velmurugan, Soundarapandian; Chakiath, Chinnamma; Andrews Donkor, Lucy; Milhous, Wilbur; Barnwell, John W.; Collins, William E.; Hoffman, Stephen L.

2010-01-01

338

Porcine Ear Skin as a Model for the Assessment of Transdermal Drug Delivery to Premature Neonates  

Microsoft Academic Search

Purpose. The purpose of this study was (i) to validate differentially tape-stripped, porcine skin as an in vitro model for the evaluation of transdermal drug delivery (TDD) to premature neonates, (ii) to determine whether the model could estimate neonatal skin permeability as a function of postconceptional age (PCA), and (iii) to demonstrate that iontophoretic delivery permits precise control of drug

Nabila Sekkat; Yogeshvar N. Kalia; Richard H. Guy

2004-01-01

339

Principles and applicability of CSF sampling for the assessment of CNS drug delivery and pharmacodynamics  

Microsoft Academic Search

Cerebrospinal fluid (CSF) concentrations are used as a surrogate measure of central nervous system (CNS) availability of drugs. Systemically administered drugs can reach CSF either directly via passage across the choroid plexus, or indirectly by passage across the blood–brain barrier (BBB) followed by diffusion\\/convection transport from the interstitial fluid (ISF) to CSF. This review focuses on the physiological and pharmacokinetic

Danny D. Shen; Alan A. Artru; Kimberly K. Adkison

2004-01-01

340

Human placental perfusion method in the assessment of transplacental passage of antiepileptic drugs  

SciTech Connect

Epilepsy is one of the most common neurological diseases, affecting about 0.5 to 1% of pregnant women. It is commonly accepted that older antiepileptic drugs bear teratogenic potential. So far, no agreement has been reached about the safest antiepileptic drug during pregnancy. It is known that nearly all drugs cross the placenta at least to some extent. Nowadays, there is very little information available of the pharmacokinetics of drugs in the feto-placental unit. Detailed information about drug transport across the placenta would be valuable for the development of safe and effective treatments. For reasons of safety, human studies on placental transfer are restricted to a limited number of drugs. Interspecies differences limit the extrapolation of animal data to humans. Several in vitro methods for the study of placental transfer have been developed over the past decades. The placental perfusion method is the only experimental method that has been used to study human placental transfer of substances in organized placental tissue. The aim of this article is to review human placental perfusion data on antiepileptic drugs. According to perfusion data, it seems that most of the antiepileptic drugs are transferred across the placenta meaning significant fetal exposure.

Myllynen, Paeivi [Department of Pharmacology and Toxicology, University of Oulu, PO Box 5000, 90014 Oulu (Finland)]. E-mail: paivi.k.myllynen@oulu.fi; Pienimaeki, Paeivi [Department of Pharmacology and Toxicology, University of Oulu, PO Box 5000, 90014 Oulu (Finland); Vaehaekangas, Kirsi [Department of Pharmacology and Toxicology, University of Oulu, PO Box 5000, 90014 Oulu (Finland); Department of Pharmacology and Toxicology, University of Kuopio, PO Box 1627, 70211 Kuopio (Finland)

2005-09-01

341

Exploiting pluripotent stem cell technology for drug discovery, screening, safety, and toxicology assessments.  

PubMed

In order for the pharmaceutical industry to maintain a constant flow of novel drugs and therapeutics into the clinic, compounds must be thoroughly validated for safety and efficacy in multiple biological and biochemical systems. Pluripotent stem cells, because of their ability to develop into any cell type in the body and recapitulate human disease, may be an important cellular system to add to the drug development repertoire. This review will discuss some of the benefits of using pluripotent stem cells for drug discovery and safety studies as well as some of the recent applications of stem cells in drug screening studies. We will also address some of the hurdles that need to be overcome in order to make stem cell-based approaches an efficient and effective tool in the quest to produce clinically successful drug compounds. PMID:24309014

McGivern, Jered V; Ebert, Allison D

2014-04-01

342

Assessing the potential impact of non-proprietary drug copies on quality of medicine and treatment in patients with relapsing multiple sclerosis: the experience with fingolimod  

PubMed Central

Background Fingolimod is a once-daily oral treatment for relapsing multiple sclerosis, the proprietary production processes of which are tightly controlled, owing to its susceptibility to contamination by impurities, including genotoxic impurities. Many markets produce nonproprietary medicines; assessing their efficacy and safety is difficult as regulators may approve nonproprietary drugs without bioequivalence data, genotoxic evaluation, or risk management plans (RMPs). This assessment is especially important for fingolimod given its solubility/bioavailability profile, genotoxicity risk, and low-dose final product (0.5 mg). This paper presents an evaluation of the quality of proprietary and nonproprietary fingolimod variants. Methods Proprietary fingolimod was used as a reference substance against which eleven nonproprietary fingolimod copies were assessed. The microparticle size distribution of each compound was assessed by laser light diffraction, and inorganic impurity content by sulfated ash testing. Heavy metals content was quantified using inductively coupled plasma optical emission spectrometry, and levels of unspecified impurities by high-performance liquid chromatography. Solubility was assessed in a range of solvents at different pH values. Key information from the fingolimod RMP is also presented. Results Nonproprietary fingolimod variants exhibited properties out of proprietary or internationally accepted specifications, including differences in particle size distribution and levels of impurities such as heavy metals. For microparticle size and heavy metals, all tested fingolimod copies were out-of-specification by several-fold magnitudes. Proprietary fingolimod has a well-defined RMP, highlighting known and potential mid- to long-term safety risks, and risk-minimization and pharmacovigilance procedures. Conclusion Nonproprietary fingolimod copies produced by processes less well controlled than or altered from proprietary production processes may reduce product reproducibility and quality, potentially presenting risks to patients. Safety data and risk-minimization strategies for proprietary fingolimod may not apply to the nonproprietary fingolimod copies evaluated here. Market authorization of nonproprietary fingolimod copies should require an appropriate RMP to minimize risks to patients.

Correale, Jorge; Chiquete, Erwin; Milojevic, Snezana; Frider, Nadina; Bajusz, Imre

2014-01-01

343

Distributions Selected for Use in Probabilistic Human Health Risk Assessments in Oregon  

Microsoft Academic Search

In 1995, Oregon enacted amendments to its state Cleanup Law that emphasize risk-based remedial action decisions and allow a responsible party to conduct probabilistic human health risk assessments. This change required selection and\\/or development of probability density functions for exposure factors frequently used in human health risk assessments. Methods used to obtain distributions for body weight, soil, water, vegetable\\/fruit, fish,

Bruce K. Hope

1999-01-01

344

Cell-based systems to assess nuclear receptor activation and their use in drug development.  

PubMed

The evolution of scientific information relating to the regulation of xenobiotic disposition has extended to the discovery of an intricate group of receptor systems now recognized as master regulators. These ligand-activated transcription factors are commonly designated as "nuclear receptors", and include CAR (NR1I3), PXR (NR1I2), PPAR (NR1C1, NR1C2, and NR1C3) and AhR (HLHE76). As regulators of gene expression, activation of these receptors can elicit a plethora of drug-drug interactions. The aforementioned nuclear receptors bind a wide range of structurally-unrelated ligands, such as steroid hormones, bile acids, and small drug-type molecules. A pivotal nuclear receptor with regards to regulation of drug-drug interactions is the pregnane X receptor (PXR). Gene expression profiling has demonstrated that PXR regulates over 60 human genes that are involved not only in physiological functions but also in the metabolism of xenobiotics. Moreover, chemical library screening suggests that about 10% of the compounds comprising the U. S. Food and Drug Administration 1 and 2, Sigma-Aldrich LOPAC collection, Biomol, and Tocris/TimTec bioactive collection libraries exhibit some form of PXR binding. For these reasons, efficient, rapid and economical systems have been developed to identify nuclear receptor ligands. Cell-based assays encompassing transiently and stably-transfected cells and mammalian two-hybrid systems are currently being employed by the pharmaceutical industry to screen compounds for binding to and/or activation of nuclear receptors. Overall, these systems have the ability to predict in vivo responses to receptor activation that culminate in drug-drug interactions and adverse drug effects. PMID:23330544

Raucy, Judy L; Lasker, Jerome M

2013-02-01

345

The assessment of antibody affinity distribution by thiocyanate elution: a simple dose-response approach.  

PubMed

We describe a simple dose-response approach to assess the affinity distribution of polyclonal antibodies. The proportion of antigen-specific antibodies dissociated by increasing concentrations of the mild chaotropic agent ammonium thiocyanate (NH4SCN) was measured by enzyme immunoassay, and the distribution of tolerances to this agent was presented in a histogram form. Such 'tolerance distribution', which is analogous to that described in classical dose-response bioassays, is proposed as a representation of the actual antibody affinity distribution. To test this approach, we assessed affinity maturation patterns of anti-Plasmodium falciparum IgG antibodies in paired sera obtained from 22 malaria patients during the acute infection and convalescence. We obtained patterns of antibody affinity distributions consistent with those previously described in immunization experiments with the aid of more complex laboratory and computational approaches. Therefore, we suggest the thiocyanate elution technique as an alternative method for rapid assessment of affinity distributions of polyclonal antibodies elicited against complex antigens, readily applicable to large number of serum samples. PMID:7499889

Ferreira, M U; Katzin, A M

1995-12-01

346

Application and assessment of Chinese arsenic drugs in treating malignant hematopathy in China.  

PubMed

Chinese arsenic drugs have been applied in Chinese medicine for several centuries. Beginning from 1970s, arsenic containing drugs have been generally used for the treatment of malignant hematologic diseases including acute promyelocytic leukemia, myelodysplastic syndrome, and multiple myeloma. No matter what ingredients of arsenic drugs were applied, either arsenic trioxide, arsenic disulfide, or arsenic containing Chinese herbal compositions including Qinghuang Powder and Realgar-Indigo naturalis formula, they all provided the distinct approaches for the management of malignant hematologic diseases, and good clinical efficacy was obtained with mild adverse reactions. Moreover, the mechanisms of action have been continually elucidated. PMID:20697951

Hu, Xiao-mei; Liu, Feng; Ma, Rou

2010-08-01

347

Non-homogeneous intrahepatic drug distribution in intraportal infusional chemotherapy demonstrated by Tc-99m-MAA perfusion SPECT.  

PubMed

Perioperative adjuvant cytotoxic chemotherapy given through a portal vein catheter may reduce the incidence of metachronous liver metastases following curative resection of colorectal carcinoma. It has generally been assumed that positioning the tip of the catheter in the stem of the portal vein will ensure homogeneous drug distribution to the whole liver. This hypothesis has been put to the test in 10 patients receiving intraportal chemotherapy according to protocol 40/81 of the Swiss Group of Clinical Cancer Research. Catheter position in the stem of the portal vein was checked angiographically the first and last day of a 7-day chemotherapy course. Perfusion scans using 99m-Tc-MAA made during therapy were compared to static liver scans obtained with 99m-Tc sulfur colloid one day after conclusion of chemotherapy. The results were evaluated on planar scans and by SPECT. Slow infusion of the tracer substance under conditions duplicating those of cytotoxic drug infusion used in the protocol resulted in decreased or missing perfusion of the left liver lobe and gross non-homogeneous perfusion in nearly all of the patients. PMID:2495231

Aeberhard, P; Bissat, A; Koella, C; Seybold, K

1989-04-01

348

Equipment management guide. Improving the drug distribution process--do you need an automated decentralized pharmacy dispensing system?  

PubMed

In this Equipment Management Guide, we provide guidance to help hospitals determine whether implementing an automated decentralized pharmacy dispensing system (ADPDS) will be an effective way to improve their drug distribution process. We describe the ADPDSs themselves and then discuss factors that hospitals should consider before deciding on such a system. Specifically, we identify several areas that many pharmacies target for improvement and discuss whether and how an ADPDS can help the facility make the desired improvements. We also provide guidance for determining the cost-effectiveness of such a system, as well as for selecting a system that will most appropriately meet the hospital's needs. In the Evaluation that follows this Guide, we present our criteria for evaluating ADPDSs and the results of our testing of three such systems. PMID:8968720

1996-12-01

349

PRECLINICAL DRUG TRIALS IN THE mdx MOUSE: ASSESSMENT OF RELIABLE AND SENSITIVE OUTCOME MEASURES  

PubMed Central

The availability of animal models for Duchenne muscular dystrophy has led to extensive preclinical research on potential therapeutics. Few studies have focused on reliability and sensitivity of endpoints for mdx mouse drug trials. Therefore, we sought to compare a wide variety of reported and novel endpoint measures in exercised mdx and normal control mice at 10, 20, and 40 weeks of age. Statistical analysis as well as power calculations for expected effect sizes in mdx preclinical drug trials across different ages showed that body weight, normalized grip strength, horizontal activity, rest time, cardiac function measurements, blood pressure, total central/peripheral nuclei per fiber, and serum creatine kinase are the most effective measurements for detecting drug-induced changes. These data provide an experimental basis upon which standardization of preclinical drug testing can be developed.

SPURNEY, CHRISTOPHER F.; GORDISH-DRESSMAN, HEATHER; GUERRON, ALFREDO D.; SALI, ARPANA; PANDEY, GOURI S.; RAWAT, RASHMI; VAN DER MEULEN, JACK H.; CHA, HEE-JAE; PISTILLI, EMIDIO E.; PARTRIDGE, TERENCE A.; HOFFMAN, ERIC P.; NAGARAJU, KANNEBOYINA

2014-01-01

350

CYP Induction-Mediated Drug Interactions: in Vitro Assessment and Clinical Implications  

Microsoft Academic Search

Cytochrome P450 (CYP) induction-mediated interaction is one of the major concerns in clinical practice and for the pharmaceutical\\u000a industry. There are two major issues associated with CYP induction: a reduction in therapeutic efficacy of comedications and\\u000a an induction in reactive metabolite-induced toxicity. Because CYP induction is a metabolic liability in drug therapy, it is\\u000a highly desirable to develop new drug

Jiunn H. Lin

2006-01-01

351

Assessing the chiral switch: approval and use of single-enantiomer drugs, 2001 to 2011.  

PubMed

Objectives: A "chiral switch" occurs in the pharmaceutical market when a drug made up of 2 enantiomer forms is replaced with a purified single-enantiomer version, often in the context of a patent expiration. We studied the prevalence of chiral switching in the United States over the past decade, including trends in use of, and expenditures on, these products in Medicaid. Study Design: Retrospective analysis. Methods: We used US Adopted Names prefixes (lev/levo/ar/es/dex/dextro) to identify all single-enantiomer drugs approved from 2001 to 2011. From publicly available US Food and Drug Administration (FDA) approval documents, we extracted the characteristics of the pivotal premarket trials for the single enantiomers. Specifically, we evaluated whether the single enantiomer was directly compared with the precursor racemic drug and whether there was evidence of superior efficacy. We used quarterly drug expenditure data from each state Medicaid program to chart trends in use of, and spending on, the single-enantiomer products and their racemic precursors during the study period. Results: From 2001 to 2011, the FDA approved 9 single-enantiomer products: dexlansoprazole, levoleucovorin, levocetirizine, armodafinil, arformoterol, eszopiclone, escitalopram, dexmethylphenidate, and esomeprazole. Of those 9 drugs, 3 had at least 1 pre-approval randomized trial that included the racemic precursor as a direct comparator, but there was no evidence of superiority of the single enantiomer over the racemic at comparable doses. Between 2001 and 2011, US Medicaid programs spent approximately $6.3 billion on these 9 single-enantiomer drugs. Conclusions: Recently approved single-enantiomer drugs showed no evidence of superior efficacy over the older racemic precursors in the pivotal trials leading to their approval, and in a majority of cases, they were not directly compared. PMID:24773330

Gellad, Walid F; Choi, Phillip; Mizah, Margaret; Good, Chester B; Kesselheim, Aaron S

2014-01-01

352

Kinetic modeling of tricarboxylic acid cycle and glyoxylate bypass in Mycobacterium tuberculosis, and its application to assessment of drug targets  

PubMed Central

Background Targeting persistent tubercule bacilli has become an important challenge in the development of anti-tuberculous drugs. As the glyoxylate bypass is essential for persistent bacilli, interference with it holds the potential for designing new antibacterial drugs. We have developed kinetic models of the tricarboxylic acid cycle and glyoxylate bypass in Escherichia coli and Mycobacterium tuberculosis, and studied the effects of inhibition of various enzymes in the M. tuberculosis model. Results We used E. coli to validate the pathway-modeling protocol and showed that changes in metabolic flux can be estimated from gene expression data. The M. tuberculosis model reproduced the observation that deletion of one of the two isocitrate lyase genes has little effect on bacterial growth in macrophages, but deletion of both genes leads to the elimination of the bacilli from the lungs. It also substantiated the inhibition of isocitrate lyases by 3-nitropropionate. On the basis of our simulation studies, we propose that: (i) fractional inactivation of both isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 is required for a flux through the glyoxylate bypass in persistent mycobacteria; and (ii) increasing the amount of active isocitrate dehydrogenases can stop the flux through the glyoxylate bypass, so the kinase that inactivates isocitrate dehydrogenase 1 and/or the proposed inactivator of isocitrate dehydrogenase 2 is a potential target for drugs against persistent mycobacteria. In addition, competitive inhibition of isocitrate lyases along with a reduction in the inactivation of isocitrate dehydrogenases appears to be a feasible strategy for targeting persistent mycobacteria. Conclusion We used kinetic modeling of biochemical pathways to assess various potential anti-tuberculous drug targets that interfere with the glyoxylate bypass flux, and indicated the type of inhibition needed to eliminate the pathogen. The advantage of such an approach to the assessment of drug targets is that it facilitates the study of systemic effect(s) of the modulation of the target enzyme(s) in the cellular environment.

Singh, Vivek Kumar; Ghosh, Indira

2006-01-01

353

Clinician uptake of obesity-related drug information: a qualitative assessment using continuing medical education activities  

PubMed Central

Background Medications necessary for disease management can simultaneously contribute to weight gain, especially in children. Patients with preexisting obesity are more susceptible to medication-related weight gain. How equipped are primary care practitioners at identifying and potentially reducing medication-related weight gain? To inform this question germane to public health we sought to identify potential gaps in clinician knowledge related to metabolic adverse drug effects of weight gain. Methods The study analyzed practitioner responses to the pre-activity questions of six continuing medical education (CME) activities from May 2009 through August 2010. Results The 20,705 consecutive, self-selected respondents indicated varied levels of familiarity with adverse metabolic effects and psychiatric indications of atypical antipsychotics. Correct responses were lower than predicted for drug indications pertaining to autism (?17% predicted); drug effects on insulin resistance (?62% predicted); chronic disease risk in mental illness (?34% predicted); and drug safety research (?40% predicted). Pediatrician knowledge scores were similar to other primary care practitioners. Conclusions Clinicians’ knowledge of medication-related weight gain may lead them to overestimate the benefits of a drug in relation to its metabolic risks. The knowledge base of pediatricians appears comparable to their counterparts in adult medicine, even though metabolic drug effects in children have only become prevalent recently.

2013-01-01

354

An information system for drug prescription and distribution in a public hospital.  

PubMed

With 773 beds and 3696 employees, the Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto (HCFMRP)-Universidade de São Paulo, is one of the largest medical institutions in Latin America. The complete process of prescribing and distributing medication at HCFMRP involves the following stages: prescribing (physicians); ordering (infirmary); separating and dispensing (main drugstore); verifying and administering (infirmary). This was a manual process, normally taking place in the morning. Bottlenecks were inevitable and the risk of errors was elevated. An information system (IS) was devised and implemented with a view to controlling such problems. This article addresses the construction of this system and reports on a survey in which different groups of users have evaluated the project. PMID:15135756

Costa, André Lucirton; de Oliveira, Márcio Mattos Borges; Machado, Roseli de Oliveira

2004-05-01

355

Variability in P-Glycoprotein Inhibitory Potency (IC50) Using Various in Vitro Experimental Systems: Implications for Universal Digoxin Drug-Drug Interaction Risk Assessment Decision Criteria  

PubMed Central

A P-glycoprotein (P-gp) IC50 working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC50 determinations. Each laboratory followed its in-house protocol to determine in vitro IC50 values for 16 inhibitors using four different test systems: human colon adenocarcinoma cells (Caco-2; eleven laboratories), Madin-Darby canine kidney cells transfected with MDR1 cDNA (MDCKII-MDR1; six laboratories), and Lilly Laboratories Cells—Porcine Kidney Nr. 1 cells transfected with MDR1 cDNA (LLC-PK1-MDR1; four laboratories), and membrane vesicles containing human P-glycoprotein (P-gp; five laboratories). For cell models, various equations to calculate remaining transport activity (e.g., efflux ratio, unidirectional flux, net-secretory-flux) were also evaluated. The difference in IC50 values for each of the inhibitors across all test systems and equations ranged from a minimum of 20- and 24-fold between lowest and highest IC50 values for sertraline and isradipine, to a maximum of 407- and 796-fold for telmisartan and verapamil, respectively. For telmisartan and verapamil, variability was greatly influenced by data from one laboratory in each case. Excluding these two data sets brings the range in IC50 values for telmisartan and verapamil down to 69- and 159-fold. The efflux ratio-based equation generally resulted in severalfold lower IC50 values compared with unidirectional or net-secretory-flux equations. Statistical analysis indicated that variability in IC50 values was mainly due to interlaboratory variability, rather than an implicit systematic difference between test systems. Potential reasons for variability are discussed and the simplest, most robust experimental design for P-gp IC50 determination proposed. The impact of these findings on drug-drug interaction risk assessment is discussed in the companion article (Ellens et al., 2013) and recommendations are provided.

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

2013-01-01

356

Interaction of nonsteroidal anti-inflammatory drugs with membranes: in vitro assessment and relevance for their biological actions.  

PubMed

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world due to their anti-inflammatory, analgesic and antipyretic properties. Nevertheless, the consumption of these drugs is still associated with the occurrence of a wide spectrum of adverse effects. Regarding the major role of membranes in cellular events, the hypothesis that the biological actions of NSAIDs may be related to their effect at the membrane level has triggered the in vitro assessment of NSAIDs-membrane interactions. The use of membrane mimetic models, cell cultures, a wide range of experimental techniques and molecular dynamics simulations has been providing significant information about drugs partition and location within membranes and also about their effect on diverse membrane properties. These studies have indeed been providing evidences that the effect of NSAIDs at membrane level may be an additional mechanism of action and toxicity of NSAIDs. In fact, the pharmacokinetic properties of NSAIDs are closely related to the ability of these drugs to interact and overcome biological membranes. Moreover, the therapeutic actions of NSAIDs may also result from the indirect inhibition of cyclooxygenase due to the disturbing effect of NSAIDs on membrane properties. Furthermore, increasing evidences suggest that the disordering effects of these drugs on membranes may be in the basis of the NSAIDs-induced toxicity in diverse organ systems. Overall, the study of NSAIDs-membrane interactions has proved to be not only important for the better understanding of their pharmacological actions, but also for the rational development of new approaches to overcome NSAIDs adverse effects. PMID:23981364

Pereira-Leite, Catarina; Nunes, Cláudia; Reis, Salette

2013-10-01

357

Assessment of real losses in potable water distribution systems: some recent developments  

Microsoft Academic Search

Considerable progress has been made over the past 10 years in the assessment and benchmarking of real losses in potable water distribution systems. Most of the advances have been based on the burst and background estimate (BABE) methodology, which was first developed in the mid-1990s by the UK water industry and has since been widely accepted and used in many

R. McKenzie; C. Seago

358

A methodology for the assessment of short duration voltage variations in electric power distribution systems  

Microsoft Academic Search

This paper deals with a new methodology for the assessment of power quality indices in electric power distribution systems. Power quality indices concerning short duration voltage variations, i.e. voltage sags and swells, are particularly introduced taking into account the needs for establishing power quality standards. The paper also presents a new proposal for a measurement protocol, a testing procedure to

N. Kagan; E. L. Ferrari; N. M. Matsuo; S. X. Duarte; J. L. Cavaretti; A. Tenorio; L. R. Souza

2002-01-01

359

Experimental assessment of the contribution of annealing twins to CSL distributions in FCC materials  

Microsoft Academic Search

The correlation between CSL distributions and annealing twins was assessed for a wide range of fcc materials using the electron backscattered diffraction technique. The maximum frequency of twin boundaries determined experimentally (?61%) is consistent with the previously proposed theoretical limit of 23. The frequency of special grain boundaries (?1–?29) was found to lie within limits defined by (1) an upper

P. Lin; G. Palumbo; K. T. Aust

1997-01-01

360

Biofilms, thermophilic amoebae and Legionella pneumophila - a quantitative risk assessment for distributed water  

Microsoft Academic Search

A simplistic quantitative microbial risk assessment (QMRA) based on the maximum risk curve (r = 1) was developed for Legionella within a water distribution system. Both biofilms and a thermophilic isolate of acanthamoebae were shown to increase the resistance of Legionella to conventional thermal disinfection by between one and two logs respectively. The level of risk presented to consumers was

M. V. Storey; N. J. Ashbolt; T. A. Stenström

2004-01-01

361

Hp-?-CD-Voriconazole In Situ Gelling System for Ocular Drug Delivery: In Vitro, Stability, and Antifungal Activities Assessment  

PubMed Central

The objective of the present study was to design ophthalmic delivery systems based on polymeric carriers that undergo sol-to-gel transition upon change in temperature or in the presence of cations so as to prolong the effect of HP-?-CD Voriconazole (VCZ) in situ gelling formulations. The in situ gelling formulations of Voriconazole were prepared by using pluronic F-127 (PF-127) or with combination of pluronic F-68 (PF-68) and sodium alginate by cold method technique. The prepared formulations were evaluated for their physical appearance, drug content, gelation temperature (Tgel), in vitro permeation studies, rheological properties, mucoadhesion studies, antifungal studies, and stability studies. All batches of in situ formulations had satisfactory pH ranging from 6.8 to 7.4, drug content between 95% and 100%, showing uniform distribution of drug. As the concentration of each polymeric component was increased, that is, PF-68 and sodium alginate, there was a decrease in Tgel with increase in viscosity and mucoadhesive strength. The in vitro drug release decreased with increase in polymeric concentrations. The stability data concluded that all formulations showed the low degradation and maximum shelf life of 2 years. The antifungal efficiency of the selected formulation against Candida albicans and Asperigillus fumigatus confirmed that designed formulation has prolonged effect and retained its properties against fungal infection.

Pawar, Pravin; Kashyap, Heena; Malhotra, Sakshi; Sindhu, Rakesh

2013-01-01

362

Noninvasive in vivo optical assessment of blood brain barrier permeability and brain tissue drug deposition in rabbits  

PubMed Central

Abstract. Osmotic disruption of the blood brain barrier (BBB) by intraarterial mannitol injection is sometimes the key step for the delivery of chemotherapeutic drugs to brain tissue. BBB disruption (BBBD) with mannitol, however, can be highly variable and could impact local drug deposition. We use optical pharmacokinetics, which is based on diffuse reflectance spectroscopy, to track in vivo brain tissue concentrations of indocyanine green (ICG), an optical reporter used to monitor BBBD, and mitoxantrone (MTX), a chemotherapy agent that does not deposit in brain tissue without BBBD, in anesthetized New Zealand white rabbits. Results show a significant increase in the tissue ICG concentrations with BBBD, and our method is able to track the animal-to-animal variation in tissue ICG and MTX concentrations after BBBD. The tissue concentrations of MTX increase with barrier disruption and are found to be correlated to the degree of disruption, as assessed by the ICG prior to the injection of the drug. These findings should encourage the development of tracers and optical methods capable of quantifying the degree of BBBD, with the goal of improving drug delivery.

Ergin, Aysegul; Wang, Mei; Zhang, Jane; Bigio, Irving; Joshi, Shailendra

2012-01-01

363

Noninvasive in vivo optical assessment of blood brain barrier permeability and brain tissue drug deposition in rabbits  

NASA Astrophysics Data System (ADS)

Osmotic disruption of the blood brain barrier (BBB) by intraarterial mannitol injection is sometimes the key step for the delivery of chemotherapeutic drugs to brain tissue. BBB disruption (BBBD) with mannitol, however, can be highly variable and could impact local drug deposition. We use optical pharmacokinetics, which is based on diffuse reflectance spectroscopy, to track in vivo brain tissue concentrations of indocyanine green (ICG), an optical reporter used to monitor BBBD, and mitoxantrone (MTX), a chemotherapy agent that does not deposit in brain tissue without BBBD, in anesthetized New Zealand white rabbits. Results show a significant increase in the tissue ICG concentrations with BBBD, and our method is able to track the animal-to-animal variation in tissue ICG and MTX concentrations after BBBD. The tissue concentrations of MTX increase with barrier disruption and are found to be correlated to the degree of disruption, as assessed by the ICG prior to the injection of the drug. These findings should encourage the development of tracers and optical methods capable of quantifying the degree of BBBD, with the goal of improving drug delivery.

Ergin, Aysegul; Wang, Mei; Zhang, Jane; Bigio, Irving; Joshi, Shailendra

2012-05-01

364

Assessment of drug candidates for broad-spectrum antiviral therapy targeting cellular pyrimidine biosynthesis.  

PubMed

Currently available antiviral drugs frequently induce side-effects or selection of drug-resistant viruses. We describe a novel antiviral principle based on targeting the cellular enzyme dihydroorotate dehydrogenase (DHODH). In silico drug design and biochemical evaluation identified Compound 1 (Cmp1) as a selective inhibitor of human DHODH in vitro (IC50 1.5±0.2nM). Crystallization data specified the mode of drug-target interaction. Importantly, Cmp1 displayed a very potent antiviral activity that could be reversed by co-application of uridine or other pyrimidine precursors, underlining the postulated DHODH-directed mode of activity. Human and animal cytomegaloviruses as well as adenoviruses showed strong sensitivity towards Cmp1 in cell culture-based infection systems with IC50 values in the low micromolar to nanomolar range. Particularly, broad inhibitory activity was demonstrated for various types of laboratory and clinically relevant adenoviruses. For replication of human cytomegalovirus in primary fibroblasts, antiviral mode of activity was attributed to the early stage of gene expression. A mouse in vivo model proved reduced replication of murine cytomegalovirus in various organs upon Cmp1 treatment. These findings suggested Cmp1 as drug candidate and validated DHODH as a promising cellular target for antiviral therapy. PMID:24149002

Marschall, Manfred; Niemann, Ina; Kosulin, Karin; Bootz, Anna; Wagner, Sabrina; Dobner, Thomas; Herz, Thomas; Kramer, Bernd; Leban, Johann; Vitt, Daniel; Stamminger, Thomas; Hutterer, Corina; Strobl, Stefan

2013-12-01

365

Standardization of Nomenclature and Causality Assessment in Drug-Induced Liver Injury: Summary of a Clinical Research Workshop  

PubMed Central

Idiosyncratic drug-induced liver injury (DILI) is an important but relatively infrequent cause of potentially severe acute and chronic liver injury. The aim of this clinical research workshop was to review and attempt to standardize the current nomenclature and terminology used in DILI research. Because DILI is a diagnosis of exclusion, selected elements of the medical history, laboratory tests, and previous reports were proposed to improve causality assessment. Definitions and diagnostic criteria regarding the onset of DILI, evolution of liver injury, risk factors, and mandatory testing versus optional testing for competing causes were reviewed. In addition, the role of intentional and inadvertent rechallenge, liver histology, and host genetic polymorphisms in establishing the diagnosis and prognosis of DILI were reviewed. Consensus was established regarding the need to develop a web-of-knowledge database that provides concise, reliable, and updated information on cases of liver injury due to drugs and herbal and dietary supplements. In addition, the need to develop drug-specific computerized causality assessment methods that are derived from prospectively phenotyped cases was a high priority. Proposed scales for grading DILI severity and assessing the likelihood of an agent causing DILI and written criteria for improving the reliability, accuracy, and reproducibility of expert opinion were reviewed. Finally, the unique challenges of assessing causality in children, patients with underlying liver disease, and subjects taking herbal and dietary supplements were discussed. Conclusion: Workshop participants concluded that multicenter referral networks enrolling patients with suspected DILI according to standardized methodologies are needed. These networks should also collect biological samples that may provide crucial insights into the mechanism(s) of DILI with the ultimate aim of preventing future cases of DILI.

Fontana, Robert J.; Seeff, Leonard B.; Andrade, Raul J.; Bjornsson, Einar; Day, Christopher P.; Serrano, Jose; Hoofnagle, Jay H.

2013-01-01

366

Distributions  

NSDL National Science Digital Library

This online, interactive lesson on distributions provides examples, exercises, and applets which explore the basic types of probability distributions and the ways distributions can be defined using density functions, distribution functions, and quantile functions.

Siegrist, Kyle

2008-12-24

367

Action of Penetration Enhancers on Human Skin as Assessed by the Permeation of Model Drugs 5Fluorouracil and Estradiol. I. Infinite Dose Technique  

Microsoft Academic Search

We have conducted permeation studies to assess the effectiveness of accelerants Azone, oleic acid (OA), decylmethyl sulfoxide (DCMS) and propylene glycol (PG) in promoting the absorption through human skin of model drugs 5-fluorouracil (5FU) and estradiol (ES). Drug permeation from saturated aqueous solutions was monitored before and after accelerant treatment (applied in aqueous and PG vehicles). With ES, the study

Michael Goodman; Brian William Barry

1988-01-01

368

Compendia for Coverage of Off-Label uUes of Drugs and Biologics in an Anticancer Chemotherapeutic Regimen. Technology Assessment.  

National Technical Information Service (NTIS)

The topic of this assessment is the evaluation of drug compendia for the purpose of informing the Centers for Medicare & Medicaid Services (CMS) on decisions about coverage of off-label uses of drugs and biologics in anticancer treatment. This coverage is...

A. P. Abernethy E. Baik G. Raman J. M. Hammond M. L. Hubbard

2007-01-01

369

Off-label use of drugs in pain medicine and palliative care: an algorithm for the assessment of its safe and legal prescription  

Microsoft Academic Search

Off-label medication use is common practice, particularly in difficult to treat patients who have already tried commonly accepted medication unsuccessfully. Health authorities try to regulate this practice to protect the patient's safety and to prevent over consumption of new and more expensive drugs. Justified off-label drug use requires a thorough assessment. Physicians, in cooperation with formulary committees, need tools to

Constans C. A. H. H. V. M. Verhagen; Anne G. H. Niezink; Yvonne Y Engels; Yechiel Y. A. Hekster; Joan J. Doornebal; Kris C. P. Vissers

2008-01-01

370

Development of a vessel-simulating flow-through cell method for the in vitro evaluation of release and distribution from drug-eluting stents.  

PubMed

A novel in vitro dissolution test for drug-eluting stents (DES) based on the compendial flow-through cell was developed. The model contains an additional compartment simulating the vessel wall enabling the examination of drug release and distribution. The compartment consists of alginate hydrogel containing a central aperture forming the lumen for stent placement and media flow. The method was tested utilizing stents coated with hydrophilic (fluorescein sodium) and hydrophobic (triamterene) fluorescent model substances as well as the cytostatic drug doxorubicin hydrochloride and compared to standard dissolution methods. The results show the suitability of the developed method to observe drug release and distribution. The determination of model substance content in the compartments media, hydrogel and stent yielded differing distribution patterns for the model compounds and enabled the observation of redistribution processes. The dissolution profiles differed from the results of compendial dissolution testing. Besides lower endpoints and slower rises of media concentrations due to distribution into the hydrogel, the release rates from the stent coatings were altered. These findings emphasize the necessity to adapt dissolution testing for DES to the unique conditions influencing delivery to the vessel wall to learn more about local distribution and to anticipate the in vivo performance of DES. PMID:18562035

Neubert, Anne; Sternberg, Katrin; Nagel, Stefan; Harder, Claus; Schmitz, Klaus-Peter; Kroemer, Heyo K; Weitschies, Werner

2008-08-25

371

Nanotherapeutics in angiogenesis: synthesis and in vivo assessment of drug efficacy and biocompatibility in zebrafish embryos  

PubMed Central

Background Carbon nanotubes have shown broad potential in biomedical applications, given their unique mechanical, optical, and chemical properties. In this pilot study, carbon nanotubes have been explored as multimodal drug delivery vectors that facilitate antiangiogenic therapy in zebrafish embryos. Methods Three different agents, ie, an antiangiogenic binding site (cyclic arginine-glycin-easpartic acid), an antiangiogenic drug (thalidomide), and a tracking dye (rhodamine), were conjugated onto single-walled carbon nanotubes (SWCNT). The biodistribution, efficacy, and biocompatibility of these triple functionalized SWCNT were tested in mammalian cells and validated in transparent zebrafish embryos. Results Accumulation of SWCNT-associated nanoconjugates in blastoderm cells facilitated drug delivery applications. Mammalian cell xenograft assays demonstrated that these antiangiogenic SWCNT nanoconjugates specifically inhibited ectopic angiogenesis in the engrafted zebrafish embryos. Conclusion This study highlights the potential of using SWCNT for generating efficient nanotherapeutics.

Cheng, Jinping; Gu, Yan-Juan; Wang, Yajun; Cheng, Shuk Han; Wong, Wing-Tak

2011-01-01

372

Preclinical Predictors of Anticancer Drug Efficacy: Critical Assessment with Emphasis on Whether Nanomolar Potency Should Be Required of Candidate Agents  

PubMed Central

In the current paradigm of anticancer drug development, candidate compounds are evaluated by testing their in vitro potency against molecular targets relevant to carcinogenesis, their effect on cultured cancer cells, and their ability to inhibit cancer growth in animal models. We discuss the key assumptions inherent in these approaches. In recent years, great emphasis has been placed on selecting for development compounds with nanomolar in vitro potency, expecting that they will be efficacious and safer based on the assumption that they can be used at lower doses (“the nanomolar rule”). However, this rule ignores critical parameters affecting efficacy and toxicity such as physiochemical and absorption, distribution, metabolism and excretion properties, off-target effects, and multitargeting activities. Thus, uncritical application of the nanomolar rule may reject efficacious compounds or select ineffective or toxic compounds. We present examples of efficacious chemotherapeutic (alkylating agents, hormonal agents, antimetabolites, thalidomide, and valproic acid) and chemopreventive (aspirin and sulindac) agents having millimolar potency and compounds with nanomolar potency (cyclooxygenase-2 inhibitors) that, nevertheless, failed or proved to be unsafe. The effect of candidate drugs on animal models of cancer is a better predictor of human drug efficacy; particularly useful are tumor xenografts. Given the cost of failure at clinical stages, it is imperative to keep in mind the limitations of the nanomolar rule and use relevant in vivo models early in drug discovery to prioritize candidates. Although in vivo models will continue having a major role in cancer drug development, more robust approaches that combine high predictive ability with simplicity and low cost should be developed.

Wong, C. C.; Cheng, Ka-Wing

2012-01-01

373

Preclinical predictors of anticancer drug efficacy: critical assessment with emphasis on whether nanomolar potency should be required of candidate agents.  

PubMed

In the current paradigm of anticancer drug development, candidate compounds are evaluated by testing their in vitro potency against molecular targets relevant to carcinogenesis, their effect on cultured cancer cells, and their ability to inhibit cancer growth in animal models. We discuss the key assumptions inherent in these approaches. In recent years, great emphasis has been placed on selecting for development compounds with nanomolar in vitro potency, expecting that they will be efficacious and safer based on the assumption that they can be used at lower doses ("the nanomolar rule"). However, this rule ignores critical parameters affecting efficacy and toxicity such as physiochemical and absorption, distribution, metabolism and excretion properties, off-target effects, and multitargeting activities. Thus, uncritical application of the nanomolar rule may reject efficacious compounds or select ineffective or toxic compounds. We present examples of efficacious chemotherapeutic (alkylating agents, hormonal agents, antimetabolites, thalidomide, and valproic acid) and chemopreventive (aspirin and sulindac) agents having millimolar potency and compounds with nanomolar potency (cyclooxygenase-2 inhibitors) that, nevertheless, failed or proved to be unsafe. The effect of candidate drugs on animal models of cancer is a better predictor of human drug efficacy; particularly useful are tumor xenografts. Given the cost of failure at clinical stages, it is imperative to keep in mind the limitations of the nanomolar rule and use relevant in vivo models early in drug discovery to prioritize candidates. Although in vivo models will continue having a major role in cancer drug development, more robust approaches that combine high predictive ability with simplicity and low cost should be developed. PMID:22448039

Wong, C C; Cheng, Ka-Wing; Rigas, Basil

2012-06-01

374

A formalism to generate probability distributions for performance-assessment modeling  

SciTech Connect

A formalism is presented for generating probability distributions of parameters used in performance-assessment modeling. The formalism is used when data are either sparse or nonexistent. The appropriate distribution is a function of the known or estimated constraints and is chosen to maximize a quantity known as Shannon`s informational entropy. The formalism is applied to a parameter used in performance-assessment modeling. The functional form of the model that defines the parameter, data from the actual field site, and natural analog data are analyzed to estimate the constraints. A beta probability distribution of the example parameter is generated after finding four constraints. As an example of how the formalism is applied to the site characterization studies of Yucca Mountain, the distribution is generated for an input parameter in a performance-assessment model currently used to estimate compliance with disposal of high-level radioactive waste in geologic repositories, 10 CFR 60.113(a)(2), commonly known as the ground water travel time criterion. 8 refs., 2 figs.

Kaplan, P.G.

1990-12-31

375

Spatial point pattern analysis of aerial survey data to assess clustering in wildlife distributions  

NASA Astrophysics Data System (ADS)

Assessing clustering in wildlife populations is crucial for understanding their dynamics. This assessment is made difficult for data obtained through aerial surveys because the shape and size of sampling units (strip transects) result in poor data supports, which generally hampers spatial analysis of these data. The problem may be solved by having more detailed data where exact locations of observed animal groups are recorded. These data, obtainable through GPS technology, are amenable to spatial analysis, thereby allowing spatial point pattern analysis to be used to assess observed spatial patterns relative to environmental factors like vegetation. Distance measures like the G-statistic and K-function classify such patterns into clustered, regular or completely random patterns, while independence between species is assessed through a multivariate extension of the K-function. Quantification of clustering is carried out using spatial regression. The techniques are illustrated with field data on three ungulates observed in an ecosystem in Kenya. Results indicate a relation between species spatial distribution and their dietary requirements, thereby concluding the usefulness of spatial point pattern analysis in investigating species spatial distribution. It also provides a technique for explaining and differentiating the distribution of wildlife species.

Khaemba, Wilson Mwale

376

A meta-analysis of the hepatitis C virus distribution in diverse racial/ethnic drug injector groups  

PubMed Central

Hepatitis C virus (HCV) is mostly transmitted through blood-to-blood contact during injection drug use via shared contaminated syringes/needles or injection paraphernalia. This paper used meta-analytic methods to assess whether HCV prevalence and incidence varied across different racial/ethnic groups of injection drug users (IDUs) sampled internationally. The 29 prevalence and 11 incidence studies identified as part of the HCV Synthesis Project were categorized into subgroups based on similar racial/ethnic comparisons. The effect estimate used was the odds or risk ratio comparing HCV prevalence or incidence rates in racial/ethnic minority groups versus those of majority status. For prevalence studies, the clearest disparity in HCV status was observed in the Canadian and Australian Aboriginal versus White comparison, followed by the US non-White versus White categories. Overall, Hispanic IDUs had greater HCV prevalence, and HCV prevalence in African-Americans was not significantly greater than that of Whites in the US. Aboriginal groups showed higher HCV seroconversion rates when compared to others, and African-Americans had lower seroconversion rates compared to other IDUs in the US. The findings suggest that certain minority groups have elevated HCV rates in comparison to other IDUs, which may be a consequence of stigma, discrimination, different risk behaviors or decreased access to health care, services and preventive education. Future research should seek to explicitly explore and explain racial/ethnic variations in HCV prevalence and incidence, and define the groups more precisely to allow for more accurate detection of possible racial/ethnic differences in HCV rates.

Lelutiu-Weinberger, Corina; Pouget, Enrique R.; Des Jarlais, Don D.C.; Cooper, Hannah L.; Scheinmann, Roberta; Stern, Rebecca; Strauss, Shiela M.; Hagan, Holly

2013-01-01

377

21 CFR 212.90 - What actions must I take to control the distribution of PET drug products?  

Code of Federal Regulations, 2013 CFR

...following: (1) The name, address, and telephone number of the receiving facility that received each batch...of the PET drug product shipped; (3) The lot number, control number, or batch number for the PET drug product...

2013-04-01

378

Assessment of laser-induced release of drugs from liposomes: An in vitro study  

SciTech Connect

We evaluated the characteristics of laser-induced release of an antimetabolite (cytosine arabinoside) from temperature-sensitive liposomes. Previous work had shown that a laser would induce breakdown of liposomes when a dye was encapsulated within the liposomes. The present investigation was performed to determine if release could be induced from liposomes that did not contain dye. In vitro, dynamic studies of the release of the drug from liposomes diluted in blood (flowing in a capillary tube at 40 microns/min) were conducted using an argon dye laser operating either in the blue-green mode (488/514 nm) or in the dye mode (577 nm). A radio-labeled marker was used to monitor the drug release. The results showed that the drug could indeed be released from liposomes that did not contain dye, at energy levels that are not likely to be harmful to the tissue. At identical power levels, the release of the drug was greater at 577 nm than at 488/514 nm, probably owing to the greater light absorbance of hemoglobin at the longer wavelength. The results indicate the potential for the site-specific release of a variety of molecules in the ocular vasculature.

Khoobehi, B.; Char, C.A.; Peyman, G.A. (Louisiana State Univ. Medical Center School of Medicine, New Orleans (USA))

1990-01-01

379

A connectivity model for assessment of HIV transmission risk in injection drug users (IDUs).  

PubMed

The purpose of this study was to produce models composed of mapping of connectivity networks of HIV transmission risk in injection drug users (IDUs). This methodology provided a novel approach and diagnostic tool for understanding HIV infection transmission risk and drug use in the typical niche of IDUs, i.e., a "shooting gallery" (a gathering site for injection drug activity). Furthermore, component IDUs may have memberships in multiple "shooting galleries" revealing subsequent interconnectivities. Charting of IDU connectivity diagrams illustrated the relationships of peripheral sites to the critical central core of high HIV transmission risk. Members of this highly interlinked and infectious central core of IDUs had high HIV transmission risk and severe drug use-producing high morbidity and mortality that resulted in great public health concern. In addition, connectivity diagrams reveal very high HIV transmission risk in component IDUs in "dual memberships", i.e., membership in more than one central core (with the highest number of partners). Therefore, IDUs with "dual memberships" were the most infectious members of the "shooting gallery". In summation, network mapping of HIV transmission risk in IDUs allows for subsequent socio-behavioral analysis and the development of focused individual and programmatic interventions. PMID:23584136

Flaer, Paul J; Cistone, Peter J; Younis, Mustafa Z; Parkash, Jai

2013-08-01

380

Beneficiary Cost Sharing Under Canadian Provincial Prescription Drug Benefit Programs: History and Assessment  

Microsoft Academic Search

Federal legislation outlined in the Medical Care Act of 1965 and the Canada Health Act of 1984 stipulates that Canadian provincial governments are to administer insurance programs for medically necessary services provided by hospitals and physicians. The legislation did not mandate provincial government coverage for prescription drugs taken outside of the hospital. Each province has, however, provided coverage to seniors

P Grootendorst

1999-01-01

381

Illicit Drugs and Alcohol in Breast Milk: Assessing Risk to Infants  

Microsoft Academic Search

There is no question that breast-feeding is beneficial to both mother and infant. Manifold advantages ensue from the process; protection against infection and reduced risk of exposure to external sources of food contamination are only two of the many. Yet, the degree and risk involved from in vivo contamination of this precious fluid through maternal use of illicit drugs, tobacco

Henry C. Nipper

382

A Condom Skill Scale: Assessing Condom Skills among Female Drug Users.  

ERIC Educational Resources Information Center

Describe the development and properties of a scale measuring demonstrated condom use skill using a sample of 261 drug-using women. Analysis of scale scores revealed high levels of condom skill among the population. Preliminary analysis suggests that the Condom Skill Scale is a potentially valid and reliable instrument, and may have application as…

Farris, Coreen A.; Fenaughty, Andrea M.; Lindemann, Dana F.

2003-01-01

383

Double Jeopardy: An Assessment of the Felony Drug Provision of the Welfare Reform Act.  

ERIC Educational Resources Information Center

In 1996 the Aid to Families with Dependent Children program was replaced with a federal block grant program called Temporary Assistance for Needy Families (TANF), which imposed time limits and work requirements on welfare recipients. The welfare legislation placed a lifetime ban on TANF and food stamp benefits for convicted drug felons, although…

Adams, Rukaiyah; Onek, David; Riker, Alissa

384

Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism  

Microsoft Academic Search

Neurophysiological studies of major depression performed using PET imaging have shown abnormalities of regional cerebral blood flow (CBF) and glucose metabolism in multiple prefrontal cortical and limbic structures that have been more generally implicated in emotional processing. The current study investigated the effects of antidepressant drug treatment in these regions using PET measures of glucose metabolism. Subjects with primary MDD

Wayne C Drevets; Wendy Bogers; Marcus E Raichle

2002-01-01

385

Assessment of benzimidazole resistance in Haemonchus contortus in sheep flocks in Ontario, Canada: comparison of detection methods for drug resistance.  

PubMed

In 2011, a field study was conducted to assess drug resistance of gastro-intestinal nematodes in sheep flocks in Ontario, Canada. Benzimidazole resistance in Haemonchus contortus was assessed by genetic analysis of eggs; measurement of resistant allele percentages at codons 167, 198 and 200 in the ?-tubulin gene was determined on pools of H. contortus eggs using pyrosequencing. Susceptibility to benzimidazoles in gastro-intestinal nematodes was also determined using a Faecal Egg Count Reduction Test (FECRT) and a Larval Development Assay (LDA). In total, 16 farms were assessed with the genetic test. Based on resistant allele frequencies, all of the farms (16/16) tested had benzimidazole resistance in H. contortus; the overall percentage of benzimidazole-resistant H. contortus (estimated prior to treatment using the Hardy-Weinberg formula) was 68.5%. The FECRT and LDA were performed on 11 and 13 farms, respectively. Resistance to fenbendazole was detected on 100% (11/11) of the farms where the FECRT was performed. The LDA revealed the presence of thiabendazole resistance in H. contortus in 92% (12/13) of the farms. Estimated percentages of resistant parasites in H. contortus populations obtained with the two biological tests and the genetic test were compared. The results of the genetic test were in agreement with the biological tests and confirmed that benzimidazole resistance in H. contortus is present in Ontario sheep flocks. Differences between the different methods of drug resistance detection are discussed in terms of cost, time and sampling. PMID:23993632

Barrere, V; Falzon, L C; Shakya, K P; Menzies, P I; Peregrine, A S; Prichard, R K

2013-11-15

386

Assessment of stability of drug biomarkers in municipal wastewater as a factor influencing the estimation of drug consumption using sewage epidemiology.  

PubMed

Stability of the selected urinary biomarkers of six illicit drugs and two therapeutic opioids in municipal wastewater was studied in order to determine errors associated with their possible transformation in the sewer. The stability was assessed in experiments conducted at 10°C and 20°C in order to simulate typical winter and summer temperature conditions in the sewer system. Among fourteen substances tested, the most unstable compounds were morphine-3-?-D glucuronide (MG), 6-acetyl morphine (6-AM), cocaine (COC) and 6-acetyl codeine (6-AC), while all other investigated compounds appeared to be relatively stable over a period of 72h. The transformation of all degradable compounds followed pseudo-first order kinetics with significantly longer half-times (t1/2) at winter conditions. At 20°C, t1/2 of MG, 6-AM, COC and 6-AC was 7h, 87h, 35h and 58h, respectively, while the corresponding t1/2 values at 10°C were 18h, 139h, 173h and 87h. The main transformation mechanism of MG, 6-AM and 6-AC was most probably their enzymatic hydrolysis to morphine (MOR) and codeine (COD), while COC transformation to benzoylecgonine (BE) was primarily governed by chemical hydrolysis. The results indicate that the effect of the observed transformation of urinary biomarkers of COC and 6-AM on the estimates of COC and heroin consumption are relatively small (<10%) if the in-sewer hydraulic retention time is lower than 12h. Acidification of the wastewater samples proved to be the good way to stabilise the wastewater samples for the analysis of all selected compounds, except for 11-nor-9-carboxy-?9-tetrahydrocannabinol (THC-COOH). This finding should be taken into account when selecting the preservation technique for multiresidual analyses of different groups of illicit drugs. PMID:24411995

Senta, Ivan; Krizman, Ivona; Ahel, Marijan; Terzic, Senka

2014-07-15

387

Assessment of drug-induced hepatotoxicity in clinical practice: A challenge for gastroenterologists  

PubMed Central

Currently, pharmaceutical preparations are serious contributors to liver disease; hepatotoxicity ranking as the most frequent cause for acute liver failure and post-commercialization regulatory decisions. The diagnosis of hepatotoxicity remains a difficult task because of the lack of reliable markers for use in general clinical practice. To incriminate any given drug in an episode of liver dysfunction is a step-by-step process that requires a high degree of suspicion, compatible chronology, awareness of the drug’s hepatotoxic potential, the exclusion of alternative causes of liver damage and the ability to detect the presence of subtle data that favors a toxic etiology. This process is time-consuming and the final result is frequently inaccurate. Diagnostic algorithms may add consistency to the diagnostic process by translating the suspicion into a quantitative score. Such scales are useful since they provide a framework that emphasizes the features that merit attention in cases of suspected hepatic adverse reaction as well. Current efforts in collecting bona fide cases of drug-induced hepatotoxicity will make refinements of existing scales feasible. It is now relatively easy to accommodate relevant data within the scoring system and to delete low-impact items. Efforts should also be directed toward the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be made. The instrument chosen would enable a confident diagnosis to be made on admission of the patient and treatment to be fine-tuned as further information is collected.

Andrade, Raul J; Robles, Mercedes; Fernandez-Castaner, Alejandra; Lopez-Ortega, Susana; Lopez-Vega, M Carmen; Lucena, M Isabel

2007-01-01

388

Flow-through sensor array applied to cytotoxicity assessment in cell cultures for drug-testing purposes.  

PubMed

The viability of cells cultured in microsystems for drug screening purposes is usually tested with a variety of colorimetric/fluorescent methods. In this work we propose an alternative way of assessing cell viability-flow-through sensor array that can be connected in series with cell microbioreactors as compatible detection system. It is shown, that the presented device is capable of cytotoxic effect detection and estimation of cell viability after treatment with 1,4-dioxane and 5-fluorouracil, which proves that it can be used for truly non-invasive, fast, reliable, continuous cell culture monitoring in microscale. PMID:23932980

Witkowska Nery, Emilia; Jastrz?bska, El?bieta; ?ukowski, Kamil; Wróblewski, Wojciech; Chudy, Micha?; Ciosek, Patrycja

2014-01-15

389

Rat granulocyte colony-forming unit (CFU-G) assay for the assessment of drug-induced hematotoxicity  

Microsoft Academic Search

To assess the drug-induced hematotoxicity to granulocyte progenitors, we established a modified colony-forming assay using rat bone marrow cells (BMCs). In the presence of various colony-stimulating factors (CSFs), rat BMCs were disseminated on methylcellulose at a concentration of 1.3×104 cells\\/cm2 (5×104 cells\\/0.5 ml\\/well in a 12-well plate). Mouse granulocyte-macrophage colony-stimulating factor (mGM-CSF) stimulated the formation of almost all macrophage colonies.

K. Matsumura-Takeda; K. Kotosai; A. Ozaki; H. Hara; S. Yamashita

2002-01-01

390

Distribution of Drug Resistance Genotypes in Plasmodium falciparum in an Area of Limited Parasite Diversity in Saudi Arabia  

PubMed Central

Two hundred and three Plasmodium falciparum isolates from Jazan area, southwest Saudi Arabia, were typed for Pfcrt, Pfmdr1, dhps, and dhfr mutations associated with resistance to chloroquine, mefloquine, halofantrine, artemisinin, sulfadoxine-pyrimethamine, and the neutral polymorphic gene Pfg377. A large proportion (33%) of isolates harbored double mutant dhfr genotype (51I,59C,108N). However, only one isolate contained mutation dhps-437G. For Pfcrt, almost all examined isolates (163; 99%) harbored the mutant genotype (72C,73V,74I,75E,76T), whereas only 49 (31%) contained the mutant Pfmdr1 genotype (86Y,184F,1034S,1042N), 109 (66%) harbored the single mutant genotype (86N,184F,1034S,1042N), and no mutations were seen in codons 1034, 1042, and 1246. Nonetheless, three new single-nucleotide polymorphisms were detected at codons 182, 192, and 102. No differences were seen in distribution of drug resistance genes among Saudis and expatriates. There was a limited multiplicity (5%), mean number of clones (1.05), and two dominant multilocus genotypes among infected individuals in Jazan. A pattern consistent with limited cross-mating and recombination among local parasite was apparent.

Bin Dajem, Saad M.; Al-Farsi, Hissa M.; Al-Hashami, Zainab S.; Al-Sheikh, Adel Ali H.; Al-Qahtani, Ahmed; Babiker, Hamza A.

2012-01-01

391

Distribution of drug resistance genotypes in Plasmodium falciparum in an area of limited parasite diversity in Saudi Arabia.  

PubMed

Two hundred and three Plasmodium falciparum isolates from Jazan area, southwest Saudi Arabia, were typed for Pfcrt, Pfmdr1, dhps, and dhfr mutations associated with resistance to chloroquine, mefloquine, halofantrine, artemisinin, sulfadoxine-pyrimethamine, and the neutral polymorphic gene Pfg377. A large proportion (33%) of isolates harbored double mutant dhfr genotype (51I,59C,108N). However, only one isolate contained mutation dhps-437G. For Pfcrt, almost all examined isolates (163; 99%) harbored the mutant genotype (72C,73V,74I,75E,76T), whereas only 49 (31%) contained the mutant Pfmdr1 genotype (86Y,184F,1034S,1042N), 109 (66%) harbored the single mutant genotype (86N,184F,1034S,1042N), and no mutations were seen in codons 1034, 1042, and 1246. Nonetheless, three new single-nucleotide polymorphisms were detected at codons 182, 192, and 102. No differences were seen in distribution of drug resistance genes among Saudis and expatriates. There was a limited multiplicity (5%), mean number of clones (1.05), and two dominant multilocus genotypes among infected individuals in Jazan. A pattern consistent with limited cross-mating and recombination among local parasite was apparent. PMID:22556074

Bin Dajem, Saad M; Al-Farsi, Hissa M; Al-Hashami, Zainab S; Al-Sheikh, Adel Ali H; Al-Qahtani, Ahmed; Babiker, Hamza A

2012-05-01

392

Deoxyribonucleic acid (DNA) biosensors for environmental risk assessment and drug studies  

Microsoft Academic Search

In the present work, electrochemical DNA biosensors are proposed as a screening device for the rapid bio-analysis of environmental pollution and DNA–drug interaction studies. The binding of small molecules to DNA immobilised on disposable screen-printed electrodes has been measured through the variation of the electrochemical signal of guanine by square wave voltammetric scans. These kinds of biosensors were used to

Graziana Bagni; Domenico Osella; Elena Sturchio; Marco Mascini

2006-01-01

393

Short Communication Kinetic assessment of the potassium ferrate(VI) oxidation of antibacterial drug sulfamethoxazole  

Microsoft Academic Search

Sulfamethoxazole (SMX), a worldwide-applied antibacterial drug, was recently found in surface waters and in sec- ondary wastewater effluents, which may result in ecotoxical effects in the environment. Herein, removal of SMX by environmentally-friendly oxidant, potassium ferrate(VI) (K2FeO4), is sought by studying the kinetics of the reaction between Fe(VI) and SMX as a function of pH (6.93-9.50) and temperature (15-45 ?

Virender K. Sharma; Santosh K. Mishra; Ajay K. Ray

394

Kinetic assessment of the potassium ferrate(VI) oxidation of antibacterial drug sulfamethoxazole  

Microsoft Academic Search

Sulfamethoxazole (SMX), a worldwide-applied antibacterial drug, was recently found in surface waters and in secondary wastewater effluents, which may result in ecotoxical effects in the environment. Herein, removal of SMX by environmentally-friendly oxidant, potassium ferrate(VI) (K2FeO4), is sought by studying the kinetics of the reaction between Fe(VI) and SMX as a function of pH (6.93–9.50) and temperature (15–45°C). The rate

Virender K. Sharma; Santosh K. Mishra; Ajay K. Ray

2006-01-01

395

Kinetic assessment of measured mass flow rates and streamwise pressure distributions in microchannel gas flows  

Microsoft Academic Search

Measured mass flow rates and streamwise pressure distributions of gas flowing through microchannels were reported by many\\u000a researchers. Assessment of these data is crucial before they are used in the examination of slip models and numerical schemes,\\u000a and in the design of microchannel elements in various MEMS devices. On the basis of kinetic solutions of the mass flow rates\\u000a and

Jing Fan; Chong Xie; Jianzheng Jiang

2007-01-01

396

On the Assessment of Multiobjective Approaches to the Adaptive Distributed Database Management Problem  

Microsoft Academic Search

. In this paper we assess the performance of three modern multiobjectiveevolutionary algorithms on a real-world optimization problemrelated to the management of distributed databases. The algorithmsassessed are the Strength Pareto Evolutionary Algorithm (SPEA), thePareto Archived Evolution Strategy (PAES), and M-PAES, which is aMemetic Algorithm based variant of PAES. The performance of these algorithmsis compared using two distinct and sophisticated multiobjectiveperformance...

Joshua D. Knowles; David Corne; Martin J. Oates

2000-01-01

397

Improving statistical distinctness in assessing trophic levels: the development of simulated normal distributions  

Microsoft Academic Search

The statistical distinctness in assessing differences of the trophic status between sampling sites was investigated in the\\u000a present study. Nutrient (phosphate, nitrate, nitrite, ammonia) and phytoplankton (chlorophyll, cell number) variables from\\u000a nine sampling stations were used for the validation of the statistical procedures. Raw data, transformed data, and simulated\\u000a data derived on normalized nutrient–phytoplankton frequency distribution were tested. The Kruskal–Wallis

Ioannis Primpas; Michael Karydis

2010-01-01

398

Assessment of size-dependent mercury distribution in King Mackerel, Scomberomorus cavalla  

SciTech Connect

The assessment of health risks from fish contamination and the issuance of advisories require accurate characterizations of the actual contaminant concentrations in fish of every relevant size. Such characterizations should not only contain statistical measures of location and variation, but provide a complete parameterization of the contaminant distribution for each given size class. This paper proposes two methods for determining such distributions from scatter diagrams of contaminant concentratio