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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. PMID:19146691

Fenneteau, Frédérique; Turgeon, Jacques; Couture, Lucie; Michaud, Véronique; Li, Jun; Nekka, Fahima

2009-01-01

2

Multimodal assessment of spatial distribution of drug-tracer uptake by brain tissue after intra-arterial injections  

NASA Astrophysics Data System (ADS)

It is challenging to track the rapid changes in drug concentrations after intra-arterial (IA) administration to elucidate the pharmacokinetics of this method of drug delivery. Traditional pharmacokinetic parameters (such as protein binding) that are highly relevant to intravenous (IV) administration do not seem to apply to IA injections. Regional drug delivery is affected by the biomechanics of drug injection, resting blood flow, and local tissue extraction. In-vivo and ex-vivo, optical methods for spatial mapping of drug deposition can assist in visualizing drug distributions and aid in the screening of potential drugs and carrier candidates. We present a multimodal approach for the assessment of drug distribution in postmortem tissue specimens using diffuse reflectance spectroscopy, multispectral imaging, and confocal microscopy and demonstrate feasibility of distinguishing route of administration advantages of liposome-dye conjugate delivery. The results of this study suggest that insight on drug dynamics gained by this aggregated approach can be used to help screen and/or optimize potential drug candidates and drug delivery protocols.

Singh-Moon, Rajinder; Chaudhuri, Durba; Wang, Mei; Straubinger, Robert; Bigio, Irving J.; Joshi, Shailendra

2014-02-01

3

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

2011-03-01

4

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. PMID:20131876

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

2010-01-01

5

Intratumor heterogeneity and its impact on drug distribution and sensitivity.  

PubMed

We provide an overview of the available information on the distribution of chemotherapeutics in human tumors, highlighting the progress made to assess the heterogeneity of drug concentrations in relation to the complex neoplastic tissue using novel analytical methods, e.g., mass spectrometry imaging. The increase in interstitial fluid pressure due to abnormal vascularization and stiffness of tumor stroma explains the variable and heterogeneous drug concentrations. Therapeutic strategies to enhance tumor drug distribution, thus possibly increasing efficacy, are discussed. PMID:24827540

Fuso Nerini, I; Morosi, L; Zucchetti, M; Ballerini, A; Giavazzi, R; D'Incalci, M

2014-08-01

6

Distributed road assessment system  

DOEpatents

A system that detects damage on or below the surface of a paved structure or pavement is provided. A distributed road assessment system includes road assessment pods and a road assessment server. Each road assessment pod includes a ground-penetrating radar antenna array and a detection system that detects road damage from the return signals as the vehicle on which the pod is mounted travels down a road. Each road assessment pod transmits to the road assessment server occurrence information describing each occurrence of road damage that is newly detected on a current scan of a road. The road assessment server maintains a road damage database of occurrence information describing the previously detected occurrences of road damage. After the road assessment server receives occurrence information for newly detected occurrences of road damage for a portion of a road, the road assessment server determines which newly detected occurrences correspond to which previously detected occurrences of road damage.

Beer, N. Reginald; Paglieroni, David W

2014-03-25

7

Preclinical assessment of abuse liability of drugs  

Microsoft Academic Search

Studies that are used in preclinical assessment of the liability of a drug to become an abuse problem are reviewed. These studies examine the capacity of a drug to produce physiological dependence or to function as a reinforcer. Studies that examine physiological dependence by assessing whether a drug reverses signs of withdrawal from a standard drug are rapid, reliable and

J. L. Katz; S. R. Goldberg

1988-01-01

8

Reducing drug related deaths: a pre-implementation assessment of knowledge,barriers and enablers for naloxone distribution through general practice  

PubMed Central

Background The Scottish Naloxone Programme aims to reduce Scotland’s high number of drug-related deaths (DRDs) caused by opiate overdose. It is currently implemented through specialist drug services but General Practitioners (GPs) are likely to have contact with drug using patients and their families and are therefore in an ideal position to direct them to naloxone schemes, or provide it themselves. This research gathered baseline data on GP’s knowledge of and willingness to be involved in DRD prevention, including naloxone administration, prior to the implementation of primary care based delivery. Methods Mixed methods were used comprising a quantitative, postal survey and qualitative telephone interviews. A questionnaire was sent to 500 GPs across Scotland. An initial mailing was followed by a reminder. A shortened questionnaire containing seven key questions was posted as a final reminder. Telephone interviews were conducted with 17 GPs covering a range of demographic characteristics and drug user experience. Results A response rate of 55% (240/439) was achieved. There was some awareness of the naloxone programme but little involvement (3.3%), 9% currently provided routine overdose prevention, there was little involvement in displaying overdose prevention information (<20%). Knowledge of DRD risk was mixed. There was tentative willingness to be involved in naloxone prescribing with half of respondents willing to provide this to drug users or friends/family. However half were uncertain GP based naloxone provision was essential to reduce DRDs. Factors enabling naloxone distribution were: evidence of effectiveness, appropriate training, and adding to the local formulary. Interviewees had limited awareness of what naloxone distribution in primary care may involve and considered naloxone supply as a specialist service rather than a core GP role. Wider attitudinal barriers to involvement with this group were expressed. Conclusions There was poor awareness of the Scottish National Naloxone Programme in participants. Results indicated GPs did not currently feel sufficiently skilled or knowledgeable to be involved in naloxone provision. Appropriate training was identified as a key requirement. PMID:24428947

2014-01-01

9

Pricing, distribution, and use of antimalarial drugs.  

PubMed

Prices of new antimalarial drugs are targeted at the "travellers' market" in developed countries, which makes them unaffordable in malaria-endemic countries where the per capita annual drug expenditures are US$ 5 or less. Antimalarials are distributed through a variety of channels in both public and private sectors, the official malaria control programmes accounting for 25-30% of chloroquine distribution. The unofficial drug sellers in markets, streets, and village shops account for as much as half of antimalarials distributed in many developing countries. Use of antimalarials through the health services is often poor; drug shortages are common and overprescription and overuse of injections are significant problems. Anxiety over drug costs may prevent patients from getting the necessary treatment for malaria, especially because of the seasonal appearance of this disease when people's cash reserves are very low. The high costs may lead them to unofficial sources, which will sell a single tablet instead of a complete course of treatment, and subsequently to increased, often irrational demand for more drugs and more injections. Increasingly people are resorting to self-medication for malaria, which may cause delays in seeking proper treatment in cases of failure, especially in areas where chloroquine resistance has increased rapidly. Self-medication is now widespread, and measures to restrict the illicit sale of drugs have been unsuccessful. The "unofficial" channels thus represent an unacknowledged extension of the health services in many countries; suggestions are advanced to encourage better self-medication by increasing the knowledge base among the population at large (mothers, schoolchildren, market sellers, and shopkeepers), with an emphasis on correct dosing and on the importance of seeking further treatment without delay, if necessary. PMID:1893512

Foster, S D

1991-01-01

10

21 CFR 1310.10 - Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act.  

Code of Federal Regulations, 2011 CFR

...the exemption of drugs distributed under the Food, Drug and Cosmetic Act. 1310.10 Section 1310.10 Food and Drugs ...the exemption of drugs distributed under the Food, Drug and Cosmetic Act. (a) The Administrator may remove from...

2011-04-01

11

21 CFR 1310.10 - Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act.  

Code of Federal Regulations, 2010 CFR

...the exemption of drugs distributed under the Food, Drug and Cosmetic Act. 1310.10 Section 1310.10 Food and Drugs ...the exemption of drugs distributed under the Food, Drug and Cosmetic Act. (a) The Administrator may remove from...

2010-04-01

12

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

Code of Federal Regulations, 2013 CFR

... false Requirements for wholesale distribution of prescription drugs. 203.50...PRESCRIPTION DRUG MARKETING Wholesale Distribution § 203.50 Requirements for wholesale distribution of prescription drugs. (a)...

2013-04-01

13

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

Code of Federal Regulations, 2012 CFR

... false Requirements for wholesale distribution of prescription drugs. 203.50...PRESCRIPTION DRUG MARKETING Wholesale Distribution § 203.50 Requirements for wholesale distribution of prescription drugs. (a)...

2012-04-01

14

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

Code of Federal Regulations, 2010 CFR

... false Requirements for wholesale distribution of prescription drugs. 203.50...PRESCRIPTION DRUG MARKETING Wholesale Distribution § 203.50 Requirements for wholesale distribution of prescription drugs. (a)...

2010-04-01

15

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

Code of Federal Regulations, 2011 CFR

... false Requirements for wholesale distribution of prescription drugs. 203.50...PRESCRIPTION DRUG MARKETING Wholesale Distribution § 203.50 Requirements for wholesale distribution of prescription drugs. (a)...

2011-04-01

16

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

... false Requirements for wholesale distribution of prescription drugs. 203.50...PRESCRIPTION DRUG MARKETING Wholesale Distribution § 203.50 Requirements for wholesale distribution of prescription drugs. (a)...

2014-04-01

17

Drugs in Thailand: Assessing Police Attitudes  

Microsoft Academic Search

This article examines the attitudes of Thai police regarding illegal drugs in the following areas: (a) drug-crime connections, (b) drug enforcement, (c) drug-related corruption, and (d) the seriousness of the drug problem The authors explore the effects of 16 independent variables on officers' attitudes derived from personal background indicators, institutional support measures, and drug offense information variables. Using data collected

Sutham Cheurprakobkit; Pomchai Kuntee; Michael S. Vauhgn

1998-01-01

18

Optimizing distribution of pandemic influenza antiviral drugs.  

PubMed

We provide a data-driven method for optimizing pharmacy-based distribution of antiviral drugs during an influenza pandemic in terms of overall access for a target population and apply it to the state of Texas, USA. We found that during the 2009 influenza pandemic, the Texas Department of State Health Services achieved an estimated statewide access of 88% (proportion of population willing to travel to the nearest dispensing point). However, access reached only 34.5% of US postal code (ZIP code) areas containing <1,000 underinsured persons. Optimized distribution networks increased expected access to 91% overall and 60% in hard-to-reach regions, and 2 or 3 major pharmacy chains achieved near maximal coverage in well-populated areas. Independent pharmacies were essential for reaching ZIP code areas containing <1,000 underinsured persons. This model was developed during a collaboration between academic researchers and public health officials and is available as a decision support tool for Texas Department of State Health Services at a Web-based interface. PMID:25625858

Singh, Bismark; Huang, Hsin-Chan; Morton, David P; Johnson, Gregory P; Gutfraind, Alexander; Galvani, Alison P; Clements, Bruce; Meyers, Lauren A

2015-02-01

19

Optimizing Distribution of Pandemic Influenza Antiviral Drugs  

PubMed Central

We provide a data-driven method for optimizing pharmacy-based distribution of antiviral drugs during an influenza pandemic in terms of overall access for a target population and apply it to the state of Texas, USA. We found that during the 2009 influenza pandemic, the Texas Department of State Health Services achieved an estimated statewide access of 88% (proportion of population willing to travel to the nearest dispensing point). However, access reached only 34.5% of US postal code (ZIP code) areas containing <1,000 underinsured persons. Optimized distribution networks increased expected access to 91% overall and 60% in hard-to-reach regions, and 2 or 3 major pharmacy chains achieved near maximal coverage in well-populated areas. Independent pharmacies were essential for reaching ZIP code areas containing <1,000 underinsured persons. This model was developed during a collaboration between academic researchers and public health officials and is available as a decision support tool for Texas Department of State Health Services at a Web-based interface. PMID:25625858

Huang, Hsin-Chan; Morton, David P.; Johnson, Gregory P.; Gutfraind, Alexander; Galvani, Alison P.; Clements, Bruce; Meyers, Lauren A.

2015-01-01

20

Using Diaries to Assess Nonprescription Drug Use among University Students  

ERIC Educational Resources Information Center

Nonprescription drug use among university students was investigated using survey and behavioral diary methodologies to assess usage of nonprescription drug use and to compare survey and diary methodologies. Surveys were completed by 183 students (136 females and 47 males) that asked how often they used nonprescription drugs and what those drugs

Acocella, Cecilia M.

2005-01-01

21

Similarity Between Obesity and Drug Addiction as Assessed  

E-print Network

Similarity Between Obesity and Drug Addiction as Assessed by Neurofunctional Imaging: A Concept behavior observed in drug-addicted subjects. The mechanism of these behaviors is not well understood. Our]: "Similarity Between Obesity and Drug Addiction as Assessed by Neurofunctional Imaging: A Concept Review." Wang

Homes, Christopher C.

22

Effects of cellular pharmacology on drug distribution in tissues.  

PubMed Central

The efficacy of targeted therapeutics such as immunotoxins is directly related to both the extent of distribution achievable and the degree of drug internalization by individual cells in the tissue of interest. The factors that influence the tissue distribution of such drugs include drug transport; receptor/drug binding; and cellular pharmacology, the processing and routing of the drug within cells. To examine the importance of cellular pharmacology, previously treated only superficially, we have developed a mathematical model for drug transport in tissues that includes drug and receptor internalization, recycling, and degradation, as well as drug diffusion in the extracellular space and binding to cell surface receptors. We have applied this "cellular pharmacology model" to a model drug/cell system, specifically, transferrin and the well-defined transferrin cycle in CHO cells. We compare simulation results to models with extracellular diffusion only or diffusion with binding to cell surface receptors and present a parameter sensitivity analysis. The comparison of models illustrates that inclusion of intracellular trafficking significantly increases the total transferrin concentration throughout much of the tissue while decreasing the penetration depth. Increasing receptor affinity or tissue receptor density reduces permeation of extracellular drug while increasing the peak value of the intracellular drug concentration, resulting in "internal trapping" of transferrin near the source; this could account for heterogeneity of drug distributions observed in experimental systems. Other results indicate that the degree of drug internalization is not predicted by the total drug profile. Hence, when intracellular drug is required for a therapeutic effect, the optimal treatment may not result from conditions that produce the maximal total drug distribution. Examination of models that include cellular pharmacology may help guide rational drug design and provide useful information for whole body pharmacokinetic studies. PMID:8519983

Rippley, R K; Stokes, C L

1995-01-01

23

Provinces create centralized system for assessing new drugs.  

PubMed

Provincial health ministers have created a common drug-review process for assessing whether new drugs should be place on provincial formularies. The new system will save money, but will it improve access? PMID:14719493

Hillson, Glen

2002-12-01

24

21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.  

Code of Federal Regulations, 2012 CFR

...exemption for drug products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG...exemption for drug products distributed under the Food, Drug and Cosmetic Act. (a) The Administrator has reinstated the...

2012-04-01

25

21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.  

Code of Federal Regulations, 2013 CFR

...exemption for drug products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG...exemption for drug products distributed under the Food, Drug and Cosmetic Act. (a) The Administrator has reinstated the...

2013-04-01

26

21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.  

...exemption for drug products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG...exemption for drug products distributed under the Food, Drug and Cosmetic Act. (a) The Administrator has reinstated the...

2014-04-01

27

21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.  

Code of Federal Regulations, 2011 CFR

...exemption for drug products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG...exemption for drug products distributed under the Food, Drug and Cosmetic Act. (a) The Administrator has reinstated the...

2011-04-01

28

21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.  

Code of Federal Regulations, 2010 CFR

...exemption for drug products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG...exemption for drug products distributed under the Food, Drug and Cosmetic Act. (a) The Administrator has reinstated the...

2010-04-01

29

Distribution of veterinary drug residues among muscles  

Technology Transfer Automated Retrieval System (TEKTRAN)

The U.S. Food and Drug Administration sets tolerances for veterinary drug residues in muscle, but does not specify which muscle should be sampled for analysis. The goal of this research was to determine if antibiotic residue levels are dependent on muscle type. In this study, penicillin G (Pen G) d...

30

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. PMID:20730049

Bate, Roger; Hess, Kimberly

2010-01-01

31

Implicit and Explicit Drug-Related Cognitions during Detoxification Treatment Are Associated with Drug Relapse: An Ecological Momentary Assessment Study  

ERIC Educational Resources Information Center

Objective: Relapse is a major problem in drug addiction treatment. Both drug craving and drug-related cognitions (e.g., attentional bias and implicit attitudes to drugs) may contribute to relapse. Using ecological momentary assessments, we examined whether craving and cognitions assessed during drug detoxification treatment were associated with…

Marhe, Reshmi; Waters, Andrew J.; van de Wetering, Ben J. M.; Franken, Ingmar H. A.

2013-01-01

32

DISSERTATION Spatially Distributed Model to Assess Watershed  

E-print Network

DISSERTATION Spatially Distributed Model to Assess Watershed Contaminant Transport and Fate OF DISSERTATION SPATIALLY DISTRIBUTED MODEL TO ASSESS WATERSHED CONTAMINANT TRANSPORT AND FATE Unmanaged to simulate chemical transport and fate at the watershed scale. In addition to runoff and sediment transport

Julien, Pierre Y.

33

Standardized stimuli to assess drug craving and drug memory in addicts  

Microsoft Academic Search

Summary.   Due to conditioning processes, originally neutral stimuli become drug-associated cues and can initiate drug craving. Standardized\\u000a stimuli are required to assess stimulus-induced activation of drug memory and craving in brain imaging and neurophysiology\\u000a studies. We developed substance-specific visual and olfactory stimuli for alcohol, tobacco, opiate and cannabis abuse and\\u000a tested them in subjects with the respective addiction and in

S. M. Grüsser; A. Heinz; H. Flor

2000-01-01

34

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

35

Pharmacological distribution diagrams: a tool for de novo drug design.  

PubMed

Discriminant analysis applied to SAR studies using topological descriptors allows us to plot frequency distribution diagrams: a function of the number of drugs within an interval of values of discriminant function vs. these values. We make use of these representations, pharmacological distribution diagrams (PDDs), in structurally heterogeneous groups where generally they adopt skewed Gaussian shapes or present several maxima. The maxima afford intervals of discriminant function in which exists a good expectancy to find new active drugs. A set of beta-blockers with contrasted activity has been selected to test the ability of PDDs as a visualizing technique, for the identification of new beta-blocker active compounds. PMID:9097233

Gálvez, J; García-Domenech, R; de Gregorio Alapont, C; de Julián-Ortiz, J V; Popa, L

1996-10-01

36

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. PMID:8581296

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

1995-01-01

37

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

38

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

39

Quantitative detection of drug dose and spatial distribution in the lung revealed by Cryoslicing Imaging.  

PubMed

Administration of drugs via inhalation is an attractive route for pulmonary and systemic drug delivery. The therapeutic outcome of inhalation therapy depends not only on the dose of the lung-delivered drug, but also on its bioactivity and regional distribution. Fluorescence imaging has the potential to monitor these aspects already during preclinical development of inhaled drugs, but quantitative methods of analysis are lacking. In this proof-of-concept study, we demonstrate that Cryoslicing Imaging allows for 3D quantitative fluorescence imaging on ex vivo murine lungs. Known amounts of fluorescent substance (nanoparticles or fluorophore-drug conjugate) were instilled in the lungs of mice. The excised lungs were measured by Cryoslicing Imaging. Herein, white light and fluorescence images are obtained from the face of a gradually sliced frozen organ block. A quantitative representation of the fluorescence intensity throughout the lung was inferred from the images by accounting for instrument noise, tissue autofluorescence and out-of-plane fluorescence. Importantly, the out-of-plane fluorescence correction is based on the experimentally determined effective light attenuation coefficient of frozen murine lung tissue (10.0±0.6cm(-1) at 716nm). The linear correlation between pulmonary total fluorescence intensity and pulmonary fluorophore dose indicates the validity of this method and allows direct fluorophore dose assessment. The pulmonary dose of a fluorescence-labeled drug (Fc?R-Alexa750) could be assessed with an estimated accuracy of 9% and the limit of detection in ng regime. Hence, Cryoslicing Imaging can be used for quantitative assessment of dose and 3D distribution of fluorescence-labeled drugs or drug carriers in the lungs of mice. PMID:25262414

Barapatre, Nirav; Symvoulidis, Panagiotis; Möller, Winfried; Prade, Friedrich; Deliolanis, Nikolaos C; Hertel, Sebastian; Winter, Gerhard; Yildirim, Ali Ö; Stoeger, Tobias; Eickelberg, Oliver; Ntziachristos, Vasilis; Schmid, Otmar

2015-01-01

40

Increased visceral fat distribution in drug-naive and drug-free patients with schizophrenia  

Microsoft Academic Search

OBJECTIVE: To investigate visceral fat distribution in patients with schizophrenia.DESIGN: Cross sectional study using CT scanning in patients with drug-naive and drug-free schizophrenia.SUBJECTS: Fifteen (13 men and two women) subjects with schizophrenia (mean age 33.7 y; mean body mass index (BMI)=26.7 kg\\/m2), and 15 age- and sex-matched controls (mean age 30.5 y; mean BMI=22.8 kg\\/2).MEASUREMENTS: Various fatness and fat distribution

JH Thakore; JN Mann; I Vlahos; A Martin; R Reznek

2002-01-01

41

An integrated drug prescription and distribution system: challenges and opportunities.  

PubMed

Using the hospital's drug prescription and distribution system as a guide, benefits and drawbacks of a medical activity management system that is tightly integrated with the supply chain management of a hospital will be discussed from the point of view of various participating healthcare actors. PMID:15058416

Lanssiers, R; Everaert, E; De Win, M; Van De Velde, R; De Clercq, H

2002-01-01

42

Implicit and Explicit Drug-Related Cognitions during Detoxification Treatment are Associated with Drug Relapse: An Ecological Momentary Assessment Study  

PubMed Central

Objective Relapse is a major problem in drug addiction treatment. Both drug craving and drug-related cognitions (e.g., attentional bias and implicit attitudes to drugs) may contribute to relapse. Using ecological momentary assessments (EMA), we examined whether craving and cognitions assessed during drug detoxification treatment were associated with relapse. Method Participants were 68 heroin-dependent inpatients undergoing clinical detoxification at an addiction treatment center. Participants carried around a personal digital assistant (PDA) for 1-week. Participants completed up to 4 random assessments (RAs) per day. They also completed an assessment when they experienced a temptation to use drugs (TA). At each assessment, participants reported their craving and attitudes to drugs. Implicit cognitions were assessed with a drug Stroop task (attentional bias) and an Implicit Association Test (implicit attitudes). Results Individuals who relapsed during the study week exhibited a larger attentional bias and more positive implicit attitudes to drugs than non-relapsers at TAs (but not RAs). In addition, compared to non-relapsers, relapsers reported higher levels of craving and more positive explicit attitudes to drugs at TAs compared to RAs. Additional within-subject analyses revealed that attentional bias for drugs at TAs increased before relapse. Conclusions Drug-related cognitive processes assessed using EMA were associated with relapse during drug detoxification. Real-time assessment of craving and cognitions may help to identify individuals at risk of relapse, and when they are at risk of relapse. PMID:23231572

Marhe, Reshmi; Waters, Andrew J.; van de Wetering, Ben J. M.; Franken, Ingmar H. A.

2012-01-01

43

21 CFR 1310.10 - Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic Act.  

Code of Federal Regulations, 2013 CFR

...JUSTICE RECORDS AND REPORTS OF LISTED CHEMICALS AND CERTAIN MACHINES § 1310.10 Removal of the exemption of drugs distributed...to the drug product. (e) Within a reasonable period of time after receipt of the application for reinstatement of...

2013-04-01

44

21 CFR 1310.10 - Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic Act.  

...JUSTICE RECORDS AND REPORTS OF LISTED CHEMICALS AND CERTAIN MACHINES § 1310.10 Removal of the exemption of drugs distributed...to the drug product. (e) Within a reasonable period of time after receipt of the application for reinstatement of...

2014-04-01

45

21 CFR 1310.10 - Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic Act.  

Code of Federal Regulations, 2012 CFR

...JUSTICE RECORDS AND REPORTS OF LISTED CHEMICALS AND CERTAIN MACHINES § 1310.10 Removal of the exemption of drugs distributed...to the drug product. (e) Within a reasonable period of time after receipt of the application for reinstatement of...

2012-04-01

46

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. PMID:1847277

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

1991-01-01

47

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

48

Assess Epithelial Permeability of Drugs from Pharmaceutical Formulations  

Microsoft Academic Search

The following chapter gives an overview of instrumented approaches to investigate the interactions of orally or pulmonary administered formulations with epithelial cell cultures in vitro. The first section is focused on the combined assessment of drug release\\/dissolution and subsequent absorp- tion\\/permeation for solid oral dosage forms. Experimental approaches to mimic the complex physiologically surroundings in the gastrointestinal tract are pre-

Stephan A. Motz; Michael Bur; Ulrich F. Schaefer; Claus-Michael Lehr

49

Physicochemical assessment of Dextran-g-Poly (?-caprolactone) micellar nanoaggregates as drug nanocarriers.  

PubMed

Self-assembling polymers in aqueous solution have attracted significant attention with recent research efforts focused on the development of new strategies to design devices useful in the field of controlled drug delivery. In this context, amphiphilic copolymers having specific structural features and self-assembling behaviors in aqueous media that would enable controlled drug release over longer time periods. In this work, we report on the synthesis and characterization of a Poly (?-caprolactone)-grafted Dextran copolymer and its use in the preparation of micellar nanoaggregates. The characterization and study of the morphology, topography, size distribution and stability of micellar nanoaggregates by Transmission Electron Microscopy (TEM), Atomic Force Microscopy (AFM), Dynamic Light Scattering (DLS) and Zeta Potential (?), respectively, were carried out. Spherical-shaped morphologies and an average size of approximately 83nm, for drug-free nanoaggregates, were observed. In addition, Zeta Potential studies showed that drug-free nanoaggregates are more stable than drug-loaded structures measured in a phosphate buffer (pH 7.2) medium. UV-vis spectrophotometry of both the drug entrapment efficiency (EE%) and in vitro drug release behavior were assessed. The EE% was determined to be 78% (w/w), and a combination of diffusion and eroding polymer matrix mechanisms for drug release were established. Finally, these results indicate that Dx-g-PCL micellar nanoaggregates are suitable for use as a potential nanocarrier having both biodegradable and biocompatible properties. PMID:25498659

Saldías, César; Velásquez, Luis; Quezada, Caterina; Leiva, Angel

2015-03-01

50

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. PMID:23531393

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

51

Mathematical modeling and finite element simulation of slow release of drugs using hydrogels as carriers with various drug concentration distributions.  

PubMed

In drug release systems using hydrogels as carriers, the presence of the polymer network will reduce the drug release rate, which can extend the release period. For a controlled-release process of drug, usually the ideal situation is to get a zero-order drug release rate. In this paper, the mathematical model of hydrogel swelling processes is constructed on the basis of a biphasic theory, and then an integrated equation that considers both water convection and drug diffusion phenomena is used to describe the drug release process. The effects of the initial drug concentration with nonuniform distributions along the radial direction of hydrogel carriers on the release of drugs are studied through simulating two-dimensional hydrogel swelling processes by means of the COMSOL Multiphysics software. The simulation results show that along with the hydrogel swelling, the drug release rate is changing, and the major influencing factors of the drug release rate are water convection and drug diffusion coefficient, which are affected by water volume fraction, drug concentration distribution in matrix, and carrier radius. The results also indicate that the initial drug concentration distribution following a sine curve can result in an ideal zero-order release process. PMID:23526640

Xu, Yihan; Jia, Yuxi; Wang, Zhao; Wang, Zhaojing

2013-05-01

52

Lab 4 GEO Assessing fish distribution  

E-print Network

ed students, download lab4_data.zip from Blackboard). B. Start ArcMap and open the project InvBound.mxd from the lab_4 folder that you previously copied to your student directory. C. The view opens showingLab 4 ­ GEO 465/565 Invisible Boundaries ____________________________ Assessing fish distribution

Wright, Dawn Jeannine

53

Critical Assessment of Implantable Drug Delivery Devices in Glaucoma Management  

PubMed Central

Glaucoma is a group of heterogeneous disorders involving progressive optic neuropathy that can culminate into visual impairment and irreversible blindness. Effective therapeutic interventions must address underlying vulnerability of retinal ganglion cells (RGCs) to degeneration in conjunction with correcting other associated risk factors (such as elevated intraocular pressure). However, realization of therapeutic outcomes is heavily dependent on suitable delivery system that can overcome myriads of anatomical and physiological barriers to intraocular drug delivery. Development of clinically viable sustained release systems in glaucoma is a widely recognized unmet need. In this regard, implantable delivery systems may relieve the burden of chronic drug administration while potentially ensuring high intraocular drug bioavailability. Presently there are no FDA-approved implantable drug delivery devices for glaucoma even though there are several ongoing clinical studies. The paper critically assessed the prospects of polymeric implantable delivery systems in glaucoma while identifying factors that can dictate (a) patient tolerability and acceptance, (b) drug stability and drug release profiles, (c) therapeutic efficacy, and (d) toxicity and biocompatibility. The information gathered could be useful in future research and development efforts on implantable delivery systems in glaucoma. PMID:24066234

Manickavasagam, Dharani; Oyewumi, Moses O.

2013-01-01

54

Technology assessment and the Food and Drug Administration  

NASA Technical Reports Server (NTRS)

The statutory standards underlying the activities of the FDA, and the problems the Agency faces in decision making are discussed from a legal point of view. The premarketing clearance of new drugs and of food additives, the two most publicized and criticized areas of FDA activity, are used as illustrations. The importance of statutory standards in technology assessment in a regulatory setting is developed. The difficulties inherent in the formulation of meaningful standards are recognized. For foods, the words of the statute are inadequate, and for drugs, a statutory recognition of the various other objectives would be useful to the regulator and the regulated.

Kaplan, A. H.; Becker, R. H.

1972-01-01

55

Novel approach of MALDI drug imaging, immunohistochemistry, and digital image analysis for drug distribution studies in tissues.  

PubMed

Drug efficacy strongly depends on the presence of the drug substance at the target site. As vascularization is an important factor for the distribution of drugs in tissues, we analyzed drug distribution as a function of blood vessel localization in tumor tissue. To explore distribution of the anticancer drugs afatinib, erlotinib, and sorafenib, a combined approach of matrix-assisted laser desorption/ionization (MALDI) drug imaging and immunohistochemical vessel staining was applied and examined by digital image analysis. The following two xenograft models were investigated: (1) mice carrying squamous cell carcinoma (FaDu) xenografts (ntumor = 13) were treated with afatinib or erlotinib, and (2) sarcoma (A673) xenograft bearing mice (ntumor = 8) received sorafenib treatment. MALDI drug imaging revealed a heterogeneous distribution of all anticancer drugs. The tumor regions containing high drug levels were associated with a higher degree of vascularization than the regions without drug signals (p < 0.05). When correlating the impact of blood vessel size to drug abundance in the sarcoma model, a higher amount of small vessels was detected in the tumor regions with high drug levels compared to the tumor regions with low drug levels (p < 0.05). With the analysis of coregistered MALDI imaging and CD31 immunohistochemical data by digital image analysis, we demonstrate for the first time the potential of correlating MALDI drug imaging and immunohistochemistry. Here we describe a specific and precise approach for correlating histological features and pharmacokinetic properties of drugs at microscopic level, which will provide information for the improvement of drug design, administration formula or treatment schemes. PMID:25263480

Huber, Katharina; Feuchtinger, Annette; Borgmann, Daniela M; Li, Zhoulei; Aichler, Michaela; Hauck, Stefanie M; Zitzelsberger, Horst; Schwaiger, Markus; Keller, Ulrich; Walch, Axel

2014-11-01

56

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

Code of Federal Regulations, 2012 CFR

...actions must I take to control the distribution of PET drug products? 212.90...POSITRON EMISSION TOMOGRAPHY DRUGS Distribution § 212.90 What actions must I take to control the distribution of PET drug products? (a)...

2012-04-01

57

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

Code of Federal Regulations, 2013 CFR

...actions must I take to control the distribution of PET drug products? 212.90...POSITRON EMISSION TOMOGRAPHY DRUGS Distribution § 212.90 What actions must I take to control the distribution of PET drug products? (a)...

2013-04-01

58

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

Code of Federal Regulations, 2011 CFR

...actions must I take to control the distribution of PET drug products? 212.90...POSITRON EMISSION TOMOGRAPHY DRUGS Distribution § 212.90 What actions must I take to control the distribution of PET drug products? (a)...

2011-04-01

59

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

60

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

61

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

62

A risk-benefit assessment of anti-obesity drugs.  

PubMed

This review evaluates the benefits and potential health risks of the currently used drugs that are approved for the pharmacological treatment of obesity. Analysis of several long term clinical trials indicates that all of these drugs are efficient in reducing excess bodyweight, and that the majority of them allow the maintenance of the reduced bodyweight for at least 1 year. However, the loss of bodyweight attributable to these drugs is in general rather modest, approaching only 0.2 kg per week during the first 6 months of treatment, and at least a partial regain of bodyweight occurs when these drugs are used for periods longer than 1 year. All of these drugs induce several adverse effects. Although most of these adverse effects are mild and transient, the prolonged use of adrenergic or serotonergic anorectic drugs, or their use as combination treatment, may induce serious and potentially life-threatening complications, such as primary pulmonary hypertension or valvular heart disease. The adrenergic appetite-suppressing drugs are not recommended for the treatment of obesity, since their safety has never been evaluated in long term clinical trials, and because of their stimulatory effects on the cardiovascular and nervous systems. The serotonergic drugs, such as fenfluramine and dexfenfluramine, have been the most widely used during the past decade; however, both these compounds have recently been withdrawn from the market, since their use was associated with serious cardiovascular complications. The safety of the prolonged therapeutic use of newer compounds such as sibutramine and orlistat has not yet been demonstrated. Therefore, none of the currently available anti-obesity medications meets the criteria of an 'ideal anti-obesity drug' and, if prescribed, these medications should be used with caution and only under careful medical supervision. Since obesity is recognised as a chronic health-threatening condition, and since classical behavioural therapeutic approaches lack long term efficacy, there is clearly a need for an efficient pharmacological treatment offering an acceptable safety profile. Such a treatment is not available at present. Development of new agents and a more careful assessment of the safety of currently available drugs are needed. PMID:10082070

Kolanowski, J

1999-02-01

63

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

64

Regulatory perspective on the importance of ADME assessment of nanoscale material containing drugs.  

PubMed

The promise of nanoscale material containing drug products to treat complex diseases is mounting. According to the literature, in addition to the liposomes, micelles, emulsions, there are novel drug delivery systems such as dendrimers and metal colloids at different stages of pre-clinical and clinical development. With the anticipation that more nanoscale material containing drug products will be submitted to the Food and Drug Administration (FDA) for approval in the future, FDA formed a Nanotechnology Task Force in 2006 to determine the critical regulatory issues regarding nanomaterials. As a result, all centers within the FDA are considering the development of guidance documents to address nanomaterial specific issues. It is well established in the literature that physico-chemical characterization (PCC) studies are crucial for nanomaterial containing drug products. However, this paper addresses the equally important topic of Absorption, Distribution, Metabolism and Excretion (ADME) studies for nanomaterials and provides examples of how physical properties affect biodistribution (i.e. the state of agglomeration, or aggregation, surface characteristics, stability of PEG). This paper also attempts to highlight some of the ADME study design issues related to nanomaterials such as the need for conducting biodistribution studies on each moiety of the multifunctional nanoparticles, dual labeled pharmacokinetic (PK) studies, and comparative PK studies on the free versus encapsulated drugs. In addition, this paper underlines the importance of long-term biodistribution and mass balance studies to understand the nanoparticle accumulation profile which may help to assess the safety and efficacy of the nanomaterial containing drug products. This review also lists some of the pre-clinical guidance documents that may help sponsors get started in developing data for inclusion in an initial investigational new drug application package for nanoscale material containing drug products. PMID:19389437

Zolnik, Banu S; Sadrieh, Nakissa

2009-06-21

65

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

PubMed

Many currently approved drugs possess weakly basic properties that make them substrates for extensive sequestration in acidic intracellular compartments such as lysosomes through an ion trapping-type mechanism. Lysosomotropic drugs often have unique pharmacokinetic properties that stem from the extensive entrapment in lysosomes, including an extremely large volume of distribution and a long half-life. Accordingly, pharmacokinetic drug-drug interactions can occur when one drug modifies lysosomal volume such that the degree of lysosomal sequestration of secondarily administered drugs is significantly altered. In this work, we have investigated potential mechanisms for drug-induced alterations in lysosomal volume that give rise to drug-drug interactions involving lysosomes. We show that eight hydrophobic amines, previously characterized as perpetrators in this type of drug-drug interaction, cause a significant expansion in lysosomal volume that was correlated with both the induction of autophagy and with decreases in the efficiency of lysosomal egress. We also show that well-known chemical inducers of autophagy caused an increase in apparent lysosomal volume and an increase in secondarily administered lysosomotropic drugs without negatively impacting vesicle-mediated lysosomal egress. These results could help rationalize how the induction of autophagy could cause variability in the pharmacokinetic properties of lysosomotropic drugs. PMID:23970383

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

2013-11-01

66

Drug distribution in wet granulation: foam versus spray.  

PubMed

Foam granulation technology is a new wet granulation approach for pharmaceutical formulations. This study evaluates the performance of foam and spray granulation in achieving uniform drug distribution using a model formulation. To observe wetting and nuclei formation, single drop/foam penetration experiments were performed on a static powder bed comprised of varying compositions of hydrophilic/hydrophobic glass ballotini, and hydrophilic lactose/hydrophobic salicylic acid respectively. High shear granulation experiments were performed in a 5L mixer using varying compositions of hydrophilic lactose and hydrophobic salicylic acid. Four percent hydroxylpropyl methylcellulose (HPMC) solution was delivered at 90?g/min as either a foam (92% FQ) or an atomized spray whilst recording impeller power consumption. After drying, the granule size distribution was measured and the granule composition was estimated using gravimetric filtration in methanol. Foam penetration was less dependent on the powder hydrophobicity compared to drop penetration. For glass ballotini powder mixtures, foam induced nucleation created nuclei with relatively uniform structure and size regardless of the powder hydrophobicity. For salicylic acid and lactose mixtures, increasing the proportion of salicylic acid reduced the nuclei granule size for both foam and drop binder addition. The granule drug distribution was not significantly affected by the binder addition method. Processing conditions, including liquid binder amount, impeller speed, wet massing, and the wettability properties of the formulation were the dominant factors for delivering homogeneous granules. The study reveals that foam and spray granulation involve different nucleation mechanisms - spray tends to incur early liquid penetration whereas foam granulation operates well in mechanical dispersion. PMID:23057532

Tan, Melvin X L; Nguyen, Thanh H; Hapgood, Karen P

2013-09-01

67

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. PMID:25031538

Lozano-Blázquez, Ana; Calvo-Pita, Cecilia; Carbajales-Álvarez, Mónica; Suárez-Gil, Patricio; Martínez-Martínez, Fernando; Calleja-Hernández, Miguel Ángel

2014-01-01

68

Novel Approach to In Vitro Drug Susceptibility Assessment of Clinical Strains of Leishmania spp.  

PubMed Central

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 (ED50s) 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 ED50 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 ED50 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

2012-01-01

69

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

E-print Network

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 ...

O'Brien, Caroline C.

70

Convection-Enhanced Drug Delivery of Interleukin-4 Pseudomonas Exotoxin (PRX321): Increased Distribution and Magnetic Resonance Monitoring  

PubMed Central

Convection-enhanced drug delivery (CED) enables achieving a drug concentration within brain tissue and brain tumors that is orders of magnitude higher than by systemic administration. Previous phase I/II clinical trials using intratumoral convection of interleukin-4 Pseudomonas exotoxin (PRX321) have demonstrated an acceptable safety and toxicity profile with promising signs of therapeutic activity. The present study was designed to assess the distribution efficiency and toxicity of this PRX321 using magnetic resonance imaging (MRI) and to test whether reformulation with increased viscosity could enhance drug distribution. Convection of low- [0.02% human serum albumin (HSA)] and high-viscosity (3% HSA) infusates mixed with gadolinium-diethylenetriamine pentaacetic acid and PRX321 were compared with low- and high-viscosity infusates without the drug, in normal rat brains. MRI was used for assessment of drug distribution and detection of early and late toxicity. Representative brain samples were subjected to histological examination. Distribution volumes calculated from the magnetic resonance images showed that the average distribution of 0.02% HSA was larger than that of 0.02% HSA with PRX321 by a factor of 1.98 (p < 0.02). CED of 3.0% HSA, with or without PRX321, tripled the volume of distribution compared with 0.02% HSA with PRX321 (p < 0.015). No drug-related toxicity was detected. These results suggest that the impeded convection of the PRX321 infusate used in previous clinical trials can be reversed by increasing infusate viscosity and lead to tripling of the volume of distribution. This effect was not associated with any detectable toxicity. A similar capability to reverse impeded convection was also demonstrated in a CED model using acetic acid. These results will be implemented in an upcoming phase IIb PRX321 CED trial with a high-viscosity infusate. PMID:19478131

Mardor, Y.; Last, D.; Daniels, D.; Shneor, R.; Maier, S. E.; Nass, D.; Ram, Z.

2009-01-01

71

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. PMID:22778659

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

2012-01-01

72

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

73

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

74

75 FR 4400 - Draft Guidance for Industry on Assessment of Abuse Potential of Drugs; Availability  

Federal Register 2010, 2011, 2012, 2013

...Guidance for Industry on Assessment of Abuse Potential of Drugs; Availability AGENCY: Food...industry entitled ``Assessment of Abuse Potential of Drugs.'' This draft guidance is...drug and other medical products with the potential for abuse that may need to be...

2010-01-27

75

A Drug Education Needs Assessment in a Rural Elementary School System: Results and Curriculum Recommendations.  

ERIC Educational Resources Information Center

This report presents the results of a needs assessment study on comprehensive drug education conducted for a small rural K-8 school. A brief review examines the literature on drug and alcohol abuse among rural youth. Parents, teachers, and students were surveyed to assess their needs, interests, and knowledge of drug and alcohol abuse. Twenty…

Sarvela, Paul D.; And Others

76

Numerical simulation on the effects of drug eluting stents at different Reynolds numbers on hemodynamic and drug concentration distribution  

PubMed Central

Background The changes of hemodynamics and drug concentration distribution caused by the implantation of drug eluting stents (DESs) in curved vessels have significant effects on In-Stent Restenosis. Methods A 3D virtual stent with 90°curvature was modelled and the distribution of wall shear stress (WSS) and drug concentration in this model were numerically studied at Reynolds numbers of 200, 400, 600, 800. Results The results showed that (1) the intensity of secondary flow at the 45° cross-section was stronger than that at the 90° cross-section; (2) As the Reynolds number increases, the WSS decreases. When the Reynolds number reaches 600, the low-WSS region only accounts for 3% of the total area. (3) The effects of Reynolds number on drug concentration in the vascular wall decreases in proportionally and then the blood velocity increased 4 times, the drug concentration in the vascular wall decreased by about 30%. (4) The size of the high drug concentration region is inversely proportional to the Reynolds number. As the blood velocity increases, the drug concentration in the DES decreases, especially at the outer bend. Conclusions It is beneficial for the patient to decrease vigorous activities and keep calm at the beginning of the stent implantation, because a substantial amount of the drug is released in the first two months of stent implantation, thus a calm status is conducive to drug release and absorption; Subsequently, appropriate exercise which increases the blood velocity is helpful in decreasing regions of low-WSS. PMID:25602685

2015-01-01

77

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

78

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

PubMed Central

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

2010-01-01

79

Comparison of Self-Reported Drug Use With Quantitative and Qualitative Urinalysis for Assessment of Drug Use in Treatment Studies  

Microsoft Academic Search

The effectiveness of substance abuse treatment programs can be monitored by self-reported drug use and objectively measured by qualitative and quantitative urinalysis. The advantages and disadvantages of each of these three methods of assessing drug use are reviewed. Data collected in a clinical trial of a behavioral treatment for cocaine abuse are used to evaluate the relationships among qualitative and

Kenzie L. Preston; Kenneth Silverman; Charles R. Schuster; Edward J. Cone

80

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

81

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. PMID:23541929

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

2013-01-01

82

The value of assessing cognitive function in drug development  

PubMed Central

This paper reviews the value and utility of measuring cognitive function in the development of new medicines by reference to the most widely used automated system in clinical research. Evidence is presented from phase 1 to 3 of the nature and quality of the information that can be obtained by applying the Cognitive Drug Research computerized assessment system to ongoing clinical trials. Valuable evidence can be obtained even in the first trial in which a novel compound is administered to man. One application of such testing is to ensure that novel compounds are relatively free from cognition-impairing properties, particularly in relation to competitor products. Another is to ensure that unwanted interactions with alcohol and other medications do not occur, or, if they do, to put them in context. In many patient populations, cognitive dysfunction occurs as a result of the disease process, and newer medicines which can treat the symptoms of the disease without further impairing function can often reveal benefits as the disease-induced cognitive dysfunction is reduced. Another major application is to identify benefits for compounds designed to enhance cognitive function. Such effects can be sought in typical phase 1 trials, or a scopolamine model of the core deficits of Alzheimer's disease can be used to screen potential antidernentia drugs. Ultimately, of course, such effects can be demonstrated using properly validated and highly sensitive automated procedures in the target populations. The data presented demonstrate that the concept of independently assessing a variety of cognitive functions is crucial in helping differentiate drugs, types of dementia, and different illnesses. Such information offers a unique insight into how the alterations to various cognitive functions will manifest themselves in everyday behavior. This reveals a major limitation of scales that yield a single score, because such limited information does not permit anything but a quantitative interpretation; and the concept of “more” cognitive function or “less” is manifestly inappropriate for something as complex and diverse as the interplay between cognitive function and human behavior. Finally, the next generations of cognitive testing are described. Testing via the telephone has just been introduced and will have dramatic effects on the logistics of conducting cognitive testing in large patient trials. Testing via the Internet is not far off either, and will come fully into play as the proportion of homes connected to the Internet increases in Europe and North America. There are no sound reasons for not wishing to include cognitive function testing in the development protocol of any novel medicine. PMID:22033754

Wesnes, Keith A.

2000-01-01

83

Causality assessment in hepatotoxicity by drugs and dietary supplements.  

PubMed

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. PMID:19032721

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

2008-12-01

84

Risk assessment of technologies for detecting illicit drugs in containers  

NASA Astrophysics Data System (ADS)

This paper provides the highlights of the role risk assessment plays in the United States technology program for nonintrusive inspection of cargo containers for illicit drugs. The Counterdrug Technology Assessment Center is coordinating the national effort to develop prototype technologies for an advanced generation, nonintrusive cargo inspection system. In the future, the U.S. Customs Service could configure advanced technologies for finding not only drugs and other contraband hidden in cargo, but for a wide variety of commodities for customs duty verification purposes. The overall nonintrusive inspection system is envisioned to consist primarily of two classes of subsystems: (1) shipment document examination subsystems to prescreen exporter and importer documents; and (2) chemical and physics-based subsystems to detect and characterize illicit substances. The document examination subsystems would use software algorithms, artificial intelligence, and neural net technology to perform an initial prescreening of the information on the shipping manifest for suspicious patterns. This would be accomplished by creating a `profile' from the shipping information and matching it to trends known to be used by traffickers. The chemical and physics-based subsystems would apply nuclear physics, x-ray, gas chromatography and spectrometry technologies to locate and identify contraband in containers and other conveyances without the need for manual searches. The approach taken includes using technology testbeds to assist in evaluating technology prototypes and testing system concepts in a fully instrumented but realistic operational environment. This approach coupled with a substance signature phenomenology program to characterize those detectable elements of benign, as well as target substances lends itself particularly well to the topics of risk assessment and elemental characterization of substances. A technology testbed established in Tacoma, Washington provides a national facility for testing and evaluating existing and emerging prototype systems in an operational environment. The results of initial tests using the advanced x-ray subsystem installed at the testbed are given in this paper. A description of typical cargo contents and those characteristics applicable to nuclear interrogation techniques are provided in the appendix.

Brandenstein, Albert E.

1995-03-01

85

Examining the Spatial Distribution of Law Enforcement Encounters among People Who Inject Drugs after Implementation of Mexico's Drug Policy Reform.  

PubMed

In 2009, Mexico decriminalized the possession of small amounts of illicit drugs for personal use in order to refocus law enforcement resources on drug dealers and traffickers. This study examines the spatial distribution of law enforcement encounters reported by people who inject drugs (PWID) in Tijuana, Mexico to identify concentrated areas of policing activity after implementation of the new drug policy. Mapping the physical location of law enforcement encounters provided by PWID (n?=?461) recruited through targeted sampling, we identified hotspots of extra-judicial encounters (e.g., physical/sexual abuse, syringe confiscation, and money extortion by law enforcement) and routine authorized encounters (e.g., being arrested or stopped but not arrested) using point density maps and the Getis-Ord Gi* statistic calculated at the neighborhood-level. Approximately half of the participants encountered law enforcement more than once in a calendar year and nearly one third of these encounters did not result in arrest but involved harassment or abuse by law enforcement. Statistically significant hotspots of law enforcement encounters were identified in a limited number of neighborhoods located in areas with known drug markets. At the local-level, law enforcement activities continue to target drug users despite a national drug policy that emphasizes drug treatment diversion rather than punitive enforcement. There is a need for law enforcement training and improved monitoring of policing tactics to better align policing with public health goals. PMID:25300503

Gaines, Tommi L; Beletsky, Leo; Arredondo, Jaime; Werb, Daniel; Rangel, Gudelia; Vera, Alicia; Brouwer, Kimberly

2014-10-10

86

A Rational Probabilistic Method for Spatially Distributed Landslide Hazard Assessment  

E-print Network

A Rational Probabilistic Method for Spatially Distributed Landslide Hazard Assessment WILLIAM C, Landslides, Probabi- listic, Computer Applications, West Virginia ABSTRACT First-order, second-moment (FOSM models to perform spatially distributed probabilistic landslide hazard analyses. This is most easily

Haneberg, William C.

87

A multi-centre rapid assessment of injecting drug use in India  

Microsoft Academic Search

In 1998, a series of five rapid situation assessments (RSA) of injecting drug use were undertaken by The Society for Service to Urban Poverty (SHARAN) covering the major Metropolitan cities of Mumbai, Chennai, Calcutta, Delhi and Imphal. The RSA determined the extent and patterns of injecting drug use (IDU), the available responses, current and planned interventions, and drug users’ perceptions

Jimmy Dorabjee; Luke Samson

2000-01-01

88

Residues of veterinary drugs in eggs and their distribution between yolk and white.  

PubMed

Veterinary drugs and feed additives (especially some coccidiostats) can be absorbed by the digestive tract of laying hens and transferred to the egg. Physicochemical characteristics of these compounds determine their pharmacokinetic behavior and distribution to and within the egg. Traditionally the quite lipid soluble drugs and additives are expected to yield residues only in the fat-rich yolk. However, the quite lipid soluble drug doxycycline--as well as many other drugs--showed during long-term administration higher residues in white than in yolk. In a model study with 11 sulfonamides differing in pK(a) value and lipid solubility, their distribution in vivo between yolk and white was determined. Neither differences in pK(a) values nor those in lipid solubility could explain the distributions found. Binding to egg white macromolecules in vivo as an explanatory factor was tested with five sulfonamides, and no correlation between binding and the distribution of sulfonamides between white and yolk was found. Literature data on the distribution of drugs between egg white and yolk showed a reasonable consistency within drugs and a large variability among drugs (as could be expected). This larger database also did not provide a clue as to what factor determines the distribution of a drug between egg white and yolk when given to laying hens. PMID:11141291

Kan, C A; Petz, M

2000-12-01

89

[Assessment of the high cost drug program on an example of the interferon treatment of multiple sclerosis].  

PubMed

Currently in Russia, there is a rather complicated situation with the distribution of expensive disease modifying drugs (DMD) purchased by the state for treatment of patients with multiple sclerosis. In this regard, it is necessary to carry out a serious organizational work in the direction of assessment of equivalence of biosimilars and original drugs concerning, first of all, efficacy and safety. Also, there is a problem of the replacement of one biosimilar by another in connection with organizational problems of shipping DMD to country regions. We present the results of the sociological research on the assessment of expensive drug provision by patients. The research has been carried out in 35 regions of the country. Based on these results, a strategy of the development of the program of provision with DMD should be developed all over the country. PMID:23528597

Vlasov, Ia V; Dolgikh, G T; Dolgilh, T A; Kurapov, M A; Nilov, A I; Tarasova, S V; Churakov, M V; Khivintseva, E V

2013-01-01

90

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

91

Assessing Drug and Alcohol Abuse: An Instrument for Planning and Evaluation.  

ERIC Educational Resources Information Center

Assessed the reliability and validity of an instrument designed to assess the extent of alcohol and drug use. Factors in a school or community contributing to use of alcohol and drugs are identified. Uses of the results for school and community planning are included. (Author/JAC)

Swisher, John D.; And Others

1984-01-01

92

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

93

Serotype Distribution and Drug Resistance in Streptococcus pneumoniae, Palestinian Territories  

PubMed Central

To determine antimicrobial drug resistance of Streptococcus pneumoniae serotypes, we analyzed isolates from blood cultures of sick children residing in the West Bank before initiation of pneumococcal vaccination. Of 120 serotypes isolated, 50.8%, 73.3%, and 80.8% of the bacteremia cases could have been prevented by pneumococcal conjugate vaccines. Serotype 14 was the most drug-resistant serotype isolated. PMID:21192863

Kattan, Randa; Abu Rayyan, Amal; Zheiman, Inas; Idkeidek, Suzan; Baraghithi, Sabri; Rishmawi, Nabeel; Turkuman, Sultan; Abu-Diab, Afaf; Ghneim, Riyad; Zoughbi, Madeleine; Dauodi, Rula; Ghneim, Raed; Issa, Abed-El-Razeq; Siryani, Issa; Al Qas, Randa; Liddawi, Rawan; Khamash, Hatem; Kanaan, Moein; Marzouqa, Hiyam

2011-01-01

94

Positron emission tomography (PET) for assessing aerosol deposition of orally inhaled drug products.  

PubMed

The topical distribution of inhaled therapies in the lung can be viewed using radionuclides and imaging. Positron emission tomography (PET) is a three-dimensional functional imaging technique providing quantitatively accurate localization of the quantity and distribution of an inhaled or injected PET radiotracer in the lung. A series of transaxial slices through the lungs are obtained, comparable to an X-ray computed tomography (CT) scan. Subsequent reformatting allows coronal and sagittal images of the distribution of radioactivity to be viewed. This article describes procedures for administering [(18)F]-fluorodeoxyglucose aerosol to human subjects for the purpose of determining dose and distribution following inhalation from an aerosol drug delivery device (ADDD). The advantages of using direct-labeled PET drugs in the ADDD are discussed with reference to the literature. The methods for designing the inhalation system, determining proper radiation shielding, calibration, and validation of administered radioactivity, scanner setup, and data handling procedures are described. Obtaining an X-ray CT or radionuclide transmission scan to provide accurate geometry of the lung and also correct for tissue attenuation of the PET radiotracer is discussed. Protocols for producing accurate images, including factors that need to be incorporated into the data calibration, are described, as well as a proposed standard method for partitioning the lung into regions of interest. Alternate methods are described for more detailed assessments. Radiation dosimetry/risk calculations for the procedures are appended, as well as a sample data collection form and spreadsheet for calculations. This article should provide guidance for those interested in using PET to determine quantity and distribution of inhaled therapeutics. PMID:23215847

Dolovich, Myrna B; Bailey, Dale L

2012-12-01

95

Comparative Genomic Assessment of Novel Broad-Spectrum Targets for Antibacterial Drugs  

PubMed Central

Single and multiple resistance to antibacterial drugs currently in use is spreading, since they act against only a very small number of molecular targets; finding novel targets for anti-infectives is therefore of great importance. All protein sequences from three pathogens (Staphylococcus aureus, Mycobacterium tuberculosis and Escherichia coli O157:H7 EDL993) were assessed via comparative genomics methods for their suitability as antibacterial targets according to a number of criteria, including the essentiality of the protein, its level of sequence conservation, and its distribution in pathogens, bacteria and eukaryotes (especially humans). Each protein was scored and ranked based on weighted variants of these criteria in order to prioritize proteins as potential novel broad-spectrum targets for antibacterial drugs. A number of proteins proved to score highly in all three species and were robust to variations in the scoring system used. Sensitivity analysis indicated the quantitative contribution of each metric to the overall score. After further analysis of these targets, tRNA methyltransferase (trmD) and translation initiation factor IF-1 (infA) emerged as potential and novel antimicrobial targets very worthy of further investigation. The scoring strategy used might be of value in other areas of post-genomic drug discovery. PMID:18629165

White, Thomas A.

2004-01-01

96

Sex, drugs, and HIV: Rapid assessment of HIV risk behaviors among street-based drug using sex workers in Durban, South Africa  

Microsoft Academic Search

South Africa is experiencing significant changes in patterns of illicit drug use, including increasing injection and non-injection drug use, and the use of drugs by persons engaged in sex work, both of which could further expand the HIV\\/AIDS epidemic. In 2005, a rapid ethnographic assessment was conducted in Durban, South Africa, to learn more about patterns of drug use and

Richard Needle; Karen Kroeger; Hrishikesh Belani; Angeli Achrekar; Charles D. Parry; Sarah Dewing

2008-01-01

97

Tissue distribution of newer anticonvulsant drugs in postmortem cases.  

PubMed

Levetiracetam, hydroxycarbazepine (the primary product of oxcarbazepine use), and topiramate were quantified using the acid/neutral drug screening procedure employed by this laboratory. Briefly, blood or tissue homogenate spiked with an internal standard (cyclopentobarbital) was buffered to pH 5 and applied to Chem Elut® columns. The columns were washed with methylene chloride, collected, and evaporated to dryness. The residue was reconstituted with 0.033 M trimethylanilinium hydroxide and injected into a gas chromatograph equipped with a DB-5 analytical column (25 m × 0.32-mm i.d.) and a nitrogen-phosphorus detector. A calibration curve using four calibrators ranging in concentration from 2 to 20 mg/L was used for quantification. Despite the limited number of cases for each drug, there were some trends suggested by the data. None of the drugs displayed significant differences in concentration between the heart blood and peripheral (subclavian) blood specimens. Only the hydroxycarbazepine quantifications in one case (case 5) showed significant differences between the two blood sites. This is consistent with other acid/neutral drugs such as acetaminophen and meprobamate. It also appears that the liver and kidney concentrations of the three drugs are on the same order of magnitude as the blood concentrations. Only the levetiracetam concentration in one case (case 3) reflected a liver or kidney concentration greater than 5 times the blood concentration. PMID:21819796

Levine, Barry; Phipps, Rebecca Jufer; Naso, Clare; Fahie, Kisha; Fowler, David

2010-10-01

98

Medication errors in hospital: computerized unit dose drug dispensing system versus ward stock distribution system  

Microsoft Academic Search

Aim: The aim of this study was to evaluate the rates and types of drug prescription and administration errors in one pediatric nephrology ward, comparing two dispensing schemes : the first one defined as handwritten prescription plus ward stock distribution system (WSDS), and the second one as computerized prescription plus unit dose drug dispensing system (UDDDS). Method: Data were collected

Jean-Eudes Fontan; Vincent Maneglier; V. X. Nguyen; F. Brion; C. Loirat

2003-01-01

99

Intracellular distribution of psychotropic drugs in the grey and white matter of the brain: the role of lysosomal trapping.  

PubMed

1. Since the brain is not a homogenous organ (i.e. the phospholipid pattern and density of lysosomes may vary in its different regions), in the present study we examined the uptake of psychotropic drugs by vertically cut slices of whole brain, grey (cerebral cortex) and white (corpus callosum, internal capsule) matter of the brain and by neuronal and astroglial cell cultures. 2. Moreover, we assessed the contribution of lysosomal trapping to total drug uptake (total uptake=lysosomal trapping+phospholipid binding) by tissue slices or cells conducting experiments in the presence and absence of 'lysosomal inhibitors', i.e., the lysosomotropic compound ammonium chloride (20 mM) or the Na(+)/H(+)-ionophore monensin (10 microM), which elevated the internal pH of lysosomes. The initial concentration of psychotropic drug in the incubation medium was 5 microM. 3. Both total uptake and lysosomal trapping of the antidepressants investigated (imipramine, amitriptyline, fluoxetine, sertraline) and neuroleptics (promazine, perazine, thioridazine) were higher in the grey matter and neurones than in the white matter and astrocytes, respectively. Lysosomal trapping of the psychotropics occurred mainly in neurones where thioridazine sertraline and perazine showed the highest degree of lysosomotropism. 4. Distribution interactions between antidepressants and neuroleptics took place in neurones via mutual inhibition of lysosomal trapping of drugs. 5. A differential number of neuronal and glial cells in the brain may mask the lysosomal trapping and the distribution interactions of less potent lysosomotropic drugs in vertically cut brain slices. 6. A reduction (via a distribution interaction) in the concentration of psychotropics in lysosomes (depot), which leads to an increase in their level in membranes and tissue fluids, may intensify the pharmacological action of the combined drugs. PMID:11606321

Daniel, W A; Wójcikowski, J; Pa?ucha, A

2001-10-01

100

Look Alike\\/ Sound Alike Algorithms for Assessing Drug Name Similarities  

Microsoft Academic Search

1.0 Background Approximately 12.5 percent of the medication errors reported to the FDA are a result of confusion between drug names, which can have a direct and serious health consequence to a patient. Factors contributing to the confusion include illegible handwriting, similar packaging and labeling, incorrect selection from a computerized list, incomplete knowledge of drug names, newly available products, or

Erica Kolatch; Jessica Toye; Bonnie Dorr

2004-01-01

101

Assessing UK drug policy from a crime control perspective  

Microsoft Academic Search

Over the entire last quarter of the 20th century the British drug problem worsened, despite the implementation of a variety of approaches and commitment of substantial criminal justice and other resources. The link between chronic use of expensive drugs and property crime makes this experience important for understanding trends in crime and justice in Britain. The worsening of the problem

Peter Reuter; Alex Stevens

2008-01-01

102

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

103

A reliability assessment methodology for distribution systems with distributed generation  

E-print Network

be applied in preliminary planning studies for such systems. The method uses a sequential Monte Carlo simulation of the distribution systemÂ?s stochastic model to generate the operating behavior and combines that with a path augmenting Max flow algorithm...

Duttagupta, Suchismita Sujaya

2006-08-16

104

Interaction Potential of the Multitargeted Receptor Tyrosine Kinase Inhibitor Dovitinib with Drug Transporters and Drug Metabolising Enzymes Assessed in Vitro  

PubMed Central

Dovitinib (TKI-258) is under development for the treatment of diverse cancer entities. No published information on its pharmacokinetic drug interaction potential is available. Thus, we assessed its interaction with important drug metabolising enzymes and drug transporters and its efficacy in multidrug resistant cells in vitro. P-glycoprotein (P-gp, MDR1, ABCB1) inhibition was evaluated by calcein assay, inhibition of breast cancer resistance protein (BCRP, ABCG2) by pheophorbide A efflux, and inhibition of organic anion transporting polypeptides (OATPs) by 8-fluorescein-cAMP uptake. Inhibition of cytochrome P450 3A4, 2C19, and 2D6 was assessed by using commercial kits. Induction of transporters and enzymes was quantified by real-time RT-PCR. Possible aryl hydrocarbon receptor (AhR) activating properties were assessed by a reporter gene assay. Substrate characteristics were evaluated by growth inhibition assays in cells over-expressing P-gp or BCRP. Dovitinib weakly inhibited CYP2C19, CYP3A4, P-gp and OATPs. The strongest inhibition was observed for BCRP (IC50 = 10.3 ± 4.5 ?M). Among the genes investigated, dovitinib only induced mRNA expression of CYP1A1, CYP1A2, ABCC3 (coding for multidrug resistance-associated protein 3), and ABCG2 and suppressed mRNA expression of some transporters and drug metabolising enzymes. AhR reporter gene assay demonstrated that dovitinib is an activator of this nuclear receptor. Dovitinib retained its efficacy in cell lines over-expressing P-gp or BCRP. Our analysis indicates that dovitinib will most likely retain its efficacy in tumours over-expressing P-gp or BCRP and gives first evidence that dovitinib might act as a perpetrator drug in pharmacokinetic drug–drug interactions. PMID:25521244

Weiss, Johanna; Theile, Dirk; Dvorak, Zdenek; Haefeli, Walter Emil

2014-01-01

105

Assessment of Distributed Object Rod Fatoohi  

E-print Network

'98 (15 mos): Joint project GSFC/ARC/SJSU - ECS Distributed Object Middleware & Alternative Technology others: CORBA Naming, RMI Registry & CDS ! Develop CDS Service Provider Interface API as plug-in to JNDI

Fatoohi, Rod

106

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

107

Cationic amphiphilic drugs cause a marked expansion of apparent lysosomal volume: Implications for an intracellular distribution-based drug interaction  

PubMed Central

How a drug distributes within highly compartmentalized mammalian cells can affect both the activity and pharmacokinetic behavior. Many commercially available drugs are considered to be lysosomotropic, meaning they are extensively sequestered in lysosomes by an ion trapping-type mechanism. Lysosomotropic drugs typically have a very large apparent volume of distribution and a prolonged half-life in vivo, despite minimal association with adipose tissue. In this report we tested the prediction that the accumulation of one drug (perpetrator) in lysosomes could influence the accumulation of a secondarily administered one (victim), resulting in an intracellular distribution-based drug interaction. To test this hypothesis cells were exposed to nine different hydrophobic amine-containing drugs, which included imipramine, chlorpromazine and amiodarone, at a 10 µM concentration for 24 to 48 hours. After exposure to the perpetrators the cellular accumulation of LysoTracker Red (LTR), a model lysosomotropic probe, was evaluated both quantitatively and microscopically. We found that all of the tested perpetrators caused a significant increase in the cellular accumulation of LTR. Exposure of cells to imipramine caused an increase in the cellular accumulation of other lysosomotropic probes and drugs including LyosTracker Green, daunorubicin, propranolol and methylamine; however, imipramine did not alter the cellular accumulation of non-lysosomotropic amine-containing molecules including MitoTracker Red and sulforhodamine 101. In studies using ionophores to abolish intracellular pH gradients we were able to resolve ion trapping-based cellular accumulation from residual pH-gradient independent accumulation. Results from these evaluations in conjunction with lysosomal pH measurements enabled us to estimate the relative aqueous volume of lysosomes of cells before and after imipramine treatment. Our results suggest that imipramine exposure caused a 4-fold expansion in the lysosomal volume, which provides the basis for the observed drug interaction. The imipramine-induced lysosomal volume expansion was shown to be both time- and temperature-dependent and reversed by exposing cells to hydroxypropyl-?-cyclodextrin, which reduced lysosomal cholesterol burden. This suggests that the expansion of lysosomal volume occurs secondary to perpetrator-induced elevations in lysosomal cholesterol content. In support of this claim, the cellular accumulation of LTR was shown to be higher in cells isolated from patients with Niemann-Pick Type C disease, which are known to hyper-accumulate cholesterol in lysosomes. PMID:22449202

Funk, Ryan S.; Krise, Jeffrey P.

2012-01-01

108

Assessment of Club Patrons’ Alcohol and Drug Use  

PubMed Central

Background Young adulthood (ages 18–25 years) represents a time when high-risk behaviors, including alcohol and drug use, peak. Electronic music dance events (EMDEs) featured at clubs provide an ecologic niche for these high-risk behaviors. Purpose This paper examines the prevalence of alcohol and drug use among EMDE patrons. Examination of personal characteristics associated with exit levels of alcohol and drug use identifies important indicators of risk taking for prevention strategies. Methods Data were collected anonymously during 2010–2012 from 2028 patrons as they entered and exited clubs in the San Francisco Bay area featuring EMDEs. Nearly half were aged ?25 years. Biological measures of drug and alcohol and self-reported personal characteristics were attained. Analyses were completed in 2012. Results At entrance, more than one fifth of patrons were positive for drug use and one fourth arrived either impaired (blood alcohol concentration [BAC]: 0.05%–0.079%) or intoxicated (BAC: >0.08%) by alcohol. At exit, one fourth tested positive for drugs, and nearly half were impaired or intoxicated by alcohol. Individual characteristics that were important for levels of risk included prior alcohol use behaviors, sexual identity, ethnic/racial identity, and transportation to the event. Gender did not differentiate for alcohol use but fewer women used drugs. Conclusions Findings confirm the importance of targeting EMDEs for prevention efforts. EMDEs attract young working adults who are engaged in heavy alcohol and/or drug use. Targeting these social settings for delivering public health prevention strategies regarding alcohol and drug use and related harms is indicated by the findings. PMID:24139778

Miller, Brenda A.; Byrnes, Hilary F.; Branner, Amy C.; Voas, Robert; B. Johnson, Mark

2014-01-01

109

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

21 Food and Drugs 4 2014-04-01 2014-04-01 false What actions must I take to control the distribution of PET drug products? 212.90 Section 212.90 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF...

2014-04-01

110

Characterization of Lung's Emphysema Distribution: Numerical Assessment of Disease Development  

E-print Network

Characterization of Lung's Emphysema Distribution: Numerical Assessment of Disease Development M, Egypt. Abstract--Chronic Obstructive Pulmonary Disease (COPD) refers to a group of lung diseases bronchitis. Pulmonary emphysema is defined as a lung disease characterized by "abnormal enlargement

Paris-Sud XI, Université de

111

Surveying Teens in School to Assess the Prevalence of Problematic Drug Use  

ERIC Educational Resources Information Center

Background: Illicit drug use by school-aged teens can adversely affect their health and academic achievement. This study used a survey administered in schools to assess the prevalence of problematic drug use among teenagers in a Midwestern community. Methods: Self-report data were collected from 11th- and 12th-grade students (N = 3974) in 16…

Falck, Russel S.; Nahhas, Ramzi W.; Li, Linna; Carlson, Robert G.

2012-01-01

112

A Choice Procedure to Assess the Aversive Effects of Drugs in Rodents  

ERIC Educational Resources Information Center

The goal of this series of experiments was to develop an operant choice procedure to examine rapidly the punishing effects of intravenous drugs in rats. First, the cardiovascular effects of experimenter-administered intravenous histamine, a known aversive drug, were assessed to determine a biologically active dose range. Next, rats responded on…

Podlesnik, Christopher A.; Jimenez-Gomez, Corina; Woods, James H.

2010-01-01

113

Assessing dietary intake of drug abusing Hispanic adults with and without HIV infection  

Technology Transfer Automated Retrieval System (TEKTRAN)

Drug abuse is an important risk factor for Human Immunodeficiency Virus (HIV) among Hispanics in the Northeastern United States and both drug abuse and HIV are associated with nutritional deficiencies. The selection of a dietary assessment method most appropriate for Hispanic adults with/without HIV...

114

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...

115

Effect of heterogeneous microvasculature distribution on drug delivery to solid tumour  

NASA Astrophysics Data System (ADS)

Most of the computational models of drug transport in vascular tumours assume a uniform distribution of blood vessels through which anti-cancer drugs are delivered. However, it is well known that solid tumours are characterized by dilated microvasculature with non-uniform diameters and irregular branching patterns. In this study, the effect of heterogeneous vasculature on drug transport and uptake is investigated by means of mathematical modelling of the key physical and biochemical processes in drug delivery. An anatomically realistic tumour model accounting for heterogeneous distribution of blood vessels is reconstructed based on magnetic resonance images of a liver tumour. Numerical simulations are performed for different drug delivery modes, including direct continuous infusion and thermosensitive liposome-mediated delivery, and the anti-cancer effectiveness is evaluated through changes in tumour cell density based on predicted intracellular concentrations. Comparisons are made between regions of different vascular density, and between the two drug delivery modes. Our numerical results show that both extra- and intra-cellular concentrations in the liver tumour are non-uniform owing to the heterogeneous distribution of tumour vasculature. Drugs accumulate faster in well-vascularized regions, where they are also cleared out more quickly, resulting in less effective tumour cell killing in these regions. Compared with direct continuous infusion, the influence of heterogeneous vasculature on anti-cancer effectiveness is more pronounced for thermosensitive liposome-mediated delivery.

Zhan, Wenbo; Gedroyc, Wladyslaw; Xu, Xiao Yun

2014-11-01

116

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. PMID:22670830

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

2013-01-01

117

Assessing the freshwater distribution of yellow eel . Lasne(1)  

E-print Network

Assessing the freshwater distribution of yellow eel Ã?. Lasne(1) , P. Laffaille(1,2) ABSTRACT, such as the European eel, that have complex life cycles, exhibit cryptic behavior, or migrate over long distances. A review of the literature suggests that eel size data could be used to assess and analyze freshwater

Paris-Sud XI, Université de

118

Opinion: Assessing the Barriers to Image Guided Drug Delivery  

PubMed Central

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 towards 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; Koo Lee, Yong-Eun; Patri, Anil K; Sept, David; Schnitzer, Jan E.; Wood, Bradford J.; Zhang, Miqin; Zheng, Gang; Farahani, Keyvan

2014-01-01

119

Assessment of Drug Transporter Function Using Fluorescent Cell Imaging  

PubMed Central

ATP-binding cassette (ABC) proteins, including the breast cancer resistance protein (BCRP) and the multidrug resistance proteins (MDRs), actively transport structurally diverse chemicals from a number of tissues. Moreover, transporters are being increasingly cited as mediators of clinically relevant drug-drug interactions. The potential outcomes of concomitantly administering two drugs that interact at the same transporter include altered disposition and toxicity and/or efficacy of one or both of the drugs. Research demonstrating the role of transporters in clinical pharmacokinetics has shed light on the need for in vitro screening methods that detect drug-transporter interactions during preclinical development. This paper describes a cell-based model for the detection of functional inhibitors of BCRP and MDR1 by measuring fluorescent substrate accumulation in suspended cells that overexpress or endogenously express these proteins using an automated cell counter. An alternate protocol is provided describing the use of a spectrophotometer with fluorescence detection capabilities to identify functional inhibitors of BCRP and MDR1 in transporter overexpressing cells. While a spectrophotometer is available in most laboratories, an automatic cell counter offers convenience, sensitivity, and speed in measuring the cellular accumulation of fluorescent substrates and identification of novel inhibitors. PMID:24510579

Bircsak, Kristin M.; Gibson, Christopher J.; Robey, Robert W.

2013-01-01

120

ASSESSMENT OF VANADIUM DISTRIBUTION IN1 SHALLOW GROUNDWATERS2  

E-print Network

ASSESSMENT OF VANADIUM DISTRIBUTION IN1 SHALLOW GROUNDWATERS2 3 4 5 Olivier Pourret1 *, Aline Dia2 1, CNRS13 Campus de Beaulieu14 35042 Rennes Cedex, France15 16 17 18 19 20 21 Keywords: vanadium) concentrations, with the aim29 to investigate the controlling factors of vanadium (V) distribution. Two spatially

Paris-Sud XI, Université de

121

Prediction of the volumes of distribution of basic drugs in humans based on data from animals  

Microsoft Academic Search

The apparent volume of distribution-after distribution equilibrium and the ratio of distributive tissue volume to the unbound fraction in the tissue (VT\\/fuT)of 10 weak basic drugs, i.e., chlorpromazine, imipramine, propranolol, disopyramide, lidocaine, quinidine, meperidine, pentazocine, chlorpheniramine, and methacyclin were compared in animal species and humans. In these two parameters, a statistically significant correlation between animals and humans was obtained, when

Yasufumi Sawada; Manabu Hanano; Yuichi Sugiyama; Hideyoshi Harashima; Tatsuji Iga

1984-01-01

122

In Vivo Assessment of Drug Efficacy against Mycobacterium abscessus Using the Embryonic Zebrafish Test System  

PubMed Central

Mycobacterium abscessus is responsible for a wide spectrum of clinical syndromes and is one of the most intrinsically drug-resistant mycobacterial species. Recent evaluation of the in vivo therapeutic efficacy of the few potentially active antibiotics against M. abscessus was essentially performed using immunocompromised mice. Herein, we assessed the feasibility and sensitivity of fluorescence imaging for monitoring the in vivo activity of drugs against acute M. abscessus infection using zebrafish embryos. A protocol was developed where clarithromycin and imipenem were directly added to water containing fluorescent M. abscessus-infected embryos in a 96-well plate format. The status of the infection with increasing drug concentrations was visualized on a spatiotemporal level. Drug efficacy was assessed quantitatively by measuring the index of protection, the bacterial burden (CFU), and the number of abscesses through fluorescence measurements. Both drugs were active in infected embryos and were capable of significantly increasing embryo survival in a dose-dependent manner. Protection from bacterial killing correlated with restricted mycobacterial growth in the drug-treated larvae and with reduced pathophysiological symptoms, such as the number of abscesses within the brain. In conclusion, we present here a new and efficient method for testing and compare the in vivo activity of two clinically relevant drugs based on a fluorescent reporter strain in zebrafish embryos. This approach could be used for rapid determination of the in vivo drug susceptibility profile of clinical isolates and to assess the preclinical efficacy of new compounds against M. abscessus. PMID:24798271

Bernut, Audrey; Le Moigne, Vincent; Lesne, Tiffany; Lutfalla, Georges; Herrmann, Jean-Louis

2014-01-01

123

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

124

Evolution of the Food and Drug Administration approach to liver safety assessment for new drugs: current status and challenges.  

PubMed

Prompted by approval in 1997 of troglitazone and bromfenac, two drugs that promptly began to show serious and sometimes fatal liver toxicity, we began at the Food and Drug Administration (FDA) a series of annual conferences in 1999 to consider issues of drug-induced liver injury (DILI). First inviting reviewers of new drug applications we opened the audiences in 2001 to pharmaceutical industry and academic consultants to industry and FDA, and slides shown at the meetings were posted on the internet to be available at the website of the American Association for the Study of Liver Diseases (AASLD)-go to ( http://www.aasld.org/dili/Pages/default.aspx ). Observations by Dr. Hyman J. Zimmerman that "drug-induced hepatocellular jaundice is a serious lesion" with possible mortality formed a basis for developing a computer program to plot peak serum values for alanine aminotransferase (ALT) and total bilirubin (TBL) in an x-y log-log graph for all subjects enrolled in clinical trials. This program had the capability to show the time course of all liver tests for individuals who had both hepatocellular injury and reduced whole liver function, plus clinical narratives to diagnose the severity and most likely cause of the abnormalities. We called the program eDISH (for evaluation of Drug-Induced Serious Hepatotoxicity), and began in 2004 to use it to assess DILI in clinical trial subjects. From 2008, comments made by the presenters at the conferences about their slides and ensuing discussions have been added to the website. All this has raised awareness of the problem, and since 1997, the FDA has not had to withdraw a single drug because of post-marketing hepatotoxicity. Many issues still remain to be resolved; among the most controversial is the best method to estimate likelihood that a given liver injury was actually caused by the drug in question. On November 9, 2012, a workshop was convened to discuss the best practices for the assessment of drug-induced liver injury (DILI) in clinical trials. PMID:25352324

Senior, John R

2014-11-01

125

Nutrition and Drug/Alcohol Rehabilitation: A Needs Assessment.  

ERIC Educational Resources Information Center

Diet histories of clients entering a drug/alcohol treatment facility showed need for improved eating habits. At least 50% had customarily low intakes of several nutrients plus calories. Nutritional adequacy improved during treatment, as did caloric excesses. Clients needed nutrition education. (Author/NB)

Madden, Judith; McIntosh, Elaine

1987-01-01

126

Assessment of drug-related problems in depressive patients  

PubMed Central

Background: Drug-related problems (DRPs) frequently occur in modern medical practice, increasing the morbidity and mortality as well as increasing cost of care. Objective: The study is to evaluate the incidence of DRPs in patients admitted to a psychiatric department. Materials and Methods: A prospective observational study was conducted for a period of 4 months at Baliga psychiatric hospital. All prescriptions of the study population were screened for DRPs such as adverse drug reactions (ADRs) and potential drug-drug interactions (pDDIs) by using computerized database system. Results: Out of 120 patients, 19 patients had observed 26 DRPs. Out of 33 patients, 19 patients had observed 26 ADRs and 14 patients had observed 24 pDDIs. The overall incidence of DRPs was 15.83%. Female patients outnumbered the male patients, in which 12 women constitute 10% followed by men 7 (5.83%). The common ADRs observed were hyponatremia and headache. Considering the outcomes, 20 (76.9%) cases recovered from ADRs and 20 (76.9%) of the ADRs were definitely preventable. Majority of ADRs were probable and were found to be mild to moderately severe. Conclusions: Age, female gender and polypharmacy were the risk factors for the developing DRPs.

Mateti, Uday Venkat; Lalwani, Tarachand; Nagappa, Anantha Naik; Bhandary, P. V.; Verupaksha, D.; Balkrishnan, Rajesh

2015-01-01

127

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

128

Drug induced QT prolongation: the measurement and assessment of the QT interval in clinical practice  

PubMed Central

There has been an increasing focus on drug induced QT prolongation including research on drug development and QT prolongation, following the removal of drugs due to torsades de pointes (TdP). Although this has improved our understanding of drug-induced QT prolongation there has been much less research aimed at helping clinicians assess risk in individual patients with drug induced QT prolongation. This review will focus on assessment of drug-induced QT prolongation in clinical practice using a simple risk assessment approach. Accurate measurement of the QT interval is best done manually, and not using the measurement of standard ECG machines. Correction for heart rate (HR) using correction formulae such as Bazett's is often inaccurate. These formulae underestimate and overestimate the duration of cardiac repolarization at low and high heart rates, respectively. Numerous cut-offs have been suggested as an indicator of an abnormal QT, but are problematic in clinical practice. An alternative approach is the QT nomogram which is a plot of QT?vs. HR. The nomogram has an ‘at risk’ line and QT-HR pairs above this line have been shown in a systematic study to be associated with TdP and the line is more sensitive and specific than Bazett's QTc of 440 ms or 500 ms. Plotting the QT-HR pair for patients on drugs suspected or known to cause QT prolongation allows assessment of the QT interval based on normal population QT variability. This risk assessment then allows the safer commencement of drugs therapeutically or management of drug induced effects in overdose. PMID:23167578

Isbister, Geoffrey K; Page, Colin B

2013-01-01

129

Effects of Variation in Drug Elimination on Five Methods for Assessing Zero-Order Drug Absorption Rates  

Microsoft Academic Search

The area function method for assessing zero-order (ko) drug absorption rates was compared to four other methods under conditions where variation occurs in the plasma concentration data and in the elimination rate constant (kel or k10) for one- or two-compartment models. For deviant kel values of a one-compartment model, the most accurate recovery of ko occurred with the area function

Haiyung Cheng; William J. Jusko

1990-01-01

130

Using geographic information systems to assess spatial patterns of drug use, selection bias and attrition among a sample of injection drug users  

Microsoft Academic Search

This study sought to assess whether frequency and type of drug use are geographically located within the city of Baltimore independent of neighborhood characteristics. The second goal was to assess geographic factors associated with sample selection and attrition. The sample consisted of 597 inner-city injection drug users who were enrolled in a HIV prevention study. The residential locations were plotted

Carl Latkin; Gregory E Glass; Terry Duncan

1998-01-01

131

Drug and Alcohol Dependence 72 (2003) 163168 An independent assessment of MEDWatch reporting for  

E-print Network

liability assessment 1. Introduction Abuse and dependence on marketed drugs are adverse events is likely to improve assessments of public health risks associated with adverse events. © 2003 Elsevier-215-399-0987. E-mail address: woody@tresearch.org (G.E. Woody). These and other adverse events associated with use

Steinbach, Joe Henry

132

The Community Assessment Inventory—Client views of supports to drug abuse treatment  

Microsoft Academic Search

A measure assessing client views of the community supports available to them was developed and tested with entrants to outpatient drug free treatment. Items for a Community Assessment Inventory (CAI) fell into four areas of potential social support for treatment entry and engagement: (1) partner and\\/or family with whom living; (2) family living outside the home; (3) friends; and (4)

Barry S. Brown; Kevin E. O’Grady; Robert J. Battjes; Elizabeth C. Katz

2004-01-01

133

Atom type preferences, structural diversity, and property profiles of known drugs, leads, and nondrugs: a comparative assessment.  

PubMed

A new characterization of known drug, lead, and representative nondrug databases was performed taking into account several properties at the atomic and molecular levels. This characterization included atom type preferences, intrinsic structural diversity (Atom Type Diversity, ATD), and other well-known physicochemical properties, as an approach for rapid assessment of druglikeness for small molecule libraries. To characterize ATD, an elaborate united atom classification, UALOGP (United Atom Log P), with 148 atom types, was developed along with associated atomic physicochemical parameters. This classification also enabled an analysis of atom type and physicochemical property distributions (for calculated log P, molar refractivity, molecular weight, total atom count, and ATD) of drug, lead, and nondrug databases, a reassessment of the Ro5 (Rule of Five) and GVW (Ghose?Viswanadhan?Wendoloski) criteria, and development of new criteria and ranges more accurately reflecting the chemical space occupied by small molecule drugs. A relative druglikeness parameter was defined for atom types in drugs, identifying the most preferred types. The present work demonstrates that drug molecules are constitutionally more diverse relative to nondrugs, while being less diverse than leads. PMID:21480669

Viswanadhan, Vellarkad N; Rajesh, Hariharan; Balaji, Vitukudi N

2011-05-01

134

A new criterion to assess distributional homogeneity in hyperspectral images of solid pharmaceutical dosage forms.  

PubMed

During galenic formulation development, homogeneity of distribution is a critical parameter to check since it may influence activity and safety of the drug. Raman hyperspectral imaging is a technique of choice for assessing the distributional homogeneity of compounds of interest. Indeed, the combination of both spectroscopic and spatial information provides a detailed knowledge of chemical composition and component distribution. Actually, most authors assess homogeneity using parameters of the histogram of intensities (e.g. mean, skewness and kurtosis). However, this approach does not take into account spatial information and loses the main advantage of imaging. To overcome this limitation, we propose a new criterion: Distributional Homogeneity Index (DHI). DHI has been tested on simulated maps and formulation development samples. The distribution maps of the samples were obtained without validated calibration model since different formulations were under investigation. The results obtained showed a linear relationship between content uniformity values and DHI values of distribution maps. Therefore, DHI methodology appears to be a suitable tool for the analysis of homogeneity of distribution maps even without calibration during formulation development. PMID:24626397

Sacré, Pierre-Yves; Lebrun, Pierre; Chavez, Pierre-François; De Bleye, Charlotte; Netchacovitch, Lauranne; Rozet, Eric; Klinkenberg, Régis; Streel, Bruno; Hubert, Philippe; Ziemons, Eric

2014-03-25

135

Influence of drug distribution and solubility on release from geopolymer pellets--a finite element method study.  

PubMed

This study investigates the influence of drug solubility and distribution on its release from inert geopolymer pellets of three different sizes (1.5 × 1.5, 3 × 6, and 6 × 6 mm), having the same geopolymer composition and containing highly potent opioid fentanyl, sumatriptan, theophylline, or saccharin. Scanning electron microscopy, nitrogen sorption, drug solubility, permeation, and release experiments were performed, and estimates of the drug diffusion coefficients and solubilities in the geopolymer matrix were derived with the aid of finite element method (FEM). FEM was further employed to investigate the effect of a nonuniform drug distribution on the drug release profile. When inspecting the release profiles for each drug, it was observed that their solubilities in the geopolymer matrix imposed a much greater influence on the drug release rate than their diffusion coefficients. Concentrating the initial drug load in FEM into nonuniformly distributed drug regions inside the matrix created drug release profiles that more closely resembled experimental data than an FEM-simulated uniform drug distribution did. The presented FEM simulations and visualization of drug release from geopolymers under varying initial and dynamic conditions should open up for more systematic studies of additional factors that influence the drug release profile from porous delivery vehicles. PMID:22308066

Jämstorp, Erik; Strømme, Maria; Bredenberg, Susanne

2012-05-01

136

Application of GIS in water distribution system assessment.  

PubMed

Water distribution system (WDS) is the most important component of water supply chain--supplying water from source to consumer. When supply system is poorly maintained, contaminants enter into the supply pipes through cracks and this leads to significant public health risk. Being underground, pipe condition assessment is a difficult task. In this paper, a case study is presented for assessment of pipe condition in a water distribution network of Moinbagh area in Hyderabad (India). The mathematical model-Pipe Condition Assessment (PCA) Model was used, which utilizes GIS based maps of water distribution network, sewer network, drains and soil as input in addition to data on physical properties of the network as well as operational parameters. The application of PCA identified that only 3% pipes in the network were in bad condition. PMID:21117426

Sargaonkar, Aabha; Islam, Raisul

2009-10-01

137

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

138

Use of the truncated shifted Pareto distribution in assessing size distribution of oil and gas fields  

USGS Publications Warehouse

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. ?? 1988 International Association for Mathematical Geology.

Houghton, J.C.

1988-01-01

139

Cop's Best Friend: Preventing the Illegal Distribution and Transportation of Prescription Drugs.  

PubMed

Law enforcement and the military have long relied on canines to provide protection of the handler and others involved in combating crime. One of the extremely important uses of canines is in the detection of illegal drugs, bombs, and other explosives to protect the President of the United States, other dignitaries, and the general public. This article discusses the details on a canine that was trained to detect major illicit pharmaceuticals. The efforts of this program were made easier with the help of a compounding pharmacist who willingly assisted the Warren County Drug Task Force in the Canine's detection training by preparing and individually labeling capsules that contained pure drug. Both parties share their experiences in this important endeavor to combat the illegal distribution and transportation of prescription drugs. PMID:23965423

Burke, John

140

Trastuzumab emtansine. An inadequately assessed combination of two cytotoxic drugs.  

PubMed

There is no consensus on second-line treatment for women with metastatic or locally advanced breast cancer over-expressing HER-2 protein in whom treatment with a taxane + trastuzumab has failed. Capecitabine is one option. Adding lapatinib does not prolong survival. Trastuzumab emtansine (Kadcyla, Roche) has received EU marketing authorisation for use in this setting. It consists of two covalently bound drugs: trastuzumab, a monoclonal antibody that binds to HER-2 receptors, and DM1, a cytotoxic microtubule inhibitor. DM1 is derived from maytansine, a cytotoxic drug abandoned in the 1980s because it proved to be too toxic after systemic administration. Clinical evaluation of trastuzumab emtansine is based on an unblinded trial versus capecitabine + lapatinib in 991 patients. The use of lapatinib in all patients in the control group is questionable. An interim analysis suggested that overall survival was about 6 months longer with trastuzumab emtansine (30.9 versus 25.1 months). In addition to the adverse effects of trastuzumab (thrombocytopenia, heart failure, etc.), trastuzumab emtansine causes frequent and potentially life-threatening hepatic toxicity, peripheral neuropathy, and urinary tract infections. Trastuzumab emtansine appears to be less toxic to the skin and mucous membranes than the capecitabine + lapatinib combination. DM1 is metabolised by cytochrome P450 isoenzymes CYP3A4 and CYP3A5 and is also a P-glycoprotein substrate, creating a potential risk of multiple pharmacokinetic interactions. Trastuzumab emtansine appears to be teratogenic and embryotoxic. The international nonproprietary name of this drug is easily confused with trastuzumab. In practice, it is best to at least wait for the full results of the only available comparative trial of trastuzumab emtansine before drawing conclusions about its harm-benefit balance and its possible use if it represents a real therapeutic advance. PMID:25629144

2014-12-01

141

Prediction and Prevention of Prescription Drug Abuse: Role of Preclinical Assessment of Substance Abuse Liability  

PubMed Central

In 2011, the prevalence of prescription drug abuse exceeded that of any other illicit drug except marijuana. Consequently, efforts to curtail abuse of new medications should begin during the drug development process, where abuse liability can be identified and addressed before a candidate medication has widespread use. The first step in this process is scheduling with the Drug Enforcement Agency so that legal access is appropriately restricted, dependent upon levels of abuse risk and medical benefit. To facilitate scheduling, the Food and Drug Administration (FDA) has published guidance for industry that describes assessment of abuse liability. The purpose of this paper is to review methods that may be used to satisfy the FDA’s regulatory requirements for animal behavioral and dependence pharmacology. Methods include psychomotor activity, self-administration (an animal model of the rewarding effects of a drug), drug discrimination (an animal model of the subjective effects of a drug), and evaluation of tolerance and dependence. Data from tests conducted at RTI with known drugs of abuse illustrate typical results, and demonstrate that RTI is capable of performing these tests. While using preclinical data to predict abuse liability is an imperfect process, it has substantial predictive validity. The ultimate goal is to increase consumer safety through appropriate scheduling of new medications. PMID:24008590

Marusich, Julie A.; Lefever, Timothy W.; Novak, Scott P.; Blough, Bruce E.; Wiley, Jenny L.

2013-01-01

142

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

143

Hospital drug distribution systems in the UK and Germany ? a study of medication errors  

Microsoft Academic Search

The aim of this study was to compare the incidence of medication errors and the stages of the drug distribution system at which they occur in a United Kingdom (UK) hospital using the ward pharmacy system, a German hospital using the unit dose system and a German hospital using their traditional system. Medication errors were identified by observing the preparation

Katja Taxis; Bryony Dean; Nick Barber

1999-01-01

144

Assessment of simvastatin niosomes for pediatric transdermal drug delivery.  

PubMed

Abstract The prevalence of childhood dyslipidemia increases and is considered as an important risk factor for the incidence of cardiovascular disease in the adulthood. To improve dosing accuracy and facilitate the determination of dosing regimens in function of the body weight, the proposed study aims at preparing transdermal niosomal gels of simvastatin as possible transdermal drug delivery system for pediatric applications. Twelve formulations were prepared to screen the influence of formulation and processing variables on critical niosomal characteristics. Nano-sized niosomes with 0.31??m number-weighted size displayed highest simvastatin release rate with 8.5% entrapment capacity. The niosomal surface coverage by negative charges was calculated according to Langmuir isotherm with n?=?0.42 to suggest that the surface association was site-independent, probably producing surface rearrangements. Hypolipidemic activities after transdermal administration of niosomal gels to rats showed significant reduction in cholesterol and triglyceride levels while increasing plasma high-density lipoproteins concentration. Bioavailability estimation in rats revealed an augmentation in simvastatin bioavailability by 3.35 and 2.9 folds from formulation F3 and F10, respectively, compared with oral drug suspension. Hence, this transdermal simvastatin niosomes not only exhibited remarkable potential to enhance its bioavailability and hypolipidemic activity but also considered a promising pediatric antihyperlipidemic formulation. PMID:25386740

Zidan, Ahmed S; Hosny, Khaled M; Ahmed, Osama A A; Fahmy, Usama A

2014-11-11

145

The maximal electroshock seizure (MES) model in the preclinical assessment of potential new antiepileptic drugs.  

PubMed

The choice of appropriate animal models for the initial in vivo testing of potential anticonvulsant compounds is one of the most important steps in the successful search for new antiepileptic drugs. The purpose of this paper is to describe the most important aspects to take into account when performing the maximal electroshock seizure (MES) test in the routine laboratory screening of new antiepileptics: the conventional and threshold MES test experimental procedures, the factors affecting experimental data (laboratory conditions, administration vehicles and drug formulations, time after drug administration, and stimulus duration and site of stimulation) and the assessment of anticonvulsant activity are discussed. PMID:19455265

Castel-Branco, M M; Alves, G L; Figueiredo, I V; Falcão, A C; Caramona, M M

2009-03-01

146

CYP induction-mediated drug interactions: in vitro assessment and clinical implications.  

PubMed

Cytochrome P450 (CYP) induction-mediated interaction is one of the major concerns in clinical practice and for the pharmaceutical industry. There are two major issues associated with CYP induction: a reduction in therapeutic efficacy of comedications and an induction in reactive metabolite-induced toxicity. Because CYP induction is a metabolic liability in drug therapy, it is highly desirable to develop new drug candidates that are not potent CYP inducer to avoid the potential of CYP induction-mediated drug interactions. For this reason, today, many drug companies routinely include the assessment of CYP induction at the stage of drug discovery as part of the selection processes of new drug candidates for further clinical development. The purpose of this article is to review the molecular mechanisms of CYP induction and the clinical implications, including pharmacokinetic and pharmacodynamic consequences. In addition, factors that affect the degree of CYP induction and extrapolation of in vitro CYP induction data to in vivo situations will also be discussed. Finally, assessment of the potential of CYP induction at the drug discovery and development stage will be discussed. PMID:16718615

Lin, Jiunn H

2006-06-01

147

Distribution of primaquine in human blood: Drug-binding to alpha 1-glycoprotein  

SciTech Connect

To clarify the distribution of the antimalarial primaquine in human blood, we measured the drug separately in the liquid, cellular, and ultrafiltrate phases. Washed red cells resuspended at a hematocrit of 0.4 were exposed to a submaximal therapeutic level of 250 ng/ml of carbon 14-labeled primaquine. The tracer was recovered quantitatively in separated plasma and red cells. Over 75% of the total labeled drug was found in red cells suspended in saline solution, but only 10% to 30% in red cells suspended in plasma. The plasma effect was not mediated by albumin. Studies with alpha 1-acid glycoprotein (AGP), tris(2-butoxyethyl)phosphate, an agent that displaces AGP-bound drugs, and cord blood known to have decreased AGP established that primaquine binds to physiologic amounts of the glycoprotein in plasma. Red cell primaquine concentration increased linearly as AGP level fell and as the free drug fraction rose. We suggest that clinical blood levels of primaquine include the red cell fraction or whole blood level because (1) erythrocytic primaquine is a sizable and highly variable component of the total drug in blood; (2) this component reflects directly the free drug in plasma, and inversely the extent of binding to AGP; (3) the amount of free primaquine may influence drug transport into specific tissues in vivo; and (4) fluctuations of AGP, an acute-phase reactant that increases greatly in patients with malaria and other infections, markedly affect the partition of primaquine in blood. Because AGP binds many basic drugs, unrecognized primaquine-drug interactions may exist.

Kennedy, E.; Frischer, H. (Rush Univ., Chicago, IL (USA))

1990-12-01

148

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. PMID:21223357

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

2011-01-01

149

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...

150

A framework for assessing the consistency of drug classes across sources  

PubMed Central

Background The objective of this study is to develop a framework for assessing the consistency of drug classes across sources, such as MeSH and ATC. Our framework integrates and contrasts lexical and instance-based ontology alignment techniques. Moreover, we propose metrics for assessing not only equivalence relations, but also inclusion relations among drug classes. Results We identified 226 equivalence relations between MeSH and ATC classes through the lexical alignment, and 223 through the instance-based alignment, with limited overlap between the two (36). We also identified 6,257 inclusion relations. Discrepancies between lexical and instance-based alignments are illustrated and discussed. Conclusions Our work is the first attempt to align drug classes with sophisticated instance-based techniques, while also distinguishing between equivalence and inclusion relations. Additionally, it is the first application of aligning drug classes in ATC and MeSH. By providing a detailed account of similarities and differences between drug classes across sources, our framework has the prospect of effectively supporting the creation of a mapping of drug classes between ATC and MeSH by domain experts. PMID:25101165

2014-01-01

151

Estimating numbers of injecting drug users in metropolitan areas for structural analyses of community vulnerability and for assessing relative degrees of service provision for injecting drug users  

Microsoft Academic Search

This article estimates the population prevalence of current injection drug users (IDUs) in 96 large US metropolitan areas\\u000a to facilitate structural analyses of its predictors and sequelae and assesses the extent to which drug abuse treatment and\\u000a human immunodeficiency virus (HIV) counseling and testing are made available to drug injectors in each metropolitan area.\\u000a We estimated the total number of

Samuel R. Friedman; Barbara Tempalski; Hannah Cooper; Theresa Perlis; Marie Keem; Risa Friedman; Peter L. Flom

2004-01-01

152

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. PMID:23763856

2013-01-01

153

Semiautomated assessment of in vitro activity of potential antileishmanial drugs.  

PubMed

We have compared the in vitro activity of six agents against macrophage-contained Leishmania tropica amastigotes determined by the conventional Giemsa staining procedure, with the activity determined by the semiautomated assessment of incorporation of radiolabeled uracil into the nucleic acid of the organisms. Although the mean 50% effective dose of Pentostam by Giemsa staining (4.1 micrograms/ml) was somewhat higher than that by uracil incorporation (2.8 micrograms/ml), the ED50S for the other two clinical agents (pentamidine, 0.035 versus 0.037 micrograms/ml; amphotericin B, 0.67 versus 0.70 micrograms/ml) and for three promising experimental agents (ketoconazole, 11.3 versus 11.3 micrograms/ml; the 8-aminoquinoline WR 6026, 1.6 versus 1.5 micrograms/ml formycin B, 0.018 versus 0.017 micrograms/ml) were virtually identical. The radiolabeling technique has several advantages over the Giemsa staining procedure. These include the need for relatively few macrophages, rapid and objective data generation, and viability of the test organism being measured. The successful application of the radiolabeling technique to at least six different chemical classes of compounds suggests that it would be useful for the routine assessment of antileishmanial activity in vitro. PMID:3002244

Berman, J D; Gallalee, J V

1985-12-01

154

Bio-relevant media to assess drug permeability: sodium taurocholate and lecithin combination or crude bile?  

PubMed

The assessment of in vivo drug absorption with in vitro permeability models demands the use of transport media with surface acting compounds. With the aim to establish their influence on in vitro permeability of 30 drugs through Caco-2 monolayers, cell vitality/integrity and micellar drug entrapment, taurocholate/lecithin (NaTC/Leci) and pig crude bile were applied. Drug permeabilities were correlated to fraction of drugs absorbed and appropriate NaTC/Leci and bile concentrations were proposed to simulate fasted/fed conditions in vitro (bile in the concentration range 1-5 v/v% or 0.2/0.05mM NaTC/Leci for fasted; 10 v/v% bile or 3/0.75mM NaTC/Leci for fed conditions) without detrimental effects on monolayer integrity/vitality (NaTC/Leci was more toxic than bile). Surfactants exerted different affinities for drugs; free drug concentration (c(free)) of some was significantly lowered only by bile, while for the others NaTC/Leci and bile significantly diminished c(free). For some substances NaTC/Leci and bile significantly increased their permeabilities (i.e. more than 3-times) in spite of profound c(free) decrease indicating the existence of an alternative absorption mechanism. Based on these data, the impact of bile on in vitro drug permeability and micellar drug entrapment cannot be adequately simulated by NaTC/Leci, because their effects on drug absorption differ. PMID:22449411

Berginc, Katja; Trontelj, Jurij; Kristl, Albin

2012-06-15

155

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

156

Rapid assessment of drug-related HIV risk among men who have sex with men in three South African cities  

Microsoft Academic Search

The current assessment was undertaken to examine the link between drug use and sexual risk behavior among men who have sex with men (MSM) in locations known to have high prevalence rates of drug use and sexual risk behavior in Cape Town, Durban and Pretoria, South Africa. Street intercepts and purposive snowball sampling were used to recruit drug-using MSM. A

Charles Parry; Petal Petersen; Sarah Dewing; Tara Carney; Richard Needle; Karen Kroeger; Latasha Treger

2008-01-01

157

Assessment of algorithms for predicting drug–drug interactions via inhibition mechanisms: comparison of dynamic and static models  

PubMed Central

AIMS Static and dynamic models (incorporating the time course of the inhibitor) were assessed for their ability to predict drug–drug interactions (DDIs) using a population-based ADME simulator (Simcyp®V8). The impact of active metabolites, dosing time and the ability to predict inter-individual variability in DDI magnitude were investigated using the dynamic model. METHODS Thirty-five in vivo DDIs involving azole inhibitors and benzodiazepines were predicted using the static and dynamic model; both models were employed within Simcyp for consistency in parameters. Simulations comprised of 10 trials with matching population demographics and dosage regimen to the in vivo studies. Predictive utility of the static and dynamic model was assessed relative to the inhibitor or victim drug investigated. RESULTS Use of the dynamic and static models resulted in comparable prediction success, with 71 and 77% of DDIs predicted within two-fold, respectively. Over 40% of strong DDIs (>five-fold AUC increase) were under-predicted by both models. Incorporation of the itraconazole metabolite into the dynamic model resulted in increased prediction accuracy of strong DDIs (80% within two-fold). Bias and imprecision in prediction of triazolam DDIs were higher in comparison with midazolam and alprazolam; >50% of triazolam DDIs were under-predicted regardless of the model used. Predicted inter-individual variability in the AUC ratio (coefficient of variation of 45%) was consistent with the observed variability (50%). CONCLUSIONS High prediction accuracy was observed using both the Simcyp dynamic and static models. The differences observed with the dose staggering and the incorporation of active metabolite highlight the importance of these variables in DDI prediction. PMID:21143503

Guest, Eleanor J; Rowland-Yeo, Karen; Rostami-Hodjegan, Amin; Tucker, Geoffrey T; Houston, J Brian; Galetin, Aleksandra

2011-01-01

158

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

159

Simulated Drug Discovery Process to Conduct a Synoptic Assessment of Pharmacy Students  

PubMed Central

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

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

2014-01-01

160

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. PMID:24278499

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

2010-01-01

161

Assessing malaria drug resistance in US military areas of operation using microarrays.  

E-print Network

Assessing malaria drug resistance in US military areas of operation using microarrays. A. Taylor Bright University of California, San Diego Background: Malaria inflicts an incredible burden of the developed world, roughly 40% of the world's population live in areas where malaria is endemic(1

Gleeson, Joseph G.

162

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...

163

Statistical assessment of dissolution and drug release profile similarity using a model-dependent approach  

Microsoft Academic Search

A general multivariate procedure for assessing the similarity of dissolution and drug release profiles was developed. A mathematical model is fit to the data, and Hotelling's T2 test is used to calculate the joint confidence region around the vector of differences between least-squares estimates of the parameters in the model. The method of Lagrange multipliers is used to determine if

Mark R. Berry; Michael D. Likar

2007-01-01

164

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

165

Two approaches for assessing photon path length distribution in pulp  

NASA Astrophysics Data System (ADS)

Pulp consists of distinguishable particles, the refractive indices of which differ from the index of the employed medium, water. We are thus dealing with an optically scattering material. Particle distribution in pulp is nowadays a focus of interest. This parameter is related to the photon path length distribution (PPLD) determined by the inhomogeneity of the scatterer. In order to assess PPLD, we use two methods. In the first, the particle properties in pulp are estimated by means of a microscope. A model for Monte Carlo simulation is then built to obtain PPLD. In the second, the signal generated by a laser pulse passing the cuvette filled with water or pulp is detected with a streak camera and the assessment of PPLD accomplished by a deconvolution procedure. To obtain the particle distribution, the two methods may be used together, so that the streak-camera measurements give PPLD, and in the following simulation process the particle distribution is found, which corresponds to the determined PPLD. The number and diversity of the sample sets currently used do not fdfill the statistical requirements of the industry. Nevertheless, the results achieved encourage us to develop the methods further.

Saarela, Juha; Tormanen, Matti; Karttunen, Kyösti; Myllylä, Risto

2005-08-01

166

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. PMID:20478918

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

2010-01-01

167

Improving the assessment of heart toxicity for all new drugs through translational regulatory science.  

PubMed

Fourteen drugs have been removed from the market worldwide because they cause torsade de pointes. Most drugs that cause torsade can be identified by assessing whether they block the human ether à gogo related gene (hERG) potassium channel and prolong the QT interval on the electrocardiogram. In response, regulatory agencies require new drugs to undergo "thorough QT" studies. However, some drugs block hERG potassium channels and prolong QT with minimal torsade risk because they also block calcium and/or sodium channels. Through analysis of clinical and preclinical data from 34 studies submitted to the US Food and Drug Administration and by computer simulations, we demonstrate that by dividing the QT interval into its components of depolarization (QRS), early repolarization (J-Tpeak), and late repolarization (Tpeak-Tend), along with atrioventricular conduction delay (PR), it may be possible to determine which hERG potassium channel blockers also have calcium and/or sodium channel blocking activity. This translational regulatory science approach may enable innovative drugs that otherwise would have been labeled unsafe to come to market. PMID:24336137

Johannesen, L; Vicente, J; Gray, R A; Galeotti, L; Loring, Z; Garnett, C E; Florian, J; Ugander, M; Stockbridge, N; Strauss, D G

2014-05-01

168

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

169

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. PMID:23696033

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

2013-01-01

170

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. PMID:24367713

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

2013-01-01

171

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

172

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

173

Quantitative risk assessment in classification of drugs with identical API content.  

PubMed

When combating counterfeits it is equally important to recognize fakes and to avoid misclassification of genuine samples. This study presents a general approach to the problem using a newly-developed method called Data Driven Soft Independent Modeling of Class Analogy. The possibility to collect representative data for both training and validation is of great importance in classification modeling. When fakes are not available, we propose to compose the test set using the legitimate drug's analogs, manufactured by various producers. These analogs should have the identical API and a similar composition of excipients. The approach shows satisfactory results both in revealing counterfeits and in accounting for the future variability of the target class drugs. The presented case studies demonstrate that theoretically predicted misclassification errors can be successfully employed for the science-based risk assessment in drug identification. PMID:24929870

Rodionova, O Ye; Balyklova, K S; Titova, A V; Pomerantsev, A L

2014-09-01

174

[Assessment of disorders after chronic psychoactive drug abuse in patients hospitalized in detoxification units].  

PubMed

The aim of this study was the assessment of disorders after chronic intake of psychoactive drugs, like marijuana, amphetamine, ecstasy, cocaine and opiates. In 2002 in the Department of Clinical Toxicology detoxification unit were treated 117 chronic drug abusers. The 76 of them use the opiates predominantly, the next 41 persons (35 men, 6 women), were heavy abusers of psychostimulant drugs. In opiate abusers typical withdrawal signs and symptoms were observed. In the group of psychostimulants users, the mean time of marijuana use was 6 years, amphetamine--5 years. The cocaine was used rarely. Among 25 persons (61%) from these group the withdrawal syndrome were established. The excitation of neurovegetative system, depression, or psychomotor effects were observed. We concluded the necessity of estimation of neurobiological changes after using of psychostimulants and that more controlled research might uncover a clinically diagnosable withdrawal syndrome in human psychostimulants users. PMID:15521592

Chrostek Maj, Jan; Kroch, Stanis?aw; Kamenczak, Aleksandra; Polewka, Andrej; Szersze?-Motyka, Jadwiga

2004-01-01

175

Assessing introduction risk using species' rank-abundance distributions.  

PubMed

Mixed-species assemblages are often unintentionally introduced into new ecosystems. Analysing how assemblage structure varies during transport may provide insights into how introduction risk changes before propagules are released. Characterization of introduction risk is typically based on assessments of colonization pressure (CP, the number of species transported) and total propagule pressure (total PP, the total abundance of propagules released) associated with an invasion vector. Generally, invasion potential following introduction increases with greater CP or total PP. Here, we extend these assessments using rank-abundance distributions to examine how CP : total PP relationships change temporally in ballast water of ocean-going ships. Rank-abundance distributions and CP : total PP patterns varied widely between trans-Atlantic and trans-Pacific voyages, with the latter appearing to pose a much lower risk than the former. Responses also differed by taxonomic group, with invertebrates experiencing losses mainly in total PP, while diatoms and dinoflagellates sustained losses mainly in CP. In certain cases, open-ocean ballast water exchange appeared to increase introduction risk by uptake of new species or supplementation of existing ones. Our study demonstrates that rank-abundance distributions provide new insights into the utility of CP and PP in characterizing introduction risk. PMID:25473007

Chan, Farrah T; Bradie, Johanna; Briski, Elizabeta; Bailey, Sarah A; Simard, Nathalie; MacIsaac, Hugh J

2015-01-22

176

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. PMID:23936771

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

2013-01-01

177

Assessment of PLGA-PEG-PLGA Copolymer Hydrogel for Sustained Drug Delivery in the Ear  

PubMed Central

Temperature sensitive copolymer systems were previously studied using modified diffusion cells in vitro for intratympanic injection, and the PLGA-PEG-PLGA copolymer systems were found to provide sustained drug delivery for several days. The objectives of the present study were to assess the safety of PLGA-PEG-PLGA copolymers in intratympanic injection in guinea pigs in vivo and to determine the effects of additives glycerol and poloxamer in PLGA-PEG-PLGA upon drug release in the diffusion cells in vitro for sustained inner ear drug delivery. In the experiments, the safety of PLGA-PEG-PLGA copolymers to inner ear was evaluated using auditory brainstem response (ABR). The effects of the additives upon drug release from PLGA-PEG-PLGA hydrogel were investigated in the modified Franz diffusion cells in vitro with cidofovir as the model drug. The phase transition temperatures of the PLGA-PEG-PLGA copolymers in the presence of the additives were also determined. In the ABR safety study, the PLGA-PEG-PLGA copolymer alone did not affect hearing when delivered at 0.05-mL dose but caused hearing loss after 0.1-mL injection. In the drug release study, the incorporation of the bioadhesive additive, poloxamer, in the PLGA-PEG-PLGA formulations was found to decrease the rate of drug release whereas the increase in the concentration of the humectant additive, glycerol, provided the opposite effect. In summary, the PLGA-PEG-PLGA copolymer did not show toxicity to the inner ear at the 0.05-mL dose and could provide sustained release that could be controlled by using the additives for inner ear applications. PMID:24438444

Feng, Liang; Ward, Jonette A.; Li, S. Kevin; Tolia, Gaurav; Hao, Jinsong; Choo, Daniel I.

2014-01-01

178

Instrumented In Vitro Approaches to Assess Epithelial Permeability of Drugs from Pharmaceutical Formulations  

Microsoft Academic Search

The following chapter gives an overview of instrumented approaches to investigate the interactions of orally or pulmonary\\u000a administered formulations with epithelial cell cultures in vitro. The first section is focused on the combined assessment\\u000a of drug release\\/dissolution and subsequent absorption\\/permeation for solid oral dosage forms. Experimental approaches to mimic\\u000a the complex physiologically surroundings in the gastrointestinal tract are presented as

Stephan A. Motz; Michael Bur; Ulrich F. Schaefer; Claus-Michael Lehr

179

[HTA-Perspective: Challenges in the early assessment of new oncological drugs].  

PubMed

Oncologic drug therapies have gained wide attention in the context of health policy priority setting for serious and socially significant diseases with high human and monetary costs. Due to uncertainties and scepticism about the actual therapeutic importance of newly approved oncology products, an early assessment programme was already established in Austria in 2007. The assessment of new oncology products is thereby faced with special challenges, since study populations are frequently not representative or the study design is laid out in such a manner that a definitive assessment of patient-relevant endpoints is not possible (cross-overs after interim assessments, surrogate parameters as primary endpoints, uncontrolled studies or those with unrealistic comparators, invalidated post-hoc identified biomarkers). On account of these major uncertainties, even the European Medicines Agency (EMA) is already contemplating multi-stage, "adaptive" approvals, and national reimbursement institutions are increasingly working with outcome-oriented, conditional reimbursement. (As supplied by publisher). PMID:23663907

Wild, Claudia; Nachtnebel, Anna

2013-01-01

180

AN ASSESSMENT OF WOOD DUCK DISTRIBUTION, ABUNDANCE AND RIPARIAN BREEDING PAIR HABITATS IN SOUTH DAKOTA  

E-print Network

AN ASSESSMENT OF WOOD DUCK DISTRIBUTION, ABUNDANCE AND RIPARIAN BREEDING PAIR HABITATS IN SOUTH #12;AN ASSESSMENT OF WOOD DUCK DISTRIBUTION, ABUNDANCE AND RIPARIAN BREEDING PAIR HABITATS IN SOUTH Wildlife and Fisheries Sciences #12;AN ASSESSMENT OF WOOD DUCK DISTRIBUTION, ABUNDANCE AND RIPARIAN

181

Effects of Established Hypolipidemic Drugs on HDL Concentration, Subclass Distribution, and Function.  

PubMed

The knowledge of an inverse relationship between plasma high-density lipoprotein cholesterol (HDL-C) concentrations and rates of cardiovascular disease has led to the concept that increasing plasma HDL-C levels would be protective against cardiovascular events. Therapeutic interventions presently available to correct the plasma lipid profile have not been designed to specifically act on HDL, but have modest to moderate effects on plasma HDL-C concentrations. Statins, the first-line lipid-lowering drug therapy in primary and secondary cardiovascular prevention, have quite modest effects on plasma HDL-C concentrations (2-10 %). Fibrates, primarily used to reduce plasma triglyceride levels, also moderately increase HDL-C levels (5-15 %). Niacin is the most potent available drug in increasing HDL-C levels (up to 30 %), but its use is limited by side effects, especially flushing.The present chapter reviews the effects of established hypolipidemic drugs (statins, fibrates, and niacin) on plasma HDL-C levels and HDL subclass distribution, and on HDL functions, including cholesterol efflux capacity, endothelial protection, and antioxidant properties. PMID:25523003

Gomaraschi, Monica; Adorni, Maria Pia; Banach, Maciej; Bernini, Franco; Franceschini, Guido; Calabresi, Laura

2015-01-01

182

Label-free imaging of drug distribution and metabolism in colon cancer cells by Raman microscopy.  

PubMed

Targeted cancer therapies block cancer growth and spread using small molecules. Many molecular targets for an epidermal growth factor receptor (EGFR) selectively compete with the adenosine triphosphate-binding site of its tyrosine kinase domain. Detection of molecular targeted agents and their metabolites in cells/tissues by label-free imaging is attractive because dyes or fluorescent labels may be toxic or invasive. Here, label-free Raman microscopy is applied to show the spatial distribution of the molecular targeted drug erlotinib within the cell. The Raman images show that the drug is clustered at the EGFR protein at the membrane and induces receptor internalization. The changes within the Raman spectrum of erlotinib measured in cells as compared to the free-erlotinib spectrum indicate that erlotinib is metabolized within cells to its demethylated derivative. This study provides detailed insights into the drug targeting mechanism at the atomic level in cells. It demonstrates that Raman microscopy will open avenues as a non-invasive and label-free technique to investigate pharmacokinetics at the highest possible resolution in living cells. PMID:24427772

El-Mashtoly, Samir F; Petersen, Dennis; Yosef, Hesham K; Mosig, Axel; Reinacher-Schick, Anke; Kötting, Carsten; Gerwert, Klaus

2014-03-01

183

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

184

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

185

Distribution and drug resistance of pathogenic bacteria isolated from cancer hospital in 2013  

PubMed Central

Objective To understand distribution and drug resistance of pathogenic bacteria from a specialized cancer hospital in 2013 in order to provide a basis for rational clinical antimicrobial agents. Methods Pathogenic bacteria identification and drug sensitivity tests were performed with a VITEK 2 compact automatic identification system and data were analyzed using WHONET5.6 software. Results Of the 1,378 strains tested, 980 were Gram-negative bacilli, accounting for 71.1%, in which Klebsiella pneumonia, Escherichia coli and Pseudomonas aeruginosa were the dominant strains. We found 328 Gram-positive coccus, accounting for 23.8%, in which the amount of Staphylococcus aureus was the highest. We identified 46 fungi, accounting for 4.1%. According to the departmental distribution within the hospital, the surgical departments isolated the major strains, accounting for 49.7%. According to disease types, lung cancer, intestinal cancer and esophagus cancer were the top three, accounting for 20.9%, 17.3% and 14.2%, respectively. No strains were resistant to imipenem, ertapenem or vancomycin. Conclusions Pathogenic bacteria isolated from the specialized cancer hospital have different resistance rates compared to commonly used antimicrobial agents; therefore antimicrobial agents to reduce the morbidity and mortality of infections should be used.

Liu, Linjuan; Li, Qi; Zhang, Qingyun; Wang, Guohong; Xu, Guobin

2014-01-01

186

Assessment of DNA damage in Japanese nurses handling antineoplastic drugs by the comet assay.  

PubMed

To clarify genotoxic effects of occupational exposure to antineoplastic drugs in Japan, we examined DNA damage, assessed by the comet assay, in 121 female nurses and 46 female clerks working at three hospitals in the northeast of Japan. The comet assay is considered to be a sensitive and rapid method for DNA strand break detection in individual cells, and tail length and tail moment are used as the comet parameters. Concerning the basal characteristics, the 46 control subjects had higher rates of smoking and coffee-drinking habits and lower hemoglobin than the 121 nurses (p<0.05). The log-transformed tail length in the nurses was significantly longer than that in the control subjects after adjusting for possible covariates such as age and smoking habit (p<0.05). Also, the log-transformed tail length was significantly longer, in the 57 nurses who had handled antineoplastic drugs in the last six months, than that in the 46 control subjects (p<0.05); but, no significant difference in tail length or tail moment was seen between the two nurse groups with and without experience of handling hazardous drugs (p>0.05). These results suggest that Japanese nurses who have worked at hospitals using antineoplastic drugs may have a potential risk of DNA damage. To minimize this risk in Japan, use of biological safety cabinet and appropriate protective equipment, in addition to staff education and training, should be implemented in the healthcare environment. PMID:18285639

Sasaki, Makiko; Dakeishi, Miwako; Hoshi, Shigeko; Ishii, Noriko; Murata, Katsuyuki

2008-01-01

187

Genome-wide assessment of the carriers involved in the cellular uptake of drugs: a model system in yeast.  

E-print Network

, these results further substantiate the notion that the cellular uptake of pharmaceutical drugs normally occurs via carrier-mediated transport and indicates that establishing the identity and tissue distribution of such carriers should be a major consideration...

Lanthaler, Karin; Bilsland, Elizabeth; Dobson, Paul D; Moss, Harry J; Pir, Pinar; Kell, Douglas B; Oliver, Stephen G

2011-10-24

188

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.

2011-03-01

189

Intracellular drug distribution-based targeting: Exploiting lysosomes to enhance the selectivity of drugs towards cancer cells  

E-print Network

their systemic toxicity. We also evaluated whether IDB selectivity can be optimized according to relevant physicochemical parameters of drug candidates, specifically the ionization constant (pKa). These evaluations provide a rationale for the design...

Ndolo, Rosemary A.

2012-08-31

190

A Challenge for Diagnosing Acute Liver Injury with Concomitant/Sequential Exposure to Multiple Drugs: Can Causality Assessment Scales Be Utilized to Identify the Offending Drug?  

PubMed Central

Drug-induced hepatotoxicity most commonly manifests as an acute hepatitis syndrome and remains the leading cause of drug-induced death/mortality and the primary reason for withdrawal of drugs from the pharmaceutical market. We report a case of acute liver injury in a 12-year-old Hispanic boy, who received a series of five antibiotics (amoxicillin, ceftriaxone, vancomycin, ampicillin/sulbactam, and clindamycin) for cervical lymphadenitis/retropharyngeal cellulitis. Histopathology of the liver biopsy specimen revealed acute cholestatic hepatitis. All known causes of acute liver injury were appropriately excluded and (only) drug-induced liver injury was left as a cause of his cholestasis. Liver-specific causality assessment scales such as Council for the International Organization of Medical Sciences/Roussel Uclaf Causality Assessment Method scoring system (CIOMS/RUCAM), Maria and Victorino scale, and Digestive Disease Week-Japan were applied to seek the most likely offending drug. Although clindamycin is the most likely cause by clinical diagnosis, none of causality assessment scales aid in the diagnosis. PMID:25506455

Lim, Roxanne; Conner, Kim; Karnsakul, Wikrom

2014-01-01

191

Admixed Phylogenetic Distribution of Drug Resistant Mycobacterium tuberculosis in Saudi Arabia  

PubMed Central

Background The phylogeographical structure of Mycobacterium tuberculosis is generally bimodal in low tuberculosis (TB) incidence countries, where genetic lineages of the isolates generally differ with little strain clustering between autochthonous and foreign-born TB patients. However, less is known on this structure in Saudi Arabia—the most important hub of human migration as it hosts a total population of expatriates and pilgrims from all over the world which is equal to that of its citizens. Methodology We explored the mycobacterial phylogenetic structure and strain molecular clustering in Saudi Arabia by genotyping 322 drug-resistant clinical isolates collected over a 12-month period in a national drug surveillance survey, using 24 locus-based MIRU-VNTR typing and spoligotyping. Principal Findings In contrast to the cosmopolitan population of the country, almost all the known phylogeographic lineages of M. tuberculosis complex (with noticeable exception of Mycobacterium africanum/West-African 1 and 2) were detected, with Delhi/CAS (21.1%), EAI (11.2%), Beijing (11.2%) and main branches of the Euro-American super-lineage such as Ghana (14.9%), Haarlem (10.6%) and Cameroon (7.8%) being represented. Statistically significant associations of strain lineages were observed with poly-drug resistance and multi drug resistance especially among previously treated cases (p value of distribution of phylogenetic lineages (p?=?0.311). Moreover, 59.5% (22/37) of the strain molecular clusters were shared between the Saudi born and immigrant TB patients. Conclusions Specific distribution of M. tuberculosis phylogeographic lineages is not observed between the autochthonous and foreign-born populations. These observations might reflect both socially favored ongoing TB transmission between the two population groups, and historically deep-rooted, prolonged contacts and trade relations of the peninsula with other world regions. More vigorous surveillance and strict adherence to tuberculosis control policies are urgently needed in the country. PMID:23383340

Varghese, Bright; Supply, Philip; Allix-Béguec, Caroline; Shoukri, Mohammed; Al-Omari, Ruba; Herbawi, Mais; Al-Hajoj, Sahal

2013-01-01

192

Exposure time independent summary statistics for assessment of drug dependent cell line growth inhibition  

PubMed Central

Background In vitro generated dose-response curves of human cancer cell lines are widely used to develop new therapeutics. The curves are summarised by simplified statistics that ignore the conventionally used dose-response curves’ dependency on drug exposure time and growth kinetics. This may lead to suboptimal exploitation of data and biased conclusions on the potential of the drug in question. Therefore we set out to improve the dose-response assessments by eliminating the impact of time dependency. Results First, a mathematical model for drug induced cell growth inhibition was formulated and used to derive novel dose-response curves and improved summary statistics that are independent of time under the proposed model. Next, a statistical analysis workflow for estimating the improved statistics was suggested consisting of 1) nonlinear regression models for estimation of cell counts and doubling times, 2) isotonic regression for modelling the suggested dose-response curves, and 3) resampling based method for assessing variation of the novel summary statistics. We document that conventionally used summary statistics for dose-response experiments depend on time so that fast growing cell lines compared to slowly growing ones are considered overly sensitive. The adequacy of the mathematical model is tested for doxorubicin and found to fit real data to an acceptable degree. Dose-response data from the NCI60 drug screen were used to illustrate the time dependency and demonstrate an adjustment correcting for it. The applicability of the workflow was illustrated by simulation and application on a doxorubicin growth inhibition screen. The simulations show that under the proposed mathematical model the suggested statistical workflow results in unbiased estimates of the time independent summary statistics. Variance estimates of the novel summary statistics are used to conclude that the doxorubicin screen covers a significant diverse range of responses ensuring it is useful for biological interpretations. Conclusion Time independent summary statistics may aid the understanding of drugs’ action mechanism on tumour cells and potentially renew previous drug sensitivity evaluation studies. PMID:24902483

2014-01-01

193

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

194

Milk excretion of ivermectin and moxidectin in dairy sheep: assessment of drug residues during cheese elaboration and ripening period.  

PubMed

Ivermectin (IVM) and moxidectin (MXD) are broad-spectrum endectocide antiparasitic drugs extensively used in food-producing animals. The patterns of IVM and MXD excretion in milk were comparatively characterized following their subcutaneous administration (200 microg.kg(-1) of body weight) to lactating dairy sheep. The relationship between milk excretion and plasma disposition kinetics of both compounds was characterized. A pool of milk collected from all of the animals in each experimental group was used for cheese elaboration. IVM and MXD residual concentrations were assessed during the cheese-making process and ripening period. IVM and MXD concentrations were measured in plasma, milk, and milk product (whey, curd, and cheese) samples using an HPLC-based methodology with fluorescence detection. IVM and MXD were extensively distributed from the bloodstream to the mammary gland, and large quantities, particularly of MXD, were excreted in milk. Residual concentrations of both compounds were recovered in milk up to 30 (IVM) and 35 (MXD) days post-treatment. The total fraction of the administered dose excreted in milk for MXD was significantly higher than that of IVM. During cheese production, the highest residual concentrations of both molecules were measured in the curd. Thirty-four percent of the total drug residue measured in the pooled milk collected from treated sheep was lost during the cheese-making process. The lowest residual concentrations were measured in the whey. IVM and MXD concentrations in the elaborated cheese tended to increase during the ripening period, reaching the highest residual level at 40 days of cheese maturation. The long persistence of milk residual concentrations of MXD and IVM in lactating dairy sheep and the high concentrations found in cheese and other milk-related products should be seriously considered before recommendation of the extralabel use of these antiparasitic drugs in dairy animals. PMID:15453688

Imperiale, Fernanda A; Busetti, Margarita R; Suárez, Victor H; Lanusse, Carlos E

2004-10-01

195

Some Factors in the Assessment of Gastric Antisecretory Drugs by a Sampling Technique *  

PubMed Central

Samples of gastric contents from patients with duodenal ulcer were more often highly acid when they drank 120 ml. of milk-cream mixture every hour than when they ate a bland diet. The volume of the drinks and the timing of the samples determined this apparent difference. Long-acting propantheline bromide reduced gastric acidity a little when the patients ate the diet and more when they took the drinks of milk-cream alone. It is concluded that the clinical usefulness of gastric antisecretory drugs can only be assessed under the actual conditions of use. PMID:18668736

Bingle, J. P.; Lennard-Jones, J. E.

1960-01-01

196

[Variation pulsimetry as a method for assessing the adequacy of electro- and drug anesthesia in uranostaphyloplasty].  

PubMed

Using variation pulsimetry, the adequacy of anesthesiological management during uranostaphyloplasty has been assessed in 34 children aged 4.5 to 9 years. The studies were performed after premedication at various stages of surgery and upon extubation. Premedication, including promedol, dimedrol, droperidol and diazepam, prevented negative psychoemotional reactions in patients right before induction to anesthesia. Combined electrical and drug anesthesia performed according to a technique described above ensured good enough nociceptive protection of patients during surgery. The adaptive compensatory reactions were most pronounced in the early postoperative period. PMID:2350040

Aznaurian, S K; Trotsevich, V A

1990-01-01

197

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. PMID:19578475

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

2008-01-01

198

Drug-induced modulation of Tc-99m pyrophosphate tissue distribution: what is involved  

SciTech Connect

More than ten years after their introduction, Tc-99m-labeled phosphates and phosphonates (TcP) continue to be of interest to the investigator and to hold promise for new clinical applications in the future. Initially, TcP compounds were valued because of their bone-seeking properties. Emphasis shifted from bone to soft tissue when Bonte et al. introduced Tc-99m-labeled pyrophosphate (TcPPi) for myocardial infarct scanning. Detailed information about TcPPi uptake in ischemic and necrotic myocardial tissue at the subcellular level has accumulated. Therefore, understanding of the mechanism of TcPPi uptake in infarcted myocardium is more detailed than understanding of uptake by bone. A new, and potentially powerful, approach to the use of TcP is being proposed by Carr et al. The authors attempt to modulate favorably the tissue distribution of TcPPi by prior administration of drugs in pharmacological quantities. The authors demonstrate that uptake of TcPPi can be enhanced in the necrotic myocardium, uptake by bone can be reduced, and the lesion-to-blood ratio can be altered favorably when vitamin D/sub 3/ or desoxycorticosterone acetate (DOCA) is administered in pharmacological doses before the TcPPi injection. A short review is presented of background information helpful for interpreting the drug effects on TcPPi uptake in bone or necrotic myocardial tissue.

Wahner, H.W.; Dewanjee, M.K.

1981-06-01

199

Dendrimer, liposomes, carbon nanotubes and PLGA nanoparticles: one platform assessment of drug delivery potential.  

PubMed

Liposomes (LIP), nanoparticles (NP), dendrimers (DEN), and carbon nanotubes (CNTs), represent eminent classes of drug delivery devices. A study was carried out herewith by employing docetaxel (DTX) as model drug to assess their comparative drug delivery potentials. Under optimized conditions, highest entrapment of DTX was observed in CNT-based formulation (DTX-CNTs, 74.70?±?4.9%) followed by nanoparticles (DTX-NP, 62.34?±?1.5%), liposome (49.2?±?1.51%), and dendrimers (28.26?±?1.74%). All the formulations were found to be of nanometric size. In vitro release studies were carried out in PBS (pH 7.0 and 4.0), wherein all the formulations showed biphasic release pattern. Cytotoxicity assay in human cervical cancer SiHa cells inferred lowest IC50 value of 1,235.09?±?41.93 nM with DTX-CNTs, followed by DTX-DEN, DTX-LIP, DTX-NP with IC50 values of 1,571.22?±?151.27, 1,653.98?±?72.89, 1,922.75?±?75.15 nM, respectively. Plain DTX showed higher hemolytic toxicity of 22.48?±?0.94%, however loading of DTX inside nanocarriers drastically reduced its hemolytic toxicity (DTX-DEN, 17.22?±?0.48%; DTX-LIP, 4.13?±?0.19%; DTX-NP, 6.43?±?0.44%; DTX-CNTs, 14.87?±?1.69%). PMID:24431104

Mody, Nishi; Tekade, Rakesh Kumar; Mehra, Neelesh Kumar; Chopdey, Prashant; Jain, Narendra Kumar

2014-04-01

200

COMPARING DISTRIBUTIONS OF SHELF LIVES FOR DRUG PRODUCTS WITH TWO COMPONENTS UNDER DIFFERENT DESIGNS  

Microsoft Academic Search

To reduce the cost of stability testing in drug research and development, both bracketing and matrixing designs are recommended in the U.S. Food and Drug Administration's (FDA) guidelines for drug products with a single active ingredient (component). When the drug product contains multiple active components, the naïve approach is to take the minimum of shelf lives obtained from individual components

Annpey Pong; Damaraju Raghavarao

2002-01-01

201

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

202

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. PMID:24485002

2014-01-01

203

Assessing the Essentiality of Leishmania donovani Nitroreductase and Its Role in Nitro Drug Activation  

PubMed Central

The nitroimidazole fexinidazole has potential as a safe and effective oral drug therapy for the treatment of visceral leishmaniasis. To date, nitroheterocyclics have not been used in the treatment of leishmaniasis, and relatively little is known about their mechanism of action. In African trypanosomes, nitro drugs are reductively activated by a type I nitroreductase (NTR), absent in mammalian cells. Modulation of nitroreductase levels in Trypanosoma brucei directly affected sensitivity to nitro compounds, with reduced concentrations of the enzyme leading to moderate nitro drug resistance. In view of the progression of fexinidazole into clinical development for visceral leishmaniasis, here we assess the essentiality of the nitroreductase in Leishmania donovani and the effect of modulating nitroreductase levels on susceptibility to fexinidazole. The failure to directly replace both endogenous copies of the NTR gene, except in the presence of an ectopic copy of the gene, suggests that the NTR gene is essential for the growth and survival of L. donovani promastigotes. Loss of a single chromosomal copy of the L. donovani NTR gene resulted in parasites that were mildly resistant (<2-fold) to the predominant in vivo metabolite of fexinidazole, while parasites overexpressing NTR were 18-fold more susceptible. These data confirm that Leishmania NTR plays a pivotal role in fexinidazole activation. Reliance on a single enzyme for prodrug activation may leave fexinidazole vulnerable to the emergence of drug resistance. However, the essentiality of the NTR in L. donovani promastigotes, combined with the limited resistance shown by NTR single knockout cells, suggests that the potential for the spread of NTR-based resistance to fexinidazole may be limited. PMID:23208716

Patterson, Stephen; Fairlamb, Alan H.

2013-01-01

204

Potentials and limitations of nonclinical safety assessment for predicting clinical adverse drug reactions: correlation analysis of 142 approved drugs in Japan.  

PubMed

The objective of this study was to elucidate the range of abilities of nonclinical safety assessment for predicting adverse drug reactions (ADRs) in humans. The dataset included 1256 ADRs with an incidence rate of 5% or more collected from 142 drugs approved in Japan from 2001 to 2010 (excluding anticancer agents and vaccines). Gastrointestinal, neurological and hepatobiliary ADRs were relatively common, followed by hematological, cutaneous, systemic and cardiovascular ADRs in the dataset. The analysis revealed that 48% of ADRs were predictable based on a comprehensive nonclinical safety assessment considering animal toxicity. Hematological and ocular ADRs, infection, and application site reactions showed a correlation of more than 70%, while musculoskeletal, respiratory and neurological ADRs showed a correlation of less than 30%. In addition to subjective patient perceptions, several laboratory parameters routinely monitored both in animals and humans showed a lower correlation, e.g., abnormalities in hepatobiliary and metabolic parameters, and blood pressure increase. Large molecule drugs showed lower correlation than small molecule drugs; ADRs were observed in various organs and consideration of pharmacological action did not significantly contribute to the prediction. It was also confirmed that the current standard of toxicology testing regarding dosing duration and dose level is adequate to detect concordant animal toxicity. This study collectively demonstrated a significant value of nonclinical safety assessment in predicting ADRs in humans. It also identified the subset of ADRs with poor predictability, highlighting the need for advanced testing that enables successful translation of animal toxicity to clinical settings with better accuracy and sensitivity. PMID:23824014

Tamaki, Chihiro; Nagayama, Takashi; Hashiba, Masamichi; Fujiyoshi, Masato; Hizue, Masanori; Kodaira, Hiroshi; Nishida, Minoru; Suzuki, Kazuhiko; Takashima, Yoshiharu; Ogino, Yamato; Yasugi, Daisaku; Yoneta, Yasuo; Hisada, Shigeru; Ohkura, Takako; Nakamura, Kazuichi

2013-01-01

205

Assessment of PEG on polymeric particles surface, a key step in drug carrier translation.  

PubMed

Injectable drug nanocarriers have greatly benefited in their clinical development from the addition of a superficial hydrophilic corona to improve their cargo pharmacokinetics. The most studied and used polymer for this purpose is poly(ethylene glycol), PEG. However, in spite of its wide use for over two decades now, there is no general consensus on the optimum PEG chain coverage-density and size required to escape from the mononuclear phagocyte system and to extend the circulation time. Moreover, cellular uptake and active targeting may have conflicting requirements in terms of surface properties of the nanocarriers which complicate even more the optimization process. These persistent issues can be largely attributed to the lack of straightforward characterization techniques to assess the coverage-density, the conformation or the thickness of a PEG layer grafted or adsorbed on a particulate drug carrier and is certainly one of the main reasons why so few clinical applications involving PEG coated particle-based drug delivery systems are under clinical trial so far. The objective of this review is to provide the reader with a brief description of the most relevant techniques used to assess qualitatively or quantitatively PEG chain coverage-density, conformation and layer thickness on polymeric nanoparticles. Emphasis has been made on polymeric particle (solid core) either made of copolymers containing PEG chains or modified after particle formation. Advantages and limitations of each technique are presented as well as methods to calculate PEG coverage-density and to investigate PEG chains conformation on the NP surface. PMID:24768790

Rabanel, Jean-Michel; Hildgen, Patrice; Banquy, Xavier

2014-07-10

206

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

207

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. PMID:22995578

2012-01-01

208

Mining hidden knowledge for drug safety assessment: topic modeling of LiverTox as a case study  

PubMed Central

Background Given the significant impact on public health and drug development, drug safety has been a focal point and research emphasis across multiple disciplines in addition to scientific investigation, including consumer advocates, drug developers and regulators. Such a concern and effort has led numerous databases with drug safety information available in the public domain and the majority of them contain substantial textual data. Text mining offers an opportunity to leverage the hidden knowledge within these textual data for the enhanced understanding of drug safety and thus improving public health. Methods In this proof-of-concept study, topic modeling, an unsupervised text mining approach, was performed on the LiverTox database developed by National Institutes of Health (NIH). The LiverTox structured one document per drug that contains multiple sections summarizing clinical information on drug-induced liver injury (DILI). We hypothesized that these documents might contain specific textual patterns that could be used to address key DILI issues. We placed the study on drug-induced acute liver failure (ALF) which was a severe form of DILI with limited treatment options. Results After topic modeling of the "Hepatotoxicity" sections of the LiverTox across 478 drug documents, we identified a hidden topic relevant to Hy's law that was a widely-accepted rule incriminating drugs with high risk of causing ALF in humans. Using this topic, a total of 127 drugs were further implicated, 77 of which had clear ALF relevant terms in the "Outcome and management" sections of the LiverTox. For the rest of 50 drugs, evidence supporting risk of ALF was found for 42 drugs from other public databases. Conclusion In this case study, the knowledge buried in the textual data was extracted for identification of drugs with potential of causing ALF by applying topic modeling to the LiverTox database. The knowledge further guided identification of drugs with the similar potential and most of them could be verified and confirmed. This study highlights the utility of topic modeling to leverage information within textual drug safety databases, which provides new opportunities in the big data era to assess drug safety. PMID:25559675

2014-01-01

209

Assessment of a candidate marker constituent predictive of a dietary substance-drug interaction: case study with grapefruit juice and CYP3A4 drug substrates.  

PubMed

Dietary substances, including herbal products and citrus juices, can perpetrate interactions with conventional medications. Regulatory guidances for dietary substance-drug interaction assessment are lacking. This deficiency is due in part to challenges unique to dietary substances, a lack of requisite human-derived data, and limited jurisdiction. An in vitro-in vivo extrapolation (IVIVE) approach to help address some of these hurdles was evaluated using the exemplar dietary substance grapefruit juice (GFJ), the candidate marker constituent 6',7'-dihydroxybergamottin (DHB), and the purported victim drug loperamide. First, the GFJ-loperamide interaction was assessed in 16 healthy volunteers. Loperamide (16 mg) was administered with 240 ml of water or GFJ; plasma was collected from 0 to 72 hours. Relative to water, GFJ increased the geometric mean loperamide area under the plasma concentration-time curve (AUC) significantly (1.7-fold). Second, the mechanism-based inhibition kinetics for DHB were recovered using human intestinal microsomes and the index CYP3A4 reaction, loperamide N-desmethylation (KI [concentration needed to achieve one-half kinact], 5.0 ± 0.9 µM; kinact [maximum inactivation rate constant], 0.38 ± 0.02 minute(-1)). These parameters were incorporated into a mechanistic static model, which predicted a 1.6-fold increase in loperamide AUC. Third, the successful IVIVE prompted further application to 15 previously reported GFJ-drug interaction studies selected according to predefined criteria. Twelve of the interactions were predicted to within the 25% predefined criterion. Results suggest that DHB could be used to predict the CYP3A4-mediated effect of GFJ. This time- and cost-effective IVIVE approach could be applied to other dietary substance-drug interactions to help prioritize new and existing drugs for more advanced (dynamic) modeling and simulation and clinical assessment. PMID:25253884

Ainslie, Garrett R; Wolf, Kristina K; Li, Yingxin; Connolly, Elizabeth A; Scarlett, Yolanda V; Hull, J Heyward; Paine, Mary F

2014-12-01

210

Application of fluorescence-interference microscope for monitoring of dry weight dynamics and drug distribution within living cells  

Microsoft Academic Search

The authors have proposed and tested the new type of the microscope with superimposed interference and fluorescence images of the living cell. The fluorescence image gives the information about the distribution of drugs in different parts of the cell. Interference microscopy technique allows implementing the quantitative analysis of a living transparent cell, for example, to measure dry cell weight and

Gennady G. Levin; Theodor V. Bulygin; Eugene Kalinin; Gennady N. Vishnyakov; Irene V. Goryainova

2001-01-01

211

? Particle track autoradiographic study of the distribution of a [ 211 At]-astatinated drug in normal tissues of the mouse  

Microsoft Academic Search

Summary The microscopic distribution of the potential endoradiotherapeutic drug, 6-[211At]-astato-2-methyl-1,4-naphthoquinol bis (diphosphate salt) in normal tissues of the mouse has been studied by ?-particle track autoradiography. The uptake into critical radiosensitive tissues, especially bone marrow, colon and lung, was low.

J. S. Mitchell; I. Brown; R. N. Carpenter

1985-01-01

212

“Herbal incense”: Designer drug blends as cannabimimetics and their assessment by drug discrimination and other in vivo bioassays  

PubMed Central

Recently, synthetic cannabinoids originally designed for testing in the laboratory only have found use recreationally in designer herbal blends, originally called “Spice”. The myriad of compounds found are for the most part potent full agonists of the cannabinoid receptor 1, producing effects similar to tetrahydrocannabinol (THC) and marijuana. Drug discrimination of these compounds offers a specific behavioral test that can help determine whether these new synthetic compounds share a similar “subjective high”with the effects of marijuana/THC. By utilization of drug discrimination and other behavioral techniques, a better understanding of these new “designer” cannabinoids may be reached to assist in treating both the acute and chronic effects of these drugs. The paper provides a brief exposé of modern cannabinoid research as a backdrop to the recreational use of designer herbal blend cannabimimetics. PMID:23891559

Järbe, Torbjörn U.C.; Gifford, Roger S.

2014-01-01

213

A pharmacy too far? Equity and spatial distribution of outcomes in the delivery of subsidized artemisinin-based combination therapies through private drug shops  

PubMed Central

Background Millions of individuals with malaria-like fevers purchase drugs from private retailers, but artemisinin-based combination therapies (ACTs), the only effective treatment in regions with high levels of resistance to older drugs, are rarely obtained through these outlets due to their relatively high cost. To encourage scale up of ACTs, the Affordable Medicines Facility – malaria is being launched to subsidize their price. The Government of Tanzania and the Clinton Foundation piloted this subsidized distribution model in two Tanzanian districts to examine concerns about whether the intervention will successfully reach poor, rural communities. Methods Stocking of ACTs and other antimalarial drugs in all retail shops was observed at baseline and in four subsequent surveys over 15 months. Exit interviews were conducted with antimalarial drug customers during each survey period. All shops and facilities were georeferenced, and variables related to population density and proximity to distribution hubs, roads, and other facilities were calculated. To understand the equity of impact, shops stocking ACTs and consumers buying them were compared to those that did not, according to geographic and socioeconomic variables. Patterning in ACT stocking and sales was evaluated against that of other common antimalarials to identify factors that may have impacted access. Qualitative data were used to assess motivations underlying stocking, distribution, and buying disparities. Results Results indicated that although total ACT purchases rose from negligible levels to nearly half of total antimalarial sales over the course of the pilot, considerable geographic variation in stocking and sales persisted and was related to a variety of socio-spatial factors; ACTs were stocked more often in shops located closer to district towns (p<0.01) and major roads (p<0.01) and frequented by individuals of higher socioeconomic status (p<0.01). However, other antimalarial drugs displayed similar patterning, indicating the existence of underlying disparities in access to antimalarial drugs in general in these districts. Conclusions As this subsidy model is scaled up across multiple countries, these results confirm the potential for increased ACT usage but suggest that additional efforts to increase access in remote areas will be needed for the scale-up to have equitable impact. Trial registration Current Controlled Trials ISRCTN39125414. PMID:20594372

2010-01-01

214

Lipophilicity assessment of basic drugs (log P(o/w) determination) by a chromatographic method.  

PubMed

A previously reported chromatographic method to determine the 1-octanol/water partition coefficient (log P(o/w)) of organic compounds is used to estimate the hydrophobicity of bases, mainly commercial drugs with diverse chemical nature and pK(a) values higher than 9. For that reason, mobile phases buffered at high pH to avoid the ionization of the solutes and three different columns (Phenomenex Gemini NX, Waters XTerra RP-18 and Waters XTerra MS C(18)) with appropriate alkaline-resistant stationary phases have been used. Non-ionizable substances studied in previous works were also included in the set of compounds to evaluate the consistency of the method. The results showed that all the columns provide good estimations of the log P(o/w) for most of the compounds included in this study. The Gemini NX column has been selected to calculate log P(o/w) values of the set of studied drugs, and really good correlations between the determined log P(o/w) values and those considered as reference were obtained, proving the ability of the procedure for the lipophilicity assessment of bioactive compounds with very different structures and functionalities. PMID:21820118

Pallicer, Juan M; Sales, Joaquim; Rosés, Martí; Ràfols, Clara; Bosch, Elisabeth

2011-09-16

215

Use of preclinical models to assess the therapeutic potential of new drug candidates for bladder cancer.  

PubMed

The purpose of this review is to demonstrate a successful use of preclinical models of bladder cancer to confirm the therapeutic potential of new promising drug candidates. The bladder has long been thought to be an ideal target for investigating therapies. When developing a new antineoplastic pharmaceutical agent, the bladder should be considered for use as an experimental model demonstrating initial proof of concept that if successful can be later assessed in further cancer indications. Non-muscle-invasive bladder carcinoma can be removed by transurethral resection but these cancers tend to recur in most patients. Conventional treatments decrease the recurrence rate but are associated with side effects and frequent failures. Thus, there is an obvious need for the development of highly effective targeted therapies with limited side effects. Accordingly, a double-promoter vector was developed, expressing diphtheria toxin A (DTA) under control of two different regulatory promoter sequences, H19 and IGF2. This vector was then used to transfect and to eradicate tumor cells in bladder cancer models, effectively destroying tumor cells without affecting normal cells. Our studies demonstrate the potential efficacy of the therapeutic vector and should be a solid base for future clinical studies. These models illuminate the path for future investigations of new drug candidates for bladder cancer. PMID:23040250

Amit, Doron; Gofrit, Ofer N; Matouk, Imad; Birman, Tatiana; Hochberg, Abraham

2012-10-01

216

Assessment of new immunosuppressive drugs in a rat cardiac allograft heterotopic model.  

PubMed

We assessed FK506 (FK) and rapamycin (RPM) in a heterotopic abdominal rat heart transplant model using a major histocompatibility mismatch (DA to LEW). The end point of our study was histologic grading of rejection (Billingham and working formulation) at 1 week. Two doses of FK (2.0 and 8.0 mg/kg p.o., q.d.) and RPM (1.5 and 6.0 mg/kg i.p., q.d.) were compared to allografts without and with ciclosporin (12.5 mg/kg p.o., q.d.) treatment. Results show: (1) weak heartbeat and full rejection on day 5 in all untreated allografts; (2) weak heartbeat and high degree of rejection in groups receiving low doses of FK and RPM; (3) strong heartbeat and mild rejection in both high FK and RPM dose groups comparable to the results of the hearts treated with ciclosporin; (4) 1 animal in each high FK and RPM dose group showed possible signs of toxicity, and (5) the strength of the heartbeat was not a reliable indicator of the efficacy of an immunosuppressive drug. We conclude that even in a major histocompatibility mismatch model at the time of the strongest immune response (1 week), all three tested drugs can reduce the degree of rejection from severe (untreated allografts) to mild if given in an adequate dosage. PMID:1380460

Walpoth, B; Galdikas, J; Vorburger, T; Altermatt, H J; Schaffner, T; Althaus, U; Billingham, M; Morris, R

1992-01-01

217

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. PMID:23432852

2013-01-01

218

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

219

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

220

A novel method for assessing in vitro oncology drug combinations using growth rates.  

PubMed

We propose a new method that allows screening oncology drug combinations using data from in vitro studies to select agents that have the promise of showing a synergistic effect in vivo. In contrast to known approaches that define combination effects either on the concentration scale or on the percent inhibition scale, we use the growth rate of treated cells as a primary indicator of treatment activity. The developed method is based on a novel statistical model that describes the growth of cancer cells that are subject to treatment with a combination of compounds. The model assumes a multicompartment cell population with transition rates between compartments modeled according to biochemical reaction properties, and cells in each compartment growing according to exponential law. This translates to a linear system of ordinary differential equations, whose solution is accurately approximated by a closed-form expression using rapid equilibrium assumptions. Special cases of the aforementioned model represent situations when the combination effect is absent or when the considered drugs act as the same compound. Assuming the normal distribution for the growth rate measurement error, we describe a formal statistical testing procedure to distinguish between different mechanisms of action for the considered compounds, and to test if a significant combination effect is being observed. PMID:22416837

Pashkevich, Maksim; Iversen, Philip; Brooks, Harold

2012-01-01

221

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

SciTech Connect

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 Na{sub v}1.5 sodium and Ca{sub v}1.2 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. - Highlights: • We study effects of anti-addiction drug ibogaine on ionic currents in cardiomyocytes. • We assess the cardiac ion channel profile of ibogaine. • Ibogaine inhibits hERG potassium, sodium and calcium channels. • Ibogaine’s effects on ion channels are a potential source of cardiac arrhythmias. • 18-Methoxycoronaridine has a lower affinity for cardiac ion channels than ibogaine.

Koenig, Xaver; Kovar, Michael; Rubi, Lena; Mike, Agnes K.; Lukacs, Peter; Gawali, Vaibhavkumar S.; Todt, Hannes [Center for Physiology and Pharmacology, Department of Neurophysiology and -pharmacology, Medical University of Vienna, 1090 Vienna (Austria); Hilber, Karlheinz, E-mail: karlheinz.hilber@meduniwien.ac.at [Center for Physiology and Pharmacology, Department of Neurophysiology and -pharmacology, Medical University of Vienna, 1090 Vienna (Austria); Sandtner, Walter [Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, 1090 Vienna (Austria)

2013-12-01

222

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. PMID:20047690

2010-01-01

223

Detecting drug-induced prolongation of the QRS complex: New insights for cardiac safety assessment  

SciTech Connect

Background: Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (I{sub Na}) may carry pro-arrhythmic risks. Due to the frequency-dependent block of I{sub Na}, this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation. Methods: Telemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic). QRS duration was determined standardly (5 beats averaged at rest) but also prior to and at the plateau of each acute increase in HR (3 beats averaged at steady state), and averaged over 1 h period from 1 h pre-dose to 5 h post-dose. Results: Compared to time-matched vehicle, at rest, only quinidine and flecainide induced increases in QRS duration (E{sub max} 13% and 20% respectively, P < 0.01–0.001) whereas mexiletine had no effect. Importantly, the increase in QRS duration was enhanced at peak HR with an additional effect of + 0.7 ± 0.5 ms (quinidine, NS), + 1.8 ± 0.8 ms (mexiletine, P < 0.05) and + 2.8 ± 0.8 ms (flecainide, P < 0.01) (calculated as QRS at basal HR-QRS at high HR). Conclusion: Electrocardiogram recordings during elevated HR, not considered during routine analysis optimised for detecting QT prolongation, can be used to sensitise the detection of QRS prolongation. This could prove useful when borderline QRS effects are detected. Analysing during acute increases in HR could also be useful for detecting drug-induced effects on other aspects of cardiac function. -- Highlights: ? We aimed to improve detection of drug-induced QRS prolongation in safety screening. ? We used telemetered dogs to test class I antiarrhythmics at low and high heart rate. ? At low heart rate only quinidine and flecainide induced an increase in QRS duration. ? At high heart rate the effects of two out of three antiarrhythmics were enhanced. ? Detection of a drug-induced prolongation of QRS was improved at high heart rate.

Cros, C., E-mail: caroline.cros@hotmail.co.uk [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Skinner, M., E-mail: Matthew.Skinner@astrazeneca.com [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Moors, J. [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom)] [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Lainee, P. [Sanofi-Aventis R and D, 371, rue du Pr Joseph Blayac, 34184 Montpellier Cedex 04 (France)] [Sanofi-Aventis R and D, 371, rue du Pr Joseph Blayac, 34184 Montpellier Cedex 04 (France); Valentin, J.P. [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom)] [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom)

2012-12-01

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7 CFR 1230.74 - Prohibited use of distributed assessments.  

...SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE PORK PROMOTION, RESEARCH, AND CONSUMER INFORMATION Pork Promotion, Research, and Consumer Information Order Expenses and Assessments §...

2014-01-01

225

7 CFR 1230.74 - Prohibited use of distributed assessments.  

Code of Federal Regulations, 2011 CFR

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2011-01-01

226

7 CFR 1230.73 - Uses of distributed assessments.  

Code of Federal Regulations, 2011 CFR

...SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE PORK PROMOTION, RESEARCH, AND CONSUMER INFORMATION Pork Promotion, Research, and Consumer Information Order Expenses and Assessments §...

2011-01-01

227

7 CFR 1230.73 - Uses of distributed assessments.  

Code of Federal Regulations, 2012 CFR

...SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE PORK PROMOTION, RESEARCH, AND CONSUMER INFORMATION Pork Promotion, Research, and Consumer Information Order Expenses and Assessments §...

2012-01-01

228

7 CFR 1230.74 - Prohibited use of distributed assessments.  

Code of Federal Regulations, 2012 CFR

...SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE PORK PROMOTION, RESEARCH, AND CONSUMER INFORMATION Pork Promotion, Research, and Consumer Information Order Expenses and Assessments §...

2012-01-01

229

7 CFR 1230.73 - Uses of distributed assessments.  

Code of Federal Regulations, 2013 CFR

...SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE PORK PROMOTION, RESEARCH, AND CONSUMER INFORMATION Pork Promotion, Research, and Consumer Information Order Expenses and Assessments §...

2013-01-01

230

7 CFR 1230.73 - Uses of distributed assessments.  

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2014-01-01

231

7 CFR 1230.73 - Uses of distributed assessments.  

Code of Federal Regulations, 2010 CFR

...SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE PORK PROMOTION, RESEARCH, AND CONSUMER INFORMATION Pork Promotion, Research, and Consumer Information Order Expenses and Assessments §...

2010-01-01

232

7 CFR 1230.74 - Prohibited use of distributed assessments.  

Code of Federal Regulations, 2013 CFR

...SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE PORK PROMOTION, RESEARCH, AND CONSUMER INFORMATION Pork Promotion, Research, and Consumer Information Order Expenses and Assessments §...

2013-01-01

233

Drug release-modulating mechanism of hydrophilic hydroxypropylmethylcellulose matrix tablets: distribution of atoms and carrier and texture analysis.  

PubMed

Although release profiles of drug from hydrophilic matrices have been well recognized, the visual distribution of hydroxypropylmethylcellulose (HPMC) and atoms inside of internal structures of hydrophilic HPMC matrices has not been characterized. In this paper, drug release mechanism from HPMC matrix tablet was investigated based on the release behaviors of HPMC, physical properties of gelled HPMC tablet and atomic distributions of formulation components using diverse instruments. A matrix tablet consisting of hydroxypropyl methylcellulose (HPMC 6, 4,000 and 100,000 mPa·s), chlorpheniramine maleate (CPM) as a model and fumed silicon dioxide (Aerosil(®) 200) was prepared via direct compression. The distribution of atoms and HPMC imaging were characterized using scanning electron microscope (SEM)/ energy-dispersive X-ray spectroscopy (EDX), and near-infrared (NIR) analysis, respectively as a function of time. A texture analyzer was also used to characterize the thickness and maintenance of gel layer of HPMC matrix tablet. The HPMC matrix tablets showed Higuchi release kinetics with no lag time against the square root of time. High viscosity grades of HPMC gave retarded release rate because of the greater swelling and gel thickness as characterized by texture analyzer. According to the NIR imaging, low-viscosity-grade HPMC (6 mPa·s) quickly leached out onto the surface of the tablet, while the high-viscosity-grade HPMC (4000 mPa·s) formed much thicker gel layer around the tablet and maintained longer via slow erosion, resulting in retarded drug release. The atomic distribution of the drug (chlorine, carbon, oxygen), HPMC (carbon, oxygen) and silicon dioxide (silica, oxygen) and NIR imaging of HPMC corresponded with the dissolution behaviors of drug as a function of time. The use of imaging and texture analyses could be applicable to explain the release- modulating mechanism of hydrophilic HPMC matrix tablets. PMID:23855499

Park, Jun-Bom; Lim, Jisung; Kang, Chin-Yang; Lee, Beom-Jin

2013-12-01

234

Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment.  

PubMed

The inability to routinely monitor drug-induced phospholipidosis (DIPL) presents a challenge in pharmaceutical drug development and in the clinic. Several nonclinical studies have shown di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP) to be a reliable biomarker of tissue DIPL that can be monitored in the plasma/serum and urine. The aim of this study was to show the relevance of di-22:6-BMP as a DIPL biomarker for drug development and safety assessment in humans. DIPL shares many similarities with the inherited lysosomal storage disorder Niemann-Pick type C (NPC) disease. DIPL and NPC result in similar changes in lysosomal function and cholesterol status that lead to the accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. To validate di-22:6-BMP as a biomarker of DIPL for clinical studies, NPC patients and healthy donors were classified by receiver operator curve analysis based on urinary di-22:6-BMP concentrations. By showing 96.7-specificity and 100-sensitivity to identify NPC disease, di-22:6-BMP can be used to assess DIPL in human studies. The mean concentration of di-22:6-BMP in the urine of NPC patients was 51.4-fold (p ? 0.05) above the healthy baseline range. Additionally, baseline levels of di-22:6-BMP were assessed in healthy non-medicated laboratory animals (rats, mice, dogs, and monkeys) and human subjects to define normal reference ranges for nonclinical/clinical studies. The baseline ranges of di-22:6-BMP in the plasma, serum, and urine of humans and laboratory animals were species dependent. The results of this study support the role of di-22:6-BMP as a biomarker of DIPL for pharmaceutical drug development and health care settings. PMID:24967688

Liu, Nanjun; Tengstrand, Elizabeth A; Chourb, Lisa; Hsieh, Frank Y

2014-09-15

235

Assessment of environmental correlates with the distribution of fish stocks using a spatially explicit model  

E-print Network

Assessment of environmental correlates with the distribution of fish stocks using a spatially-mail: msundermeyer@umassd.edu phone: (508) 999-8812 fax: (508) 910-6371 Running title: Assessing environmental;INTRODUCTION We present here a method for assessing the explanatory skill of environmental correlates

Robinson, Allan R.

236

Assessment of excess fluid distribution in chronic hemodialysis patients using bioimpedance spectroscopy  

Microsoft Academic Search

Assessment of excess fluid distribution in chronic hemodialysis patients using bioimpedance spectroscopy. Sodium and water homeostasis is abnormal in hemodialysis (HD) patients, however, the distribution of the excess fluid (extracellular vs. intracellular) has not been fully characterized. We studied the distribution of fluid using bioimpedance spectroscopy to determine if HD patients have an excess of fluid in any specific compartment

Bruce J Fisch; David M Spiegel

1996-01-01

237

Truncated AUCs in the assessment of the bioequivalence of topiramate, a long half-life drug.  

PubMed

This study was conducted in order to assess the bioequivalence of two tablet formulations containing topiramate (CAS 97240-79-4), 25 mg. Twenty-four healthy volunteers were enrolled in an open-label, randomised, crossover, 2 periods x 2 sequences, with a minimum washout period of 21 days, single dose study. Blood samples were collected prior to study drug administration and 0.167, 0.333, 0.500, 0.667, 1.00, 1.33, 1.67, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 12.0, 24.0, 48.0, 96.0, 144, 192, and 264 h post-dose in each period. Plasma levels of topiramate from the 23 subjects who completed the study, were determined by high-pressure liquid chromatography with tandem mass detection, HPLC/MS/MS (lower limit of quantification 9.98 ng/mL). Pharmacokinetic parameters used for bioequivalence assessment (AUC(last), AUC(inf) and C(max)) were determined from the plasma concentration data using non-compartmental analysis. Mean +/- standard deviation elimination half-life for the reference formulation was 84.18 +/- 14.61h whereas for the test formulation it was 80.82 +/- 11.50h. The 90% Confidence Intervals (90 CI) were 98.00-111.35% for C(max), 98.44-103.76% for AUC(last) and 96.61-103.00% for AUC(inf), that is, within the ranges defined in the protocol for acceptance of bioequivalence. The 90 CIs obtained for the truncated AUCs were as follows: 100.27-105.32% for AUC0-48, 99.28-104.62% for AUC0-48, 99.13-104.56% for AUC0-96, 95.67-104.82% for AUC0-144, and 100.04-103.76% for AUC0-192. Both analysed formulations are bioequivalent irrespective of whether the conventional or truncated AUC approach is used. This study demonstrated that topiramate can be viewed as a long half-life drug and that the truncated AUC ap proach could be considered for bioequivalence assessment. PMID:17598694

Almeida, Susana; Spínola, Ana Cristina; Filipe, Augusto; Trabelsi, Fethi; Farré, Ana

2007-01-01

238

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

PubMed

Ivacaftor is approved in the USA for the treatment of cystic fibrosis (CF) in patients with a G551D-CFTR mutation or one of eight other CFTR mutations. A series of in vitro experiments conducted early in the development of ivacaftor indicated ivacaftor and metabolites may have the potential to inhibit cytochrome P450 (CYP) 2C8, CYP2C9, CYP3A, and CYP2D6, as well as P-glycoprotein (P-gp). Based on these results, a series of clinical drug-drug interaction (DDI) studies were conducted to evaluate the effect of ivacaftor on sensitive substrates of CYP2C8 (rosiglitazone), CYP3A (midazolam), CYP2D6 (desipramine), and P-gp (digoxin). In addition, a DDI study was conducted to evaluate the effect of ivacaftor on a combined oral contraceptive, as this is considered an important comedication in CF patients. The results indicate ivacaftor is a weak inhibitor of CYP3A and P-gp, but has no effect on CYP2C8 or CYP2D6. Ivacaftor caused non-clinically significant increases in ethinyl estradiol and norethisterone exposure. Based on these results, caution and appropriate monitoring are recommended when concomitant substrates of CYP2C9, CYP3A and/or P-gp are used during treatment with ivacaftor, particularly drugs with a narrow therapeutic index, such as warfarin. PMID:25103957

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

2015-01-01

239

Assessment of Alcohol and Other Drug Use by Runaway Youths: A Test-Retest Study of the Form 90  

PubMed Central

While excellent adolescent alcohol and drug screening tools are available, there are relatively few, if any, psychometrically validated measures to use in the assessment of adolescent treatment outcome. This study conducted a test-retest exercise of the Form 90 Drug and Alcohol (Form 90 DnA) to determine the stability of adolescent responses when administering the day-by-day calendar/grid approach. Homeless youth (N = 37) with alcohol, drug, or alcohol and drug abuse/dependence combined were recruited to participate in the test-retest study. High pre-post stability in means was obtained on measures of frequency of substance use in general, and on specific measures of alcohol, cocaine, marijuana use. The findings from this paper provide support for the reliability and validity of the Form 90 for use with adolescent runaways with a substance abuse or dependence diagnosis. PMID:18563208

Slesnick, Natasha; Tonigan, J. Scott

2008-01-01

240

Relevance of Campus Climate for Alcohol and Other Drug Use among LGBTQ Community College Students: A Statewide Qualitative Assessment  

ERIC Educational Resources Information Center

Literature suggests that individuals who identify as LGBTQ may engage in more alcohol and other drug (AOD) use/abuse than others. Little data is available about these populations on college campuses where AOD use may be seen as part of the general campus climate and culture. This article will describe a qualitative needs assessment conducted on 10…

Manning, Patricia; Pring, Lauren; Glider, Peggy

2012-01-01

241

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

242

Silica xerogel as an implantable carrier for controlled drug delivery--evaluation of drug distribution and tissue effects after implantation.  

PubMed

The purpose of the present study was to examine controlled delivery of toremifene citrate from subcutaneously implanted silica xerogel carrier and to evaluate silica xerogel related tissue effects after implantation. Toremifene citrate was incorporated into hydrolyzed silica sol in a room temperature process. Toremifene citrate treated silica xerogel implants were tested both in vitro and in vivo using healthy mice. Silica xerogel with tritium-labelled toremifene was implanted subcutaneously in mice for 42 d. To determine the amount of tritiated toremifene remaining in the silica discs at the implantation site, the discs were excised periodically and radioactivity measured. The amount of tritiated toremifene in the implant after 42 d was still about 16% and the amount of silica xerogel about 25%. In a histopathological study silica xerogel did not show any tissue irritation at the site of the implantation. A fibrotic capsule was formed around the implant. No silica xerogel related histological changes in liver, kidney, lymph nodes and uterus were observed during the implantation period. The silica xerogel discs showed a sustained release of toremifene citrate over 42 d. Histologically, toremifene-related changes in the uterus were also detectable at all studied time points. These findings suggest that silica xerogel is a promising carrier material for implantable controlled drug delivery system. PMID:10632401

Kortesuo, P; Ahola, M; Karlsson, S; Kangasniemi, I; Yli-Urpo, A; Kiesvaara, J

2000-01-01

243

The role of health technology assessment bodies in shaping drug development.  

PubMed

The use of health technology assessment (HTA) to inform policy-making is established in most developed countries. Compared to licensing agencies, HTA agencies have different interests and, therefore, different evidence requirements. Criteria for coverage or reimbursement decisions on pharmaceutical compounds vary; however, it is common to include, as part of the HTA, a comparative effectiveness evaluation. This type of clinical data might go beyond that required for market authorization, thus creating an additional evidence gap between the regulatory and the reimbursement submission. The relevance of submissions to HTA agencies is consistently increasing in a pharmaceutical company's perspective, as market prospects are strongly influenced by third-party payers' coverage. In this study, we aim to describe current HTA activities with a potential impact throughout the drug development process of pharmaceuticals, with a comparative emphasis on the systems in place in Italy and in the UK. Based on an extensive literature and website review, we identified three major classes of HTA activities, beyond mainstream HTA, with the potential to influence the drug development program: 1) horizon scanning and early HTA; 2) bipartite and tripartite early dialogue between manufacturers, regulators, and HTA assessors; and 3) managed market entry agreements. From early stages of clinical research up to postauthorization studies, there is a trend toward increased collaboration between parties, anticipation of market access evidence collection, and postmarketing risk-sharing. Heterogeneity of HTA practices increases the complexity of the market access environment. Overall, there are signals that market access departments are gaining importance in the pharmaceutical companies, but there is still a lack of evidence and reporting on how the increasing relevance of HTA has reshaped the way clinical development is designed and managed. PMID:25419117

Ciani, Oriana; Jommi, Claudio

2014-01-01

244

The role of health technology assessment bodies in shaping drug development  

PubMed Central

The use of health technology assessment (HTA) to inform policy-making is established in most developed countries. Compared to licensing agencies, HTA agencies have different interests and, therefore, different evidence requirements. Criteria for coverage or reimbursement decisions on pharmaceutical compounds vary; however, it is common to include, as part of the HTA, a comparative effectiveness evaluation. This type of clinical data might go beyond that required for market authorization, thus creating an additional evidence gap between the regulatory and the reimbursement submission. The relevance of submissions to HTA agencies is consistently increasing in a pharmaceutical company’s perspective, as market prospects are strongly influenced by third-party payers’ coverage. In this study, we aim to describe current HTA activities with a potential impact throughout the drug development process of pharmaceuticals, with a comparative emphasis on the systems in place in Italy and in the UK. Based on an extensive literature and website review, we identified three major classes of HTA activities, beyond mainstream HTA, with the potential to influence the drug development program: 1) horizon scanning and early HTA; 2) bipartite and tripartite early dialogue between manufacturers, regulators, and HTA assessors; and 3) managed market entry agreements. From early stages of clinical research up to postauthorization studies, there is a trend toward increased collaboration between parties, anticipation of market access evidence collection, and postmarketing risk-sharing. Heterogeneity of HTA practices increases the complexity of the market access environment. Overall, there are signals that market access departments are gaining importance in the pharmaceutical companies, but there is still a lack of evidence and reporting on how the increasing relevance of HTA has reshaped the way clinical development is designed and managed. PMID:25419117

Ciani, Oriana; Jommi, Claudio

2014-01-01

245

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. PMID:24340120

Chu, Brian K.; Deming, Michael; Biritwum, Nana-Kwadwo; Bougma, Windtaré R.; Dorkenoo, Améyo M.; El-Setouhy, Maged; Fischer, Peter U.; Gass, Katherine; Gonzalez de Peña, 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

246

Cortical EEG oscillations and network connectivity as efficacy indices for assessing drugs with cognition enhancing potential.  

PubMed

Synchronization of electroencephalographic (EEG) oscillations represents a core mechanism for cortical and subcortical networks, and disturbance in neural synchrony underlies cognitive processing deficits in neurological and neuropsychiatric disorders. Here, we investigated the effects of cognition enhancers (donepezil, rivastigmine, tacrine, galantamine and memantine), which are approved for symptomatic treatment of dementia, on EEG oscillations and network connectivity in conscious rats chronically instrumented with epidural electrodes in different cortical areas. Next, EEG network indices of cognitive impairments with the muscarinic receptor antagonist scopolamine were modeled. Lastly, we examined the efficacy of cognition enhancers to normalize those aberrant oscillations. Cognition enhancers elicited systematic ("fingerprint") enhancement of cortical slow theta (4.5-6 Hz) and gamma (30.5-50 Hz) oscillations correlated with lower activity levels. Principal component analysis (PCA) revealed a compact cluster that corresponds to shared underlying mechanisms as compared to different drug classes. Functional network connectivity revealed consistent elevated coherent slow theta activity in parieto-occipital and between interhemispheric cortical areas. In rats instrumented with depth hippocampal CA1-CA3 electrodes, donepezil elicited similar oscillatory and coherent activities in cortico-hippocampal networks. When combined with scopolamine, the cognition enhancers attenuated the leftward shift in coherent slow delta activity. Such a consistent shift in EEG coherence into slow oscillations associated with altered slow theta and gamma oscillations may underlie cognitive deficits in scopolamine-treated animals, whereas enhanced coherent slow theta and gamma activity may be a relevant mechanism by which cognition enhancers exert their beneficial effect on plasticity and cognitive processes. The findings underscore that PCA and network connectivity are valuable tools to assess efficacy of novel therapeutic drugs with cognition enhancing potential. PMID:25181033

Ahnaou, A; Huysmans, H; Jacobs, T; Drinkenburg, W H I M

2014-11-01

247

Computational modeling of drug distribution in the posterior segment of the eye: effects of device variables and positions.  

PubMed

A computational model was developed to simulate drug distribution in the posterior segment of the eye after intravitreal injection and ocular implantation. The effects of important factors in intravitreal injection such as injection time, needle gauge and needle angle on the ocular drug distribution were studied. Also, the influences of the position and the type of implant on the concentration profile in the posterior segment were investigated. Computational Fluid Dynamics (CFD) calculations were conducted to describe the 3D convective-diffusive transport. The geometrical model was constructed based on the human eye dimensions. To simulate intravitreal injection, unlike previous studies which considered the initial shape of the injected drug solution as a sphere or cylinder, the more accurate shape was obtained by level-set method in COMSOL. The results showed that in intravitreal injection the drug concentration profile and its maximum value depended on the injection time, needle gauge and penetration angle of the needle. Considering the actual shape of the injected solution was found necessary to obtain the real concentration profile. In implant insertion, the vitreous cavity received more drugs after intraocular implantation, but this method was more invasive compared to the periocular delivery. Locating the implant in posterior or anterior regions had a significant effect on local drug concentrations. Also, the shape of implant influenced on concentration profile inside the eye. The presented model is useful for optimizing the administration variables to ensure optimum therapeutic benefits. Predicting and quantifying different factors help to reduce the possibility of tissue toxicity and to improve the treatment efficiency. PMID:24946303

Jooybar, Elaheh; Abdekhodaie, Mohammad J; Farhadi, Fatolla; Cheng, Yu-Ling

2014-09-01

248

Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment  

PubMed Central

Causality assessment of suspected drug induced liver injury (DILI) and herb induced liver injury (HILI) is hampered by the lack of a standardized approach to be used by attending physicians and at various subsequent evaluating levels. The aim of this review was to analyze the suitability of the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale as a standard tool for causality assessment in DILI and HILI cases. PubMed database was searched for the following terms: drug induced liver injury; herb induced liver injury; DILI causality assessment; and HILI causality assessment. The strength of the CIOMS lies in its potential as a standardized scale for DILI and HILI causality assessment. Other advantages include its liver specificity and its validation for hepatotoxicity with excellent sensitivity, specificity and predictive validity, based on cases with a positive reexposure test. This scale allows prospective collection of all relevant data required for a valid causality assessment. It does not require expert knowledge in hepatotoxicity and its results may subsequently be refined. Weaknesses of the CIOMS scale include the limited exclusion of alternative causes and qualitatively graded risk factors. In conclusion, CIOMS appears to be suitable as a standard scale for attending physicians, regulatory agencies, expert panels and other scientists to provide a standardized, reproducible causality assessment in suspected DILI and HILI cases, applicable primarily at all assessing levels involved. PMID:24653791

Teschke, Rolf; Wolff, Albrecht; Frenzel, Christian; Schwarzenboeck, Alexander; Schulze, Johannes; Eickhoff, Axel

2014-01-01

249

Assessing the impact of tumor evolution on oncology drug development and commercialization  

E-print Network

This thesis investigates the commercial viability of developing and commercializing targeted oncology drugs directed at a specific tumor mutation instead of all forms and mutations of a single target. While oncologic drugs ...

Sterk, Joseph P. (Sterk, Joseph Phillip)

2011-01-01

250

Rapid assessment of drug use and sexual HIV risk patterns among vulnerable drugusing populations in Cape Town, Durban and Pretoria, South Africa  

Microsoft Academic Search

This exploratory study examines the links between drug use and high-risk sexual practices and HIV in vulnerable drug-using populations in South Africa, including commercial sex workers (CSWs), men who have sex with men (MSM), injecting drug users (IDUs) and non-injecting drug users who are not CSWs or MSM (NIDUs). A rapid assessment ethnographic study was undertaken using observation, mapping, key

Charles Parry; Petal Petersen; Tara Carney; Sarah Dewing; Richard Needle

2008-01-01

251

Independent Orbiter Assessment (IOA): Assessment of the electrical power distribution and control subsystem, volume 1  

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. The IOA product for the EPD and C analysis consisted of 1671 failure mode analysis worksheets that resulted in 468 potential critical items being identified. Comparison was made to the proposed NASA Post 51-L baseline which consisted of FMEAs and 158 CIL items. Volume 1 contains the EPD and C subsystem description, analysis results, ground rules and assumptions, and some of the IOA worksheets.

Schmeckpeper, K. R.

1988-01-01

252

Development, validation and utility of an in vitro technique for assessment of potential clinical drug-drug interactions involving P-glycoprotein.  

PubMed

Regulatory interest is increasing for drug transporters generally and P-glycoprotein (Pgp) in particular, primarily in the area of drug-drug interactions. To aid in both identifying and discharging the potential liabilities associated with drug-transporter interactions, the pharmaceutical industry has a growing requirement for routine and robust non-clinical assays. An assay was designed, optimised and validated to determine the in vitro inhibitory potency of new chemical entities (NCEs) towards human Pgp-mediated transport. [3H]-Digoxin was established as a suitable probe substrate by investigating its characteristics in the in vitro system (MDCKII-MDR1 cells grown in 24-multiwell inserts). The inhibitory potencies (apparent IC50) of known Pgp inhibitors astemizole, GF120918, ketoconazole, itraconazole, quinidine, verapamil and quinine were determined over at least a 1000-fold concentration range. Validation was carried out using manual and automatic techniques. [3H]-Digoxin was found to be stable and have good mass balance in the system. In contrast to [A-->B] transport, [3H]-digoxin [B-->A] transport rates were readily measured with good reproducibility. There was no evidence of saturation of transport up to 10 microM digoxin and 30 nM digoxin was selected for routine assay use, reflecting clinical therapeutic concentrations. IC50 values ranged over approximately 100-fold with excellent reproducibility. Results from manual and automated versions were in close agreement. This method is suitable for routine use to assess the in vitro inhibitory potency of NCEs on Pgp-mediated digoxin transport. Comparison of IC50 values against clinical interaction profiles for the probe inhibitors indicated the in vitro assay is predictive of clinical digoxin-drug interactions mediated via Pgp. PMID:16406207

Keogh, John P; Kunta, Jeevan R

2006-04-01

253

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

254

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. PMID:21211001

2011-01-01

255

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

256

Age related changes in fractional elimination pathways for drugs: assessing the impact of variable ontogeny on metabolic drug-drug interactions.  

PubMed

The magnitude of any metabolic drug-drug interactions (DDIs) depends on fractional importance of inhibited pathway which may not necessarily be the same in young children when compared to adults. The ontogeny pattern of cytochrome P450 (CYP) enzymes (CYPs 1A2, 2B6, 2C8, 2C9, 2C18/19, 2D6, 2E1, 3A4) and renal function were analyzed systematically. Bootstrap methodology was used to account for variability, and to define the age range over which statistical differences existed between each pair of specific pathways. A number of DDIs were simulated (Simcyp Pediatric v12) for virtual compounds to highlight effects of age on fractional elimination and consequent magnitude of DDI. For a theoretical drug metabolized 50% by each of CYP2D6 and CYP3A4 pathways at birth, co-administration of ketoconazole (3 mg/kg) resulted in a 1.65-fold difference between inhibited versus uninhibited AUC compared to 2.4-fold in 1 year olds and 3.2-fold in adults. Conversely, neonates could be more sensitive to DDI than adults in certain scenarios. Thus, extrapolation from adult data may not be applicable across all pediatric age groups. The use of pediatric physiologically based pharmacokinetic (p-PBPK) models may offer an interim solution to uncovering potential periods of vulnerability to DDI where there are no existing clinical data derived from children. PMID:23720017

Salem, Farzaneh; Johnson, Trevor N; Barter, Zoe E; Leeder, J Steven; Rostami-Hodjegan, Amin

2013-08-01

257

Preclinical assessment of CNS drug action using eye movements in mice  

PubMed Central

The drug development process for CNS indications is hampered by a paucity of preclinical tests that accurately predict drug efficacy in humans. Here, we show that a wide variety of CNS-active drugs induce characteristic alterations in visual stimulus–induced and/or spontaneous eye movements in mice. Active compounds included sedatives and antipsychotic, antidepressant, and antiseizure drugs as well as drugs of abuse, such as cocaine, morphine, and phencyclidine. The use of quantitative eye-movement analysis was demonstrated by comparing it with the commonly used rotarod test of motor coordination and by using eye movements to monitor pharmacokinetics, blood-brain barrier penetration, drug-receptor interactions, heavy metal toxicity, pharmacologic treatment in a model of schizophrenia, and degenerative CNS disease. We conclude that eye-movement analysis could complement existing animal tests to improve preclinical drug development. PMID:21821912

Cahill, Hugh; Rattner, Amir; Nathans, Jeremy

2011-01-01

258

Evaluation of drug transporter interactions in drug discovery and development.  

PubMed

Drug transporters play an important role in the absorption, distribution, excretion and toxicity of both endogenous and exogenous compounds. Transporters may act as physiological 'gatekeepers' in the regulation of the pharmacological and/or toxicological effects of drugs by limiting distribution to tissues responsible for their effect and/or toxicity. This review will first provide a brief outline of the characteristics of membrane bound drug transporter families and their respective roles in regulating drug pharmacokinetics. This background then provides the context for a discussion of the characterization of a drug candidate as a substrate, inhibitor and/or inducer of drug transporter(s), followed by an assessment of the in vitro and in vivo preclinical methods used in drug discovery and development for screening molecules to identify potential transporter interactions. Finally, specific examples of the translation of in vitro findings to the in vivo effects are discussed to link the current understanding of the impact of drug transporters to clinical pharmacology. Thus, the goal is to provide the drug discovery scientist with a cadre of concepts, strategies, and tools for ultimately making rational decisions in drug design and delivery resulting in the optimization of drug concentrations at the target of pharmacology. PMID:20053160

Lai, Yurong; Sampson, Kathleen E; Stevens, Jeffrey C

2010-02-01

259

Assessment of intestinal permeability changes induced by nonsteroidal anti-inflammatory drugs in the rat.  

PubMed

Intestinal permeability was investigated as an alternative to intestinal ulceration for measuring nonsteroidal anti-inflammatory drug (NSAID) gut damage in the rat and developed as a method for routine measurement. NSAID dose-response curves produced using the two indices of damage showed that intestinal permeability is as sensitive and reproducible as ulceration, although changes could not be detected before visible ulceration occurred. Lactulose, [51Cr]-EDTA and [14C]-carboxyinulin were compared as possible in vivo markers of rat intestinal permeability. Measurement of [51Cr]-EDTA permeation was found to be the most sensitive and reproducible method. Dose-response curves produced by measuring [51Cr]-EDTA permeation were used to compare the potency of the two NSAIDs piroxicam and (S+) ibuprofen; piroxicam was found to be 10 times more potent in increasing intestinal permeability than (S+)-ibuprofen. These studies show that intestinal permeability measurement is a useful alternative to other methods of assessing NSAID adverse effect and is easily and rapidly performed. PMID:7496048

Ford, J; Martin, S W; Houston, J B

1995-09-01

260

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

261

Dog left ventricular midmyocardial myocytes for assessment of drug-induced delayed repolarization: short-term variability and proarrhythmic potential  

PubMed Central

Background and purpose: Evaluation of the potential for delayed ventricular repolarization and proarrhythmia by new drugs is essential. We investigated if dog left ventricular midmyocardial myocytes (LVMMs) that can be used as a preclinical model to assess drug effects on action potential duration (APD) and whether in these cells, short-term variability (STV) or triangulation could predict proarrhythmic potential. Experimental approach: Beagle LVMMs and Purkinje fibres (PFs) were used to record APs. Effects of six reference drugs were assessed on APD at 50% (APD50) and 90% (APD90) of repolarization, STV(APD), triangulation (ratio APD90/APD50) and incidence of early afterdepolarizations (EADs) at 1 and 0.5 Hz. Key results: LVMMs provided stable recordings of AP, which were not affected by four sequential additions of dimethyl sulphoxide. Effects of dofetilide, d-sotalol, cisapride, pinacidil and diltiazem, but not of terfenadine, on APD in LVMMs were found to be comparable with those recorded in PFs. LVMMs, but not PFs, exhibited a proarrhythmic response to IKr blockers. Incidence of EADs was not related to differences in AP prolongation or triangulation, but corresponded to beat-to-beat variability of repolarization, here quantified as STV of APD. Conclusions and implications: LVMMs provide a suitable preclinical model to assess the effects of new drugs on APD and also yield additional information about putative indicators of proarrhythmia that add value to an integrated QT/TdP risk assessment. Our findings support the concept that increased STV(APD) may predict drug-induced proarrhythmia. This article is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010 PMID:19663882

Abi-Gerges, Najah; Valentin, Jean-Pierre; Pollard, Chris E

2010-01-01

262

45 CFR 156.295 - Prescription drug distribution and cost reporting.  

Code of Federal Regulations, 2012 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...

2012-10-01

263

45 CFR 156.295 - Prescription drug distribution and cost reporting.  

...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...

2014-10-01

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

COMMENT ON: APPLYING SPECIES-SENSITIVITY DISTRIBUTIONS IN ECOLOGICAL RISK ASSESSMENT: ASSUMPTION OF DISTRIBUTION TYPE AND SUFFICIENT NUMBER OF SPECIES  

EPA Science Inventory

Newman et al. (2000) addressed some important issues regarding the characterization of species-sensitivity distributions (SSDs) used in ecological risk assessments. A common assumption is that SSDs are log-normal, and this allows data sets to be analyzed by standard parametric me...

266

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

267

ASSESSING THE BENEFITS OF PRODUCTION-DISTRIBUTION COORDINATION IN AN  

E-print Network

. These serve different types of customers (over-the-fence, pick-up, and delivery) through various delivery at the production sites in liquid form for distribution to pick-up and delivery (generally via truck or rail inventories of the products are maintained at the production sites and customer locations to ensure

Grossmann, Ignacio E.

268

Cetyl gellan copolymer micelles and hydrogels: in vitro and pharmacodynamic assessment for drug delivery.  

PubMed

In this study, gellan polymer was conferred amphiphilic character by conjugating alkyl carbon chain (C16) to its backbone via etherification reaction. The amphiphilic copolymer self-assembled into water and formed spherical micellar structures with a mean diameter of 832 nm. Copolymer micellization caused a considerable rise in solubility of simvastatin in water. Later on, the micelle-incorporated drug and pure drug were loaded into aluminium gellan hydrogel beads and characterized. Scanning electron microscopy revealed spherical shape of the beads. The drug entrapment efficiency of the beads (917-927 ?m) was found to be 90-94%. Higher dissolution efficiency and consequently, higher rate of drug dissolution was evident in phosphate buffer solution (pH 6.8) than in HCl solution (pH 1.2). The changes in drug release rate as a function of pH correlated with the swelling behaviour of beads. The release of drug was controlled by anomalous diffusion mechanism. Fourier transform infrared spectroscopy and X-ray diffraction analyses suggested compatibility of drug in the beads. The gellan beads, loaded with micellar drug, reduced 83.45% LDL-cholesterol level in rabbit model following 18 h of oral administration. Thus, the gellan beads containing micellar drug showed their potential in controlling drug release rate and improving pharmacodynamic activity. PMID:25316420

Kundu, Payel; Maiti, Sabyasachi

2015-01-01

269

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

270

The effect of the drying temperature on the properties of wet-extruded calcium stearate pellets: Pellet microstructure, drug distribution, solid state and drug dissolution.  

PubMed

Although drying is widely applied during the manufacturing of solid dosage forms, its potential effect on the product's (key) properties is often underestimated. Hence, the present study addresses drying related modifications of wet-extruded pellets comprising calcium stearate (CaSt, matrix former) and ibuprofen (model drug). After spheronization, the pellets were tray dried at different temperatures. The dried pellets were evaluated regarding their microstructure, the ibuprofen distribution, solid state modifications and the resulting in-vitro dissolution profiles. The ibuprofen distribution profiles along the pellets' cross-sections varied for the different drying conditions. The profiles turned from inhomogeneous to uniform with increasing drying temperature. Temperatures above 20°C yielded solid state modifications, including ibuprofen transition into the amorphous state and the formation of eutectic compositions. As none of the batches exhibited a high specific surface area associated with an open, well-interconnected pore system, the dissolution profiles were a function of the ibuprofen distribution. Differences in the solid state did not contribute to the dissolution behavior, since the CaSt matrix did not swell or dissolve in the dissolution medium. These findings show that drying may considerably affect the final product properties even for moderate drying conditions. PMID:25526671

Schrank, S; Kann, B; Saurugger, E; Hainschitz, M; Windbergs, M; Glasser, B J; Khinast, J; Roblegg, E

2015-01-30

271

Illicit Drug Use Among South Korean Offenders: Assessing the Generality of Social Learning Theory.  

PubMed

Since the mid-1990s, illicit drug use has become a problem in Korean society. This trend is likely due to the rapid globalization and expansion that occurred with the Internet revolution, which led to greater numbers of people socially learning about drug culture. The current study attempts to uncover criminogenic causality of such social learning about drug use by studying adult felony drug offenders in South Korea. The data used for the study were obtained from self-reported surveys, originally collected by the Korean Institution of Criminology (KIC). The final sample comprised 1,452 felony offenders convicted of illicit drug use, and their responses were analyzed with a set of multiple logistic regression tests. The current study found supportive evidence for the generalizability of social learning theory from the sample of the South Korean adult drug offenders. We argue that the current study provides additional empirical evidence that supports the generalizability of social learning theory. PMID:24752638

Yun, Minwoo; Kim, Eunyoung

2014-04-21

272

Comparison of the Bayesian approach and a simple algorithm for assessment of adverse drug events  

Microsoft Academic Search

The differential diagnosis of severe adverse drug events can be based on clinical judgment, algorithms, or the Bayesian approach. The Bayesian Adverse Reactions Diagnostic Instrument (BARDI) calculates the posterior probability (PsP) in favor of a specific drug cause based on background (e.g., epidemiologic) and case information (e.g., time of onset). Although BARDI discriminates between drug- and nondrug-induced adverse events, its

Krista L. Lanctôt; Claudio A. Naranjo

1995-01-01

273

Environmental justice, impact assessment and the politics of knowledge: The implications of assessing the social distribution of environmental outcomes  

SciTech Connect

Claims of environmental injustice have increasingly become part of environmental conflicts, both explicitly through the work of environmental justice campaigning groups and implicitly through the arguments deployed about the rights and wrongs of a given situation. Such claims can centre on different notions of justice, including those concerned with questions of distribution and procedure. This paper focuses on distributional or outcome justice and explores what implications follow when the distributional concerns of environmental justice are included in the practice of impact assessment processes, including through social impact assessment (SIA). The current use of impact assessment methods in the UK is reviewed showing that although practices are evolving there is a little routine assessment of distributional inequalities. It is argued that whilst this should become part of established practice to ensure that inequalities are revealed and matters of justice are given a higher profile, the implications for conflict within decision making processes are not straightforward. On the one hand, there could be scope for conflict to be ameliorated by analysis of inequalities informing the debate between stakeholders, and facilitating the implementation of mitigation and compensation measures for disadvantaged groups. On the other hand, contestation over how evidence is produced and therefore what it shows, and disagreement as to the basis on which justice and injustice are to be determined, means that conflict may also be generated and sustained within what are essentially political and strategic settings.

Walker, Gordon, E-mail: g.p.walker@lancaster.ac.u [Lancaster Environment Centre, Lancaster University, Lancaster, LA1 4YQ (United Kingdom)

2010-09-15

274

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

275

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

276

Magnetic Field Distribution and Application of a Transcranial Magnetic Stimulation for Drug Addicts  

Microsoft Academic Search

This article introduces the property of magnetic field distribution and application of TMS developed by BJUT. The TMS generates time-varying magnetic field to stimulate the particular area in human brain. To obtain the distribution of magnetic density, we carried out survey by utilizing a Gauss meter, from three aspects: the distribution of magnetic density in axial direction, in radial direction

Yu Chang; Miao Song; Bin Gao; Ningning Chen; Ling Li; Hongxing Wang

2009-01-01

277

In vitro, in vivo and pharmacokinetic assessment of amikacin sulphate laden polymeric nanoparticles meant for controlled ocular drug delivery  

NASA Astrophysics Data System (ADS)

The rationale of current exploration was to formulate positively charged amikacin-loaded polymeric nanoparticles providing a controlled release attribute. Amikacin sulphate-loaded nanoparticles were prepared by w/o/w emulsification solvent evaporation approach succeeded by high-pressure homogenization. Two bioadhesive positively charged polymers, Eudragit® RS 100 and Eudragit® RL 100, were used in the blend, with variable ratios of drug and polymer. The formulations were assessed in terms of particle size and zeta potential. Thermal gravimetric analysis was brought out on the samples of drug, polymer and drug polymer complex. Drug loading and release attributes of the nanoparticles were scrutinized and antimicrobial activity in contrast to Staphylococcus aureus was appraised. Ocular irritation test, in vivo ocular retention study, in vivo release profile (permeation study) and in vivo antibacterial activity of polymeric nanosuspensions were executed. No rupture consequence but a lengthened drug release was contemplated from all formulations. Amikacin sulphate release from the polymeric nanoparticles reflected a better fit with Korsmeyer-Peppas model. In the course of the antibacterial activity of nanoparticles against S. aureus, formulation AE1 displays the most prominent inhibitory effect as compared with marketed formulation of amikacin sulphate.

Sharma, Upendra Kumar; Verma, Amita; Prajapati, Sunil Kuamr; Pandey, Himanshu; Pandey, Avinash C.

2015-02-01

278

Comparative assessment of drug-eluting balloons in an advanced porcine model of coronary restenosis.  

PubMed

The advent of drug-eluting balloon (DEB) therapy has represented an important development in interventional cardiology. Nevertheless, preclinical data with this technology remain scant, and comparative studies have not previously been published. Bare metal stents were implanted in the coronary arteries of 15 pigs followed by balloon angioplasty. Animals were allocated to treatment with a 60-second inflation of one of four different balloon catheters: a conventional untreated plain angioplasty balloon (PBA, Biotronik AG), the Pantera Lux DEB (3.0 ?g/mm2 paclitaxel; BTHC excipient, Biotronik AG), the Elutax DEB (2.0 ?g/mm2 paclitaxel; no excipient; Aachen Resonance), or the SeQuent Please DEB (3.0 ?g/mm2 paclitaxel; iopromide excipient: B. Braun). Twenty-eight days following balloon deployment, animals underwent repeat angiography for quantitative coronary angiography analysis and euthanasia for histopathologic assessment. By histology, the mean neointimal thickness was 0.44 ± 0.19 mm with PBA, 0.35 ± 0.13 mm with Pantera Lux , 0.61 ± 0.20 mm with Elutax , and 0.47 ± 0.21 mm with SeQuent Please DEB (p=0.02). In comparison with PBA, deployment of the Pantera Lux or the SeQuent Please DEB resulted in delayed healing characterised by significant increases in fibrin, neointimal cell vacuity and delayed re-endothelialisation. In conclusion, investigation of comparative DEB performance in a porcine model of advanced coronary restenosis reveals significant heterogeneity of neointimal suppression between the devices tested with numerically lowest values seen in the Pantera Lux group. On the other hand, evidence of delayed healing was observed in the most effective DEB groups. PMID:21301785

Joner, M; Byrne, R A; Lapointe, J-M; Radke, P W; Bayer, G; Steigerwald, K; Wittchow, E

2011-05-01

279

Combining ESI, ASL and PET for quantitative assessment of drug-resistant focal epilepsy.  

PubMed

When localization of the epileptic focus is uncertain, the epileptic activity generator may be more accurately identified with non-invasive imaging techniques which could also serve to guide stereo-electroencephalography (sEEG) electrode implantation. The aim of this study was to assess the diagnostic value of perfusion magnetic resonance imaging with arterial spin labeling (ASL) in the identification of the epileptogenic zone, as compared to the more invasive positron-emission tomography (PET) and other established investigation methods for source imaging of electroencephalography (EEG) data. In 6 patients with drug-resistant focal epilepsy, standard video-EEG was performed to identify clinical seizure semeiology, and high-density EEG, ASL and FDG-PET to non-invasively localize the epileptic focus. A standardized source imaging procedure, low-resolution brain electromagnetic tomography constrained to the individual matter, was applied to the averaged spikes of high-density EEG. Quantification of current density, cerebral blood flow, and standardized uptake value were compared over the same anatomical areas. In most of the patients, source in the interictal phase was associated with an area of hypoperfusion and hypometabolism. Conversely, in the patients presenting with early post-ictal discharges, the brain area identified by electrical source imaging (ESI) as the generating zone appeared to be hyperperfused. In 2 patients in whom the focus remained uncertain, the postoperative follow-up showed the disappearance of epileptic activity. As an innovative and more comprehensive approach to the study of epilepsy, the combined use of ESI, perfusion MRI, and PET may play an increasingly important role in the non-invasive evaluation of patients with refractory focal epilepsy. PMID:23792219

Storti, Silvia Francesca; Boscolo Galazzo, Ilaria; Del Felice, Alessandra; Pizzini, Francesca Benedetta; Arcaro, Chiara; Formaggio, Emanuela; Mai, Roberto; Manganotti, Paolo

2014-11-15

280

Assessment of multiparametric MRI in a human glioma model to monitor cytotoxic and antiangiogenic drug effects  

E-print Network

drug effects LEMASSON Benjamin, Msc1,2,3 , CHRISTEN Thomas, MSc2,3 , TIZON Xavier, PhD1 , FARION Régine anti-tumoral drugs Key words: Apparent diffusion coefficient of water (ADC), blood volume fraction (BVf), brain tumor, Contrast enhancement MRI, therapies, vessel size index (VSI). Abbreviations used: ADC

Paris-Sud XI, Université de

281

Multiple Measures of Outcome in Assessing a Prison-Based Drug Treatment Program  

ERIC Educational Resources Information Center

Evaluations of prison-based drug treatment programs typically focus on one or two dichotomous outcome variables related to recidivism. In contrast, this paper uses multiple measures of outcomes related to crime and drug use to examine the impact of prison treatment. Crime variables included self-report data of time to first illegal activity,…

Prendergast, Michael L.; Hall, Elizabeth A.; Wexler, Harry K.

2003-01-01

282

Assessing the distribution of sedimentary C40 carotenoids through time.  

PubMed

A comprehensive marine biomarker record of green and purple sulfur bacteria (GSB and PSB, respectively) is required to test whether anoxygenic photosynthesis represented a greater fraction of marine primary productivity during the Precambrian than the Phanerozoic, as current models of ocean redox evolution suggest. For this purpose, we analyzed marine rock extracts and oils from the Proterozoic to the Paleogene for C40 diagenetic products of carotenoid pigments using new analytical methods. Gas chromatography coupled with tandem mass spectrometry provides a new perspective on the temporal distributions of carotenoid biomarkers for phototrophic sulfur bacteria, specifically okenane, chlorobactane, and paleorenieratane. According to conventional paleoredox interpretations, this revised stratigraphic distribution of the GSB and PSB biomarkers implies that the shallow sunlit surface ocean (<24 m) became sulfidic more frequently in the geologic past than was previously thought. We reexamine whether there is evidence supporting a planktonic source of GSB and PSB pigments in marine systems or whether additional factors are required to explain the marine phototrophic sulfur bacteria record. To date, planktonic GSB and PSB and their pigments have been identified in restricted basins and lakes, but they have yet to be detected in the unrestricted, transiently sulfidic, marine systems. Based on modern observations, additional environmental factors, including basin restriction, microbial mats, or sediment transport, may be required to fully explain GSB and PSB carotenoids in the geologic record. PMID:25631735

French, K L; Rocher, D; Zumberge, J E; Summons, R E

2015-03-01

283

Characterisation of neutron fields: challenges in assessing the directional distribution.  

PubMed

The SCK·CEN has carried out neutron field characterisation campaigns at several nuclear reactors. The main goal of these measurement campaigns was to evaluate the performance of different neutron personal dosemeters. To be able to evaluate the performance of neutron personal dosemeters in terms of Hp(10), knowledge of the directional distribution is indispensable. This distribution was estimated by placing several personal dosemeters on all six sides of a slab phantom. The interpretation and conversion of this information into a reliable value for Hp(10) requires great care. The data were analysed using three methods. In the first approach, a linear interpolation was performed on three perpendicular axes. In the other two approaches, an icosahedron was used to model the angle of incidence of the neutrons and a linear interpolation or a Bayesian analysis was performed. This study describes the limitations and advantages of each of these methods and provides recommendations for their use to estimate the personal dose equivalent Hp(10) for neutron dosimetry. PMID:24966340

Cauwels, Vanessa; Vanhavere, Filip; Reginatto, Marcel

2014-10-01

284

Benefit-risk assessment of current antiarrhythmic drug therapy of atrial fibrillation.  

PubMed

Over the last decade, several rhythm-versus rate-control trails in patients with atrial fibrillation (AF) have failed to demonstrate benefit of the rhythm control strategy with respect to mortality and morbidity. This had let to the guideline recommendation that antiarrhythmic drug therapy should be considered predominantly for symptomatic improvement of patients. Recent trails and meta-analyses have demonstrated that amiodarone is the most antiarrhythmic drug currently available. However, its use has been associated with many adverse effects. Currently, dronedarone is the only available antiarrhythmic drug which has shown a reduction in cardiovascular hospitalizations in medium-risk AF patients. However, the drug was associated with increased mortality in patients with recently decompensated heart failure. Hence, antiarrhythmic drug therapy has to be evaluated in patients with AF on an individual patients basis. PMID:22246949

Hohnloser, Stefan H

2012-01-01

285

Problematizing ‘drugs’: A cultural assessment of recreational pharmaceutical use among young adults in the US  

PubMed Central

Recent trends in the recreational use of pharmaceuticals among young adults in the United States highlight a number of issues regarding the problematization of drugs. Two constructions of recreational pharmaceutical use are analyzed. On the one hand, categorical frameworks based upon epidemiological data are created by institutions and media and depict recreational pharmaceutical use as illicit in unqualified, absolute terms. This is done through discourses that equate nonmedical pharmaceutical use with culturally established forms of illicit drug use. On the other hand, users’ multi-dimensional constructions of recreational pharmaceutical use emphasise social context, personal experience, and individual risk perceptions. The problematization of recreational pharmaceutical use points to intergenerational conflicts, as well as to struggles over definitions of “drug abuse” and “hard drugs”, and highlights the impact of pharmaceuticalization on recreational drug use among young people. PMID:24431478

QUINTERO, GILBERT

2013-01-01

286

Assessing the Long-Term Impact of Drug Court Participation on Recidivism with Generalized Estimating Equations  

PubMed Central

Drug courts are one of the most common strategies for dealing with the large proportion of criminal offenders who are drug-involved, yet methodological limitations limit the conclusions that can be drawn from many existing evaluations of their effectiveness. The current study examined the long-term impact of drug court participation compared to regular probation on the recidivism of 475 drug-involved offenders under supervision in Hillsborough County, Florida. Using a combination of self-reported data (collected through in-person interviews at baseline, i.e., the beginning of supervision) and administrative records, the study employed a repeated measures framework (examining five six-month time periods from baseline to 30 months post-baseline) and generalized estimating equations to compare the likelihood of being arrested between drug court participants and a matched sample of comparison offenders. The results indicate that participation in drug court was associated with a significant decrease in the likelihood of being arrested in the 12 to 18 months post-baseline time period. Although the drug court effect was somewhat delayed (it was not significant prior to 12 months) and short-lived (it was not significant after 18 months), the fact that significant program effects were observed during a time period that coincides with the conclusion of drug court participation for graduates and a time period well beyond initial program exposure, suggests that drug court participants are more likely than comparable offenders not exposed to drug court to remain arrest free when no longer under community supervision. PMID:17604918

Krebs, Christopher P.; Lindquist, Christine H.; Koetse, Willem; Lattimore, Pamela K.

2007-01-01

287

Assessment of quantitative imaging of contaminant distributions in porous media  

NASA Astrophysics Data System (ADS)

In this article an experimental setup designed to assist in the characterization of complex solute transport problems in porous media is described. Glass beads representing the medium are confined in a 2-D transparent Perspex box and a water flow transports a fluorescent dye. Under suitable illumination, the dye emits visible light which is collected by a CCD camera. The image acquired by this non-invasive optical technique is processed to estimate the 2-dimensional distribution of tracer concentrations by using an appropriate calibration curve that links fluorescent intensity and solute concentration. Details about the dye choice and discussion about photobleaching are reported. An analysis of the experimental error on the concentration profile is also presented. A few recent results of a study on contaminant plume within a homogenous porous matrix constituted by glass beads having mean diameter of 1 mm or 2 mm shows the performance of constructed model.

Catania, F.; Massabò, M.; Valle, M.; Bracco, G.; Paladino, O.

2008-01-01

288

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

289

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

290

Non-invasive assessment of diastolic function in hypertrophic cardiomyopathy on and off beta adrenergic blocking drugs.  

PubMed Central

Beta adrenergic blocking drugs in hypertrophic cardiomyopathy provide symptomatic relief but their effect on long-term prognosis is uncertain. Thirty patients were studied non-invasively by simultaneous recordings of echocardiogram, apex-cardiogram, phonocardiogram, and electrocardiogram in order to assess diastolic abnormalities on and off oral beta adrenergic blocking drugs. While on treatment these patients had a mean dose of propranolol 200 mg/day. The treatment was stopped for one week and then non-invasive assessment was repeated. The following diastolic time intervals were studied: isovolumic relaxation period (A2-mitral valve opening); rapid relaxation period (A2-O point of the apexcardiogram), and the period from mitral valve opening to the O point of the apexcardiogram (Mo-O) when most of the filling of the left ventricle occurs. The prolongation of the rapid relaxation period reflects a reduced rate of fall of the left ventricular pressure when the pressure differential does not change between A2 and the O point of the apexcardiogram, and in this study this period was prolonged in 19, shortened in eight, and remained the same in three patients after beta blockade. The Mo-O point was prolonged in 22, shortened in seven, and was unchanged in one patient after beta adrenergic blocking drugs. All these results were independent of heart rate. In conclusion the response of diastolic time intervals to beta blocking drugs in hypertrophic cardiomyopathy was variable but there was a significant number of patients in whom the time available for filling of the left ventricle was prolonged, suggesting better filling possibly because of improved distensibility of the left ventricle after beta adrenergic blocking drugs. PMID:6125160

Alvares, R F; Goodwin, J F

1982-01-01

291

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

292

The Valley of Death in anticancer drug development: a re-assessment  

PubMed Central

The past decade has seen an explosion in our understanding of cancer biology and with it many new potential disease targets. Yet our ability to translate these advances into therapies is poor, with a failure rate approaching 90%. Much discussion has been devoted to this so-called ‘Valley of Death’ in anticancer drug development, but the problem persists. Could we have overlooked some straight-forward explanations to this highly complex problem? Important aspects of tumor physiology, drug pharmacokinetics, preclinical models, drug delivery, and clinical translation are not often emphasized and could be critical. This perspective summarizes current views on the problem and suggests feasible alternatives. PMID:22410081

Adams, David J.

2012-01-01

293

Therapeutic drug monitoring for triazoles: A needs assessment review and recommendations from a Canadian perspective  

PubMed Central

Invasive fungal infections cause significant morbidity and mortality in patients with concomitant underlying immunosuppressive diseases. The recent addition of new triazoles to the antifungal armamentarium has allowed for extended-spectrum activity and flexibility of administration. Over the years, clinical use has raised concerns about the degree of drug exposure following standard approved drug dosing, questioning the need for therapeutic drug monitoring (TDM). Accordingly, the present guidelines focus on TDM of triazole antifungal agents. A review of the rationale for triazole TDM, the targeted patient populations and available laboratory methods, as well as practical recommendations based on current evidence from an extended literature review are provided in the present document. PMID:25587296

Laverdiere, Michel; Bow, Eric J; Rotstein, Coleman; Autmizguine, Julie; Broady, Raewyn; Garber, Gary; Haider, Shariq; Hussaini, Trana; Husain, Shahid; Ovetchkine, Philippe; Seki, Jack T; Théorêt, Yves

2014-01-01

294

The risk of multiple addictions. Guidelines for assessing a woman's alcohol and drug use.  

PubMed Central

Psychotropic drugs have been overly prescribed for women of all ages for all manner of symptoms. Patients' and physicians' expectations about appropriate diagnosis and treatment, combined with the relative invisibility of women's alcohol and legal and illicit drug use, can lead to quick but temporary prescription solutions that may put women at risk for multiple addictions. This is a special problem for adolescent, minority, and elderly women, about whom we know little yet hold strong stereotypes. Moreover, while prescriptions may alleviate patients' symptoms, they do little to correct the underlying situation. Physicians are encouraged to review their prescribing habits and to learn more about their women patients' use of alcohol, cigarettes, previously prescribed medications, and recreational drugs, as well as a tendency to self-medicate. Physicians should also have available alternative strategies to prescribing psychotropic drugs. Images PMID:3074574

Matteo, S

1988-01-01

295

78 FR 36787 - Rechanneling the Current Cardiac Risk Paradigm: Arrhythmia Risk Assessment During Drug...  

Federal Register 2010, 2011, 2012, 2013

...will be held at the FDA White Oak Campus, 10903 New Hampshire Ave., Building 31 Conference Center, the Great Room (rm. 1503...Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, rm. 4183, Silver Spring, MD 20993,...

2013-06-19

296

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. PMID:23620485

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

2013-01-01

297

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. PMID:23575242

2013-01-01

298

Prediction of human volume of distribution values for drugs using linear and nonlinear quantitative structure pharmacokinetic relationship models.  

PubMed

In the present study the volume of distribution values in humans of 121 drugs was estimated using quantitative structure pharmacokinetic relationship analysis. The multiple linear regression (MLR) method and nonlinear artificial neural network (ANN) and support vector machines (SVM) were employed for modeling. The theoretically calculated molecular descriptors were used for modeling and best set of descriptors selected by correlation based feature selection (CFS) method. The performance and predictive capability of linear method was investigated and compared with nonlinear method. The ANN gave better model with an average fold error of 1.66. The test set prediction accuracy shows human volume of distribution values could be predicted, on average, within 2-fold of the actual value. PMID:24464707

Louis, Bruno; Agrawal, Vijay K

2014-03-01

299

COMPARISON OF IN VITRO METHODS AND THE IN VIVO METABOLISM OF LINDANE FOR ASSESSING THE EFFECTS OF REPEATED ADMINISTRATION OF ETHANOL ON HEPATIC DRUG METABOLISM  

EPA Science Inventory

In vitro methods of assessing alterations in drug metabolism and the measurement of lindane metabolites in urine were compared for their ability to determine the influence of ethanol on drug metabolism. Ethanol was administered to young adult female rats daily for seven days at d...

300

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

301

Physical evidence in drug intelligence, Part 1: rationale based on hierarchic distribution of drugs using pyrolysis gas chromatography –mass spectrometry as an example  

Microsoft Academic Search

A complementary intelligence-gathering tool is described for drug-crime investigation. Scientific analysis and interpretation of packaging materials from seized shipments of illicit drugs will assist law enforcement by creating a more holistic description of each seizure, thus allowing further inferences to be drawn and ultimately assisting in a more thorough understanding of the flow of drugs to or within a particular

Juuso Huttunen; Chris Austin; Michael Dawson; Claude Roux; James Robertson

2007-01-01

302

Residual hazard assessment related to handling of antineoplastic drugs: safety system evolution and quality assurance of analytical measurement.  

PubMed

Despite improvement of operating procedures and publication of safety guidelines, contamination is still observed in healthcare settings where antineoplastic drugs (ADs) are handled. Even after cleaning work areas, some residual contamination may still be present. Zero percent contamination is not a realistic goal, but the scientific community should set zero contamination as its main goal. The strategies to reach this objective may be traced based on the followings: (a) a wider number of drugs should be monitored; (b) safety equipment and devices must be available to the workers; (c) the likely source of widespread contamination in workplaces is the safety cabinet; (d) direct determination of the parent drug or its metabolite in urine is the recommended approach because it provides higher sensitivity and specificity; (e) reliable analytical methods are necessary to measure the extent of contamination; and (f) analytical methods intended to be applied for routine testing must be assessed through method validation studies. These studies rely on the determination of overall method performance parameters including uncertainty measurement. Our laboratory has developed and validated a number of analytical methods for the determination of several drugs in environmental and biological samples. Surveys were carried out in several hospitals, and there has been progressive, significant decrease in the number of positive samples, mostly due to the improvement of working procedures and safety measures. PMID:17119242

Turci, Roberta; Minoia, Claudio

2006-09-01

303

Rapid Assessment Response (RAR) study: drug use, health and systemic risks—Emthonjeni Correctional Centre, Pretoria, South Africa  

PubMed Central

Background Correctional centre populations are one of the populations most at risk of contracting HIV infection for many reasons, such as unprotected sex, violence, rape and tattooing with contaminated equipment. Specific data on drug users in correctional centres is not available for the majority of countries, including South Africa. The study aimed to identify the attitudes and knowledge of key informant (KI) offender and correctional centre staff regarding drug use, health and systemic-related problems so as to facilitate the long-term planning of activities in the field of drug-use prevention and systems strengthening in correctional centres, including suggestions for the development of appropriate intervention and rehabilitation programmes. Method A Rapid Assessment Response (RAR) methodology was adopted which included observation, mapping of service providers (SP), KI interviews (staff and offenders) and focus groups (FGs). The study was implemented in Emthonjeni Youth Correctional Centre, Pretoria, South Africa. Fifteen KI staff participants were interviewed and 45 KI offenders. Results Drug use is fairly prevalent in the centre, with tobacco most commonly smoked, followed by cannabis and heroin. The banning of tobacco has also led to black-market features such as transactional sex, violence, gangsterism and smuggling in order to obtain mainly prohibited tobacco products, as well as illicit substances. Conclusion HIV, health and systemic-related risk reduction within the Correctional Service sector needs to focus on measures such as improvement of staff capacity and security measures, deregulation of tobacco products and the development and implementation of comprehensive health promotion programmes. PMID:24708609

2014-01-01

304

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

305

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

306

Incorporating remotely sensed tree canopy cover data into broad scale assessments of wildlife habitat distribution and conservation  

Microsoft Academic Search

Remote sensing provides critical information for broad scale assessments of wildlife habitat distribution and conservation. However, such efforts have been typically unable to incorporate information about vegetation structure, a variable important for explaining the distribution of many wildlife species. We evaluated the consequences of incorporating remotely sensed information about horizontal vegetation structure into current assessments of wildlife habitat distribution and

Sebastián Martinuzzi; Lee A. Vierling; William A. Gould; Kerri T. Vierling; Andrew T. Hudak

2009-01-01

307

Assessing the viability of microsponges as gastro retentive drug delivery system of curcumin: optimization and pharmacokinetics.  

PubMed

The work was aimed to validate the gastroretentive potential of microsponges via optimization of targeted floating curcumin microsponges for improved site specific absorption for gastric cancer Modified quasi emulsion solvent diffusion method was used to formulate microsponges using 3(2) full factorial design. The effect of different levels of ethyl cellulose and polyvinyl alcohol concentration, selected as independent variables was determined on the % entrapment efficiency, % buoyancy and % cumulative drug release. Modified rosette rise apparatus was used for in vitro release and the release data best fitted Higuchi's model and mechanism of drug release was diffusion (n). The optimized formulation (MS5) demonstrated favourable % entrapment efficiency (90.7 ± 1.7), % buoyancy (82.0 ± 2.0) and % cumulative drug release (85.2 ± 1.07) with maximum desirability factor of 0.816. SEM revealed spherical and porous microsponges. DSC confirmed molecular dispersion of the drug in the microsponges polymeric matrix. DRIFT revealed no chemical interaction between the drug and polymer used. The in vitro permeation of curcumin through gastric mucin gel layer affirmed the capability of microsponges to deliver drug across mucin r and reach the target site to treat gastric cancer. Anticancer oral dose of microsponges was calculated as 50mg by cytotoxicity assay in human cancer cell line KB. The pharmacokinetic evaluation of MS5 in rabbits revealed 10-fold increase in bioavailability as compared to native curcumin, demonstrated the superiority of microsponges over native curcumin as gastro retentive drug delivery system. This study presents a new approach based on floating ability of microsponges for treatment of gastric cancer. PMID:24184218

Arya, Priyanka; Pathak, Kamla

2014-01-01

308

Report of the Workshop on Selecting Input Distributions For Probabilistic Assessments  

NSDL National Science Digital Library

The Environmental Protection Agency provides online access to the Report of the Workshop on Selecting Input Distributions for Probabilistic Assessments. This report highlights the main points discussed at an EPA workshop held in April 1998 by the Eastern Research Group. The goal of the workshop and report was to "assist EPA in developing a framework and guidance for selecting input distributions for probabilistic risk assessments." The abstract can be viewed in HTML format, while the full-text article is available in .pdf format.

1999-01-01

309

Testing for bimodality in frequency distributions of data suggesting polymorphisms of drug metabolism--hypothesis testing.  

PubMed Central

1. The theory of methods of hypothesis testing in relation to the detection of bimodality in density distributions is discussed. 2. Practical problems arising from these methods are outlined. 3. The power of three methods of hypothesis testing was compared using simulated data from bimodal distributions with varying separation between components. None of the methods could determine bimodality until the separation between components was 2 standard deviation units and could only do so reliably (greater than 90%) when the separation was as great as 4-6 standard deviation units. 4. The robustness of a parametric and a non-parametric method of hypothesis testing was compared using simulated unimodal distributions known to deviate markedly from normality. Both methods had a high frequency of falsely indicating bimodality with distributions where the components had markedly differing variances. 5. A further test of robustness using power transformation of data from a normal distribution showed that the algorithms could accurately determine unimodality only when the skew of the distribution was in the range 0-1.45. PMID:2611088

Jackson, P R; Tucker, G T; Woods, H F

1989-01-01

310

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

311

Use and assessment of complementary and alternative therapies by intravenous drug users.  

PubMed

Intravenous drug users often have many health conditions in addition to their drug addiction, yet may be isolated from conventional sources of care. They have never before been examined for their use of complementary and alternative medicine (CAM) therapies. Our purpose was to study the prevalence and predictors of CAM use among persons with a history of intravenous drug use through a cross-sectional survey of intravenous drug users examining their utilization of health services, including CAM therapies. A total of 548 persons with a history of intravenous drug use, recruited from a needle-exchange program and a methadone maintenance clinic, both in Providence, Rhode Island, participated. Overall prevalence of any CAM use in the past 6 months, frequency of use of individual named CAM therapies and domains, and demographic and clinical characteristics associated with CAM users, reasons for CAM use and self-perceived effectiveness of CAM were also measured. Of the 548 participants, 45% reported use of at least one CAM therapy. The top three therapies--religious healing, relaxation techniques, and meditation--were all from the mind-body domain. Having a higher education and lower self-rated health were the two strongest predictors of CAM use, followed by having a regular doctor or clinic, being white and younger. There was a high level of self-perceived effectiveness of CAM therapies (4.1 on a scale of 1-5), and CAM users were likely to use CAM for reasons related to their addiction. PMID:12765213

Manheimer, Eric; Anderson, Bradley J; Stein, Michael D

2003-05-01

312

GWAMAR: Genome-wide assessment of mutations associated with drug resistance in bacteria  

PubMed Central

Background Development of drug resistance in bacteria causes antibiotic therapies to be less effective and more costly. Moreover, our understanding of the process remains incomplete. One promising approach to improve our understanding of how resistance is being acquired is to use whole-genome comparative approaches for detection of drug resistance-associated mutations. Results We present GWAMAR, a tool we have developed for detecting of drug resistance-associated mutations in bacteria through comparative analysis of whole-genome sequences. The pipeline of GWAMAR comprises several steps. First, for a set of closely related bacterial genomes, it employs eCAMBer to identify homologous gene families. Second, based on multiple alignments of the gene families, it identifies mutations among the strains of interest. Third, it calculates several statistics to identify which mutations are the most associated with drug resistance. Conclusions Based on our analysis of two large datasets retrieved from publicly available data for M. tuberculosis, we identified a set of novel putative drug resistance-associated mutations. As a part of this work, we present also an application of our tool to detect putative compensatory mutations. PMID:25559874

2014-01-01

313

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

314

Zebrafish: an emerging technology for in vivo pharmacological assessment to identify potential safety liabilities in early drug discovery.  

PubMed

The zebrafish is a well-established model organism used in developmental biology. In the last decade, this technology has been extended to the generation of high-value knowledge on safety risks of novel drugs. Indeed, the larval zebrafish appear to combine advantages of whole organism phenotypic assays and those (rapid production of results with minimal resource engagement) of in vitro high-throughput screening techniques. Thus, if appropriately evaluated, it can offer undeniable advantages in drug discovery for identification of target and off-target effects. Here, we review some applications of zebrafish to identify potential safety liabilities, particularly before lead/candidate selection. For instance, zebrafish cardiovascular system can be used to reveal decreases in heart rate and atrial-ventricular dissociation, which may signal human ether-a-go-go-related gene (hERG) channel blockade. Another main area of interest is the CNS, where zebrafish behavioural assays have been and are further being developed into screening platforms for assessment of locomotor activity, convulsant and proconvulsant liability, cognitive impairment, drug dependence potential and impaired visual and auditory functions. Zebrafish also offer interesting possibilities for evaluating effects on bone density and gastrointestinal function. Furthermore, available knowledge of the renal system in larval zebrafish can allow identification of potential safety issues of drug candidates on this often neglected area in early development platforms. Although additional validation is certainly needed, the zebrafish is emerging as a versatile in vivo animal model to identify off-target effects that need investigation and further clarification early in the drug discovery process to reduce the current, high degree of attrition in development. PMID:18552866

Barros, T P; Alderton, W K; Reynolds, H M; Roach, A G; Berghmans, S

2008-08-01

315

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

316

Development of Polysorbate 80/Phospholipid mixed micellar formation for docetaxel and assessment of its in vivo distribution in animal models  

NASA Astrophysics Data System (ADS)

Docetaxel (DTX) is a very important member of taxoid family. Despite several alternative delivery systems reported recently, DTX formulated by Polysorbate 80 and alcohol (Taxotere®) is still the most frequent administration in clinical practice. In this study, we incorporated DTX into Polysorbate 80/Phospholipid mixed micelles and compared its structural characteristics, pharmacokinetics, biodistribution, and blood compatibility with its conventional counterparts. Results showed that the mixed micelles loaded DTX possessed a mean size of approximately 13 nm with narrow size distribution and a rod-like micelle shape. In the pharmacokinetics assessment, there was no significant difference between the two preparations ( P > 0.05), which demonstrated that the DTX in the two preparations may share a similar pharmacokinetic process. However, the Polysorbate 80/Phospholipid mixed micelles can increase the drug residence amount of DTX in kidney, spleen, ovary and uterus, heart, and liver. The blood compatibility assessment study revealed that the mixed micelles were safe for intravenous injection. In conclusion, Polysorbate 80/Phospholipid mixed micelle is safe, can improve the tumor therapeutic effects of DTX in the chosen organs, and may be a potential alternative dosage form for clinical intravenous administration of DTX.

Song, Hua; Geng, Hongquan; Ruan, Jing; Wang, Kan; Bao, Chenchen; Wang, Juan; Peng, Xia; Zhang, Xueqing; Cui, Daxiang

2011-04-01

317

In vitro assessment of drug release from semi-solid lipid matrices  

Microsoft Academic Search

The paper describes the results of a study in which the in vitro drug release characteristics of a compound with a poor water solubility from different semi-solid lipid matrix formulations are studied. The method using a biphasic dissolution medium avoids the major technical problem encountered during dissolution studies with this type of dosage form. It allows to make a comparative

R. Kinget; H. De Greef

1995-01-01

318

Niche markets and evidence assessment in transition: a critical review of proposed drug reforms.  

PubMed

In response to rising demands and treatment costs, and the need to achieve better value for money in the face of tight fiscal constraints, both the National Health Service and the public drug reimbursement system are undergoing important reforms. Concurrently, the pharmaceutical sector itself is also alleged to be experiencing significant changes, perhaps most notably, a decline of the blockbuster model of drug development and a growing focus on niche market products. As pharmaceutical development strategies evolve and the resulting drug products become more complex, regulatory and policy responses must be able to evolve along with them. We explore how in numerous jurisdictions, including the UK, proposals for 'adaptive licensing' on the regulatory side and 'performance-based risk sharing agreements' on the funding side are shifting the focus of drug regulation and reimbursement towards more incremental access to new therapies and more post-market evidence generation. However, serious questions remain about how such reforms can be successfully implemented and whether they can balance demands for earlier access to promising new therapies with the need for robust evidence on safety, efficacy, and cost-effectiveness. PMID:24841527

Gibson, Shannon G; Lemmens, Trudo

2014-01-01

319

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

320

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

321

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 72 h. 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, 87 h, 35 h and 58 h, respectively, while the corresponding t1/2 values at 10°C were 18 h, 139 h, 173 h and 87 h. 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

322

Development of Risk Assessment Methodology for Land Application and Distribution and Marketing of Municipal Sludge  

EPA Science Inventory

This is one of a series of reports that present methodologies for assessing the potential risks to humans or other organisms from the disposal or reuse of municipal sludge. The sludge management practices addressed by this series include land application practices, distribution a...

323

Spatially distributed pesticide exposure assessment in the Central Valley, California, USA  

E-print Network

Spatially distributed pesticide exposure assessment in the Central Valley, California, USA Yuzhou of pesticide sources. a r t i c l e i n f o Article history: Received 24 September 2009 Received in revised level a b s t r a c t Field runoff is an important transport mechanism by which pesticides move

Zhang, Minghua

324

An Assessment of Rainforest Distribution and Threats in the West Usambara Mountains, Tanzania  

Microsoft Academic Search

Biodiversity hotspots across the globe have gained increasing attention in recent years. To accurately assess natural resource values and threats, timely information which characterizes the distribution and extent of natural land cover is needed. Many hotspots are in developing countries that have neither the resources nor the capability to carry out these tasks. This study seeks to address these issues

J. Halperin; T. Shear

2005-01-01

325

A First Assessment of Mycobacterium tuberculosis Genetic Diversity and Drug-Resistance Patterns in Twelve Caribbean Territories  

PubMed Central

With the exception of some French-speaking islands, data on tuberculosis (TB) in the Caribbean are scarce. In this study, we report a first assessment of genetic diversity of a convenience sample of Mycobacterium tuberculosis strains received from twelve Caribbean territories by spoligotyping and describe their drug-resistance patterns. Of the 480 isolates, 40 (8.3%) isolates showed resistance to at least one anti-TB drug. The proportion of drug-resistant strains was significantly higher in The Bahamas (21.4%; P = 0.02), and Guyana (27.5%; P < 0.0001), while it was significantly lower in Jamaica (2.4%; P = 0.03) than in other countries of the present study. Regarding genetic diversity, 104 distinct spoligotype patterns were observed: 49 corresponded to clustered strains (2 to 93 strains per cluster), while 55 remained unclustered among which 16 patterns were not reported previously. Combining the study results with regional data retrieved from the international SITVIT2 database underlined a connection between frequency of certain M. tuberculosis phylogenetic lineages and the language spoken, suggesting historical (colonial) and ongoing links (trade, tourism, and migratory flows) with European countries with which they shared a common past. PMID:24795893

Millet, Julie; Baboolal, Shirematee; Akpaka, Patrick E.

2014-01-01

326

A first assessment of Mycobacterium tuberculosis genetic diversity and drug-resistance patterns in twelve Caribbean territories.  

PubMed

With the exception of some French-speaking islands, data on tuberculosis (TB) in the Caribbean are scarce. In this study, we report a first assessment of genetic diversity of a convenience sample of Mycobacterium tuberculosis strains received from twelve Caribbean territories by spoligotyping and describe their drug-resistance patterns. Of the 480 isolates, 40 (8.3%) isolates showed resistance to at least one anti-TB drug. The proportion of drug-resistant strains was significantly higher in The Bahamas (21.4%; P = 0.02), and Guyana (27.5%; P < 0.0001), while it was significantly lower in Jamaica (2.4%; P = 0.03) than in other countries of the present study. Regarding genetic diversity, 104 distinct spoligotype patterns were observed: 49 corresponded to clustered strains (2 to 93 strains per cluster), while 55 remained unclustered among which 16 patterns were not reported previously. Combining the study results with regional data retrieved from the international SITVIT2 database underlined a connection between frequency of certain M. tuberculosis phylogenetic lineages and the language spoken, suggesting historical (colonial) and ongoing links (trade, tourism, and migratory flows) with European countries with which they shared a common past. PMID:24795893

Millet, Julie; Baboolal, Shirematee; Streit, Elisabeth; Akpaka, Patrick E; Rastogi, Nalin

2014-01-01

327

Assessment of oral side effects of Antiepileptic drugs and traumatic oro-facial injuries encountered in Epileptic children  

PubMed Central

Background: Epilepsy is a chronic disorder with unpredictably recurring seizure. Uncontrolled attacks can put patients at risk of suffering oro-facial trauma. Antiepileptic drugs (AED) provide satisfactory control of seizures in most of the patients with epilepsy. However use of AED has been found to cause many side effects inclusive of side effects in the oral cavity also. Materials & Methods: This study was conducted on 150 epileptic children, who were on anti epileptic medication for one year. Results: Gingival over growth was seen as common side effect of the AED drugs. Lip and cheek biting were the most common soft tissue injury, while tooth fracture was the most common hard tissue dental injury. Conclusion: General physicians, physicians & dentists should be well aware of the potential side effects of AED. A Dentist should be well versed and trained to manage oro-facial injuries in the emergency department. How to cite the article: Ghafoor PA, Rafeeq M, Dubey A. Assessment of oral side effects of Antiepileptic drugs and traumaticoro-facial injuries encountered in Epileptic children. J Int Oral Health 2014;6(2):126-8. PMID:24876713

Ghafoor, P A Fazal; Rafeeq, Mohammed; Dubey, Alok

2014-01-01

328

Impact of drying on solid state modifications and drug distribution in ibuprofen-loaded calcium stearate pellets.  

PubMed

Drying is a common pharmaceutical process, whose potential to alter the final drug properties-even at relatively low temperatures-is often neglected. The present study addresses the impact of drying at 20 and 50 °C on wet-extruded calcium stearate (CaSt) pellets. Drying at 20 °C caused the majority of ibuprofen to accumulate at the pellet surface due to a strong convective flow from the pellet's center to the surface. In contrast, pellets dried at 50 °C still contained ibuprofen in the pellet's interior due to the higher drying rate and the associated film breakage during drying. Moreover, the higher drying temperature caused CaSt to form a second lamellar phase and ibuprofen to convert (partly) into its amorphous state. Overall, the drying process affected the solid state and the spatial ibuprofen distribution within the pellet. Knowledge of these effects can aid in tailoring advanced multipellet formulations. PMID:24400735

Schrank, S; Kann, B; Saurugger, E; Ehmann, H; Werzer, O; Windbergs, M; Glasser, B J; Zimmer, A; Khinast, J; Roblegg, E

2014-02-01

329

12 CFR Appendix A to Part 741 - Examples of Partial-Year NCUSIF Assessment and Distribution Calculations Under § 741.4  

...Partial-Year NCUSIF Assessment and Distribution Calculations Under § 741.4 A...Partial-Year NCUSIF Assessment and Distribution Calculations Under § 741.4 ...times the institution's premium/distribution ratio * * *. i. To...

2014-01-01

330

12 CFR Appendix A to Part 741 - Examples of Partial-Year NCUSIF Assessment and Distribution Calculations Under § 741.4  

Code of Federal Regulations, 2013 CFR

...Partial-Year NCUSIF Assessment and Distribution Calculations Under § 741.4 A...Partial-Year NCUSIF Assessment and Distribution Calculations Under § 741.4 ...times the institution's premium/distribution ratio * * *. i. To...

2013-01-01

331

12 CFR Appendix A to Part 741 - Examples of Partial-Year NCUSIF Assessment and Distribution Calculations Under § 741.4  

Code of Federal Regulations, 2012 CFR

...Partial-Year NCUSIF Assessment and Distribution Calculations Under § 741.4 A...Partial-Year NCUSIF Assessment and Distribution Calculations Under § 741.4 ...times the institution's premium/distribution ratio * * *. i. To...

2012-01-01

332

12 CFR Appendix A to Part 741 - Examples of Partial-Year NCUSIF Assessment and Distribution Calculations Under § 741.4  

Code of Federal Regulations, 2011 CFR

...Partial-Year NCUSIF Assessment and Distribution Calculations Under § 741.4 A...Partial-Year NCUSIF Assessment and Distribution Calculations Under § 741.4 ...times the institution's premium/distribution ratio * * *. i. To...

2011-01-01

333

Assessment of drugs against Cryptosporidium parvum using a simple in vitro screening method  

Microsoft Academic Search

A rapid semi-quantitative screening method was devised for assessing the anticryptosporidial and cytotoxic effects of putative chemotherapeutic compounds. The method is suitable as an initial rapid screening procedure from which compounds demonstrating anticryptosporidial activity can be identified for further analysis. It has the advantages of speed, low cost and concurrent assessment of anticryptosporidial and cytotoxic effects and allows accurate determination

Anthony Armson; Bruno P. Meloni; James A. Reynoldson; R. C. Andrew Thompson

1999-01-01

334

Asking About Sexual Orientation During Assessment for Drug and Alcohol Concerns: A Pilot Study  

Microsoft Academic Search

An assessment tool was designed to assist service providers in identifying lesbian, gay and bisexual (LGB) clients who present for assistance related to substance use concerns. Items were designed to facilitate self-disclosure of the individual's sexual orientation and identify concerns of LGB clients that will be relevant to treatment planning for substance use concerns. Therapists in general assessment and LGB-specialized

Angela M. Barbara; Gloria Chaim

2004-01-01

335

Treating Indigenous Australians with Alcohol\\/Drug Problems: Assessing Quality of Life  

Microsoft Academic Search

This study investigated the quality of life (QoL) of clients in an Indigenous Australian residential alcohol and drug treatment center. Qualitative and quantitative data were collected from a random sample of Indigenous clients utilizing the Self Evaluated Individual Quality of Life–Direct Weight tool. The findings from this study provide support for the inclusion of QoL as important in understanding the

Richard Chenhall; Kate Senior

2012-01-01

336

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

SciTech Connect

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 used cytotoxicity assays for parent compound toxicity. The interassay variability was determined. The cytotoxicity assays were also compared with a reliable alternative time resolved respirometric assay. The set of training compounds consisted of well known hepatotoxins; amiodarone, carbamazepine, clozapine, diclofenac, tacrine, troglitazone and verapamil. The sensitivity of both cell systems in each tested assay was determined. Results show that careful selection of assay parameters and inclusion of a kinetic time resolved assay improves prediction for non-metabolism mediated toxicity using Hep G2 cells as indicated by a sensitivity ratio of 1. The drugs with EC{sub 50} values 100 {mu}M or lower were considered toxic. The difference in the sensitivity of the two cell systems to carbamazepine which causes toxicity via reactive metabolites emphasizes the importance of human cell based in-vitro assays. Using the described system, primary rat hepatocytes do not offer advantage over the Hep G2 cells in parent compound toxicity evaluation. Moreover, respiration method is non invasive, highly sensitive and allows following the time course of toxicity. Respiration assay could serve as early indicator of changes that subsequently lead to toxicity.

Noor, Fozia [Biochemical Engineering Institute, Saarland University, Campus A 1.5, D-66123 Saarbruecken (Germany)], E-mail: fozia.noor@mx.uni-saarland.de; Niklas, Jens [Biochemical Engineering Institute, Saarland University, Campus A 1.5, D-66123 Saarbruecken (Germany)], E-mail: j.niklas@mx.uni-saarland.de; Mueller-Vieira, Ursula [Pharmacelsus GmbH, Science Park 2, D-66123 Saarbruecken (Germany)], E-mail: mueller@pharmacelsus.de; Heinzle, Elmar [Biochemical Engineering Institute, Saarland University, Campus A 1.5, D-66123 Saarbruecken (Germany)], E-mail: e.heinzle@mx.uni-saarland.de

2009-06-01

337

Performance of an In-House Human Immunodeficiency Virus Type 1 Genotyping System for Assessment of Drug Resistance in Cuba  

PubMed Central

As commercial human immunodeficiency virus type 1 drug resistance assays are expensive, they are not commonly used in resource-limited settings. Hence, a more affordable in-house procedure was set up taking into account the specific epidemiological and economic circumstances of Cuba. The performance characteristics of the in-house assay were evaluated using clinical samples with various subtypes and resistance patterns. The lower limit of amplification was determined on dilutions series of 20 clinical isolates and ranged from 84 to 529 RNA copies/mL. For the assessment of trueness, 14 clinical samples were analyzed and the ViroSeq HIV-1 Genotyping System v2.0 was used as the reference standard. The mean nucleotide sequence identity between the two assays was 98.7% ± 1.0. Additionally, 99.0% of the amino acids at drug resistance positions were identical. The sensitivity and specificity in detecting drug resistance mutations was respectively 94.1% and 99.5%. Only few discordances in drug resistance interpretation patterns were observed. The repeatability and reproducibility were evaluated using 10 clinical samples with 3 replicates per sample. The in-house test was very precise as nucleotide sequence identity among paired nucleotide sequences ranged from 98.7% to 99.9%. The acceptance criteria were met by the in-house test for all performance characteristics, demonstrating a high degree of accuracy. Subsequently, the applicability in routine clinical practice was evaluated on 380 plasma samples. The amplification success rate was 91% and good quality consensus sequences encoding the entire protease and the first 335 codons in reverse transcriptase could be obtained for 99% of the successful amplicons. The reagent cost per sample using the in-house procedure was around € 80 per genotyping attempt. Overall, the in-house assay provided good results, was feasible with equipment and reagents available in Cuba and was half as expensive as commercial assays. PMID:25671421

Alemán, Yoan; Vinken, Lore; Kourí, Vivian; Pérez, Lissette; Álvarez, Alina; Abrahantes, Yeissel; Fonseca, Carlos; Pérez, Jorge; Correa, Consuelo; Soto, Yudira; Schrooten, Yoeri; Vandamme, Anne-Mieke; Van Laethem, Kristel

2015-01-01

338

Determination of anti-anxiety and anti-epileptic drugs in hospital effluent and a preliminary risk assessment.  

PubMed

In this study, an analytical methodology was developed for the determination of psycho-active drugs in the treated effluent of the University Hospital at the Federal University of Santa Maria, RS - Brazil. Samples were collected from point A (Emergency) and point B (General effluent). The adopted methodology included a pre-concentration procedure involving the use of solid phase extraction and determination by liquid chromatography coupled to mass spectrometry. The limit of detection for bromazepam and lorazepam was 4.9 ± 1.0 ng L(-1) and, for carbamazepine, clonazepam and diazepam was 6.1 ± 1.5 ng L(-1). The limit of quantification was 30.0 ± 1.1 ng L(-1), for bromazepam, clonazepam and lorazepam; for carbamazepine was 50.0 ± 1.8 ng L(-1) and was 40.0 ± 1.0 ng L(-1) for diazepam. The mean concentrations in the Emergency and General effluent treated currents were as follows: for bromazepam, 195 ± 6 ng L(-1) and 137 ± 7 ng L(-1); for carbamazepine, 590 ± 6 ng L(-1) and 461 ± 10 ng L(-1); for diazepam, 645 ± 1 ng L(-1) and 571 ± 10 ng L(-1); for lorazepam, 96 ± 7 ng L(-1) and 42 ± 4 ng L(-1); and for clonazepam, 134 ± 10 ng L(-1) and 57 ± 10 ng L(-1). A preliminary risk assessment was conducted: carbamazepine and diazepam require considerable attention owing to their environmental toxicity. The occurrence of these psychoactive-drugs and the environmental risks that they pose demonstrated the need for a more efficient treatment system. As far we are aware, there have been no comparable studies to this on the hazards of hospital effluents in Brazil, and very few that have carried out a risk assessment of psycho-active drugs in hospital effluent in general. PMID:24034828

de Almeida, Carlos Alberto A; Brenner, Carla G B; Minetto, Luciane; Mallmann, Carlos A; Martins, Ayrton F

2013-11-01

339

Renal excretion of clofarabine: assessment of dose-linearity and role of renal transport systems on drug excretion.  

PubMed

The renal excretion of clofarabine was studied in vitro in the isolated perfused rat kidney (IPK) model and in vivo in rats. Clofarabine excretion was studied at four doses (160, 800, 2000 and 4000microg) in the IPK, targeting perfusate levels of 2, 10, 25, 50microg/mL, respectively. Clofarabine (2microg/mL) was also co-perfused with known inhibitors of the, organic cation (cimetidine, ranitidine and tyramine) and organic anion (probenecid, ellagic acid) transport systems. Additionally, the effect of medications including, itraconazole, digoxin, fludarabine and cytarabine (Ara-C) on clofarabine excretion was, evaluated. Based on IPK results, in vivo studies were performed to assess the plasma, pharmacokinetics and urinary recovery of clofarabine (6.5mg/kg, IV) pretreatment, with cimetidine (250mg/kg, IV). Clofarabine clearance was non-linear in the IPK, although at concentrations that were approximately 10- to 100-fold higher than maximum concentrations observed in humans. Excretion ratio data indicated a shift from net, secretion (XR=1.2+/-0.33) to net reabsorption (XR=0.78+/-0.40) at the highest dose, tested. Clofarabine clearance was significantly reduced upon co-administration with, cimetidine (0.83+/-0.22-->0.32+/-0.058mL/min). In vivo data correlated with IPK results as clofarabine clearance decreased 61% (20.2-7.80mL/min/kg), upon co-administration with cimetidine in rats. The results suggest that clofarabine is a substrate for a cimetidine-sensitive organic cation transporter system in the kidney, presumably OCT2. The magnitude of the cimetidine-clofarabine interaction was similar, in IPK and in vivo, demonstrating the utility of the IPK model in characterizing renal, drug excretion and assessing potential drug-drug interactions. PMID:20347037

Ajavon, Antoinette D; Bonate, Peter L; Taft, David R

2010-06-14

340

Statistical analysis of polymorphic drug metabolism data using the Rosin Rammler Sperling Weibull distribution.  

PubMed

The Rosin Rammler Sperling Weibull distribution and its use in the analysis of complex data is explained with reference to metoprolol and acebutolol AUC values and isoniazid plasma concentrations. The technique is then applied to sparteine and debrisoquine data to resolve populations into distinct sub-groups. Goodness of fit is measured by applying the chi 2 test to the untransformed data. The method is simple to use and sub-groups can be identified rapidly. Each sub-group can be characterised by a simple exponential equation. PMID:6653637

Jack, D B

1983-01-01

341

Medical imaging in new drug clinical development  

PubMed Central

Medical imaging can help answer key questions that arise during the drug development process. The role of medical imaging in new drug clinical trials includes identification of likely responders; detection and diagnosis of lesions and evaluation of their severity; and therapy monitoring and follow-up. Nuclear imaging techniques such as PET can be used to monitor drug pharmacokinetics and distribution and study specific molecular endpoints. In assessing drug efficacy, imaging biomarkers and imaging surrogate endpoints can be more objective and faster to measure than clinical outcomes, and allow small group sizes, quick results and good statistical power. Imaging also has important role in drug safety monitoring, particularly when there is no other suitable biomarkers available. Despite the long history of radiological sciences, its application to the drug development process is relatively recent. This review highlights the processes, opportunities, and challenges of medical imaging in new drug development. PMID:22263053

Wang, Yi-Xiang; Deng, Min

2010-01-01

342

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

343

Biochemical and analytical development of the CIME cocktail for drug fate assessment in humans.  

PubMed

Phenotyping based on drug metabolism activity appears to be informative regarding mechanism-based interactions during drug development. We report here the first steps of the development of the innovative CIME cocktail. This cocktail is designed not only for the major cytochrome P450, with caffeine, amodiaquine, tolbutamide, omeprazole, dextromethorphan and midazolam as substrates of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A, respectively, but also phase II enzymes UGT 1A1/6/9 with acetaminophen, P-gp and OATP1B1 with digoxin and rosuvastatin, and renal function with memantine. An assay combining ultra-performance liquid chromatography using a 1.7 microm particle size column with tandem mass spectrometry (UPLC/MS/MS) was set up for the simultaneous quantification of the 20 substrates and metabolites after extraction from human plasma using solid-phase extraction. The method was validated in the spirit of the FDA guidelines. Mean accuracy ranged from 87.7 to 115%, the coefficient of variance (CV%) of intra- and inter-run from 1.7 to 16.4% and from 1.6 to 14.9%, respectively, and for the limit of quantification (LOQ) with ten lots of plasma, accuracy ranged from 84 to 115% and CV% precision was <16%. Short-term stability was evaluated in eluate (4 h, room temperature), plasma (24 h, room temperature), the autosampler (24 h, 4 degrees C) and in three freeze/thaw cycles in plasma. All except three analytes were stable under these conditions. For the three others a specific process can be followed. This robust, fast and sensitive assay in human plasma provides an analytical tool for ten-probe drugs of the CIME cocktail. Clinical samples will be assayed in the near future using this new assay method. PMID:20658680

Videau, Orianne; Delaforge, Marcel; Levi, Mikael; Thévenot, Etienne; Gal, Olivier; Becquemont, Laurent; Beaune, Philippe; Bénech, Henri

2010-08-30

344

Waste prevention in liquid detergent distribution: a comparison based on life cycle assessment.  

PubMed

The distribution of liquid detergents through self-dispensing systems has been adopted in some Italian retail stores over the last few years. By enabling the consumer to refill several times the same container, it is proposed as a less waste-generating and more environmentally friendly alternative to the traditional distribution with single-use plastic containers. For this reason, its implementation is encouraged by the national waste prevention programme recently adopted in Italy. In order to assess such claims, a life cycle assessment was carried out to evaluate whether detergent distribution through self-dispensing systems actually allows to achieve the expected reduction in waste generation and environmental impacts. The focus was on the distribution within the large-scale retail trade and on the categories of laundry detergents, fabric softeners and hand dishwashing detergents. For each of them, a set of baseline single-use scenarios were compared with two alternative waste prevention scenarios, where the detergent is distributed through self-dispensing systems. Beyond waste generation, also the Cumulative Energy Demand and thirteen midpoint-level potential impact indicators were calculated for the comparison. Results showed that a reduction in waste generation up to 98% can be achieved, depending on the category of detergent, on the baseline scenario of comparison and on the number of times the refillable container is used. A progressive reduction in the energy demand and in most of the potential impacts was also observed, starting from a minimum number of uses of the refillable container. PMID:25209251

Nessi, Simone; Rigamonti, Lucia; Grosso, Mario

2014-11-15

345

Distribution of nanoparticles throughout the cerebral cortex of rodents and non-human primates: Implications for gene and drug therapy  

PubMed Central

When nanoparticles/proteins are infused into the brain, they are often transported to distal sites in a manner that is dependent both on the characteristics of the infusate and the region targeted. We have previously shown that adeno-associated virus (AAV) is disseminated within the brain by perivascular flow and also by axonal transport. Perivascular distribution usually does not depend strongly on the nature of the infusate. Many proteins, neutral liposomes and AAV particles distribute equally well by this route when infused under pressure into various parenchymal locations. In contrast, axonal transport requires receptor-mediated uptake of AAV by neurons and engagement with specific transport mechanisms previously demonstrated for other neurotropic viruses. Cerebrospinal fluid (CSF) represents yet another way in which brain anatomy may be exploited to distribute nanoparticles broadly in the central nervous system. In this study, we assessed the distribution and perivascular transport of nanoparticles of different sizes delivered into the parenchyma of rodents and CSF in non-human primates. PMID:24672434

Salegio, Ernesto A.; Streeter, Hillary; Dube, Nikhil; Hadaczek, Piotr; Samaranch, Lluis; Kells, Adrian P.; San Sebastian, Waldy; Zhai, Yuying; Bringas, John; Xu, Ting; Forsayeth, John; Bankiewicz, Krystof S.

2014-01-01

346

Three-dimensional human arterial wall models for in vitro permeability assessment of drug and nanocarriers.  

PubMed

Monolayers of endothelial cells (1L-ECs) have been generally used as in vitro vascular wall models to study the vascular mechanisms and transport of substances. However, these two-dimensional (2D-) system cannot represent the properties of native vascular walls which have a 3D-structure and are composed of not only ECs, but also smooth muscle cells (SMCs) and other surrounding tissues. Here in, 5-layered (5L) 3D-arterial wall models (5L-AWMs) composed of EC monolayer and 4-layered SMCs were constructed by hierarchical cell manipulation. We applied the 5L-AWMs to evaluate their barrier function and permeability to nano-materials in order to analyze drug, or drug nanocarrier permeability to the blood vessel in vitro. Barrier property of the 3D-AWMs was confirmed by Zonula occludens (ZO-1) staining and their transendothelial electrical resistance (TEER), which was comparable to 1L-ECs, while the SMCs showed close to zero. The effect of substance size to permeability across the 5L-AWMs was clearly observed from dextrans with various molecular weights, which agreed well with the known phenomena of the in vivo blood vessels. Importantly, transport of nano-materials could be observed across the depth of 5L-AWMs, suggesting the advantage of 3D-AWMs over general 2D-systems. By using this system, we evaluate the transport of 35nm phenylalanine-modified poly(?-Glutamic Acid) nanoparticles (?-PGA-Phe NPs) as a candidate of biodegradable drug carrier. Interestingly, despite of having comparable size to dextran-2000k (28nm), the ?-PGA-Phe NPs distinctly showed approximately 20 times faster transport across the 5L-AWMs, suggesting the effect of intrinsic properties of the substance on the transport. This in vitro evaluation system using the 3D-AWMs is therefore useful for the design and development of nano-drug carriers for treatment of vascular diseases, such as atherosclerosis. PMID:25475732

Chetprayoon, Paninee; Matsusaki, Michiya; Akashi, Mitsuru

2015-01-01

347

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

PubMed

Orteronel is a nonsteroidal, selective inhibitor of 17,20-lyase that was recently in phase 3 clinical development as a treatment for castration-resistant prostate cancer. In humans, the primary clearance route for orteronel is renal excretion. Human liver microsomal studies indicated that orteronel weakly inhibits CYP1A2, 2C8, 2C9 and 2C19, with IC50 values of 17.8, 27.7, 30.8 and 38.8?µm, respectively, whereas orteronel does not inhibit CYP2B6, 2D6 or 3A4/5 (IC50 ?>?100?µm). Orteronel also does not exhibit time-dependent inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4/5. The results of a static model indicated an [I]/Ki ratio >0.1 for CYP1A2, 2C8, 2C9 and 2C19. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to assess the potential for drug-drug interactions (DDIs) between orteronel and theophylline, repaglinide, (S)-warfarin and omeprazole, which are sensitive substrates of CYP1A2, 2C8, 2C9 and 2C19, respectively. Simulation of the area under the plasma concentration-time curve (AUC) of these four CYP substrates in the presence and absence of orteronel revealed geometric mean AUC ratios <1.25. Therefore, in accordance with the 2012 US FDA Draft Guidance on DDIs, orteronel can be labeled a 'non-inhibitor' and further clinical DDI evaluation is not required. In PBPK models of moderate and severe renal impairment, the AUC of orteronel was predicted to increase by 52% and 83%, respectively. These results are in agreement with those of a clinical trial in which AUC increases of 38% and 87% were observed in patients with moderate and severe renal impairment, respectively. Copyright © 2014 John Wiley & Sons, Ltd. PMID:25264242

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

2014-12-01

348

Development and evaluation of an ITS1 "Touchdown" PCR for assessment of drug efficacy against animal African trypanosomosis.  

PubMed

Animal African trypanosomoses (AAT) are caused by flagellated protozoa of the Trypanosoma genus and contribute to considerable losses in animal production in Africa, Latin America and South East Asia. Trypanosoma congolense is considered the economically most important species. Drug resistant T. congolense strains present a threat to the control of AAT and have triggered research into discovery of novel trypanocides. In vivo assessment of trypanocidal efficacy relies on monitoring of treated animals with microscopic parasite detection methods. Since these methods have poor sensitivity, follow-up for up to 100 days after treatment is recommended to increase the chance of detecting recurrent parasitaemia waves. Molecular techniques are more amendable to high throughput processing and are generally more sensitive than microscopic detection, thus bearing the potential of shortening the 100-day follow up period. The study presents a "Touchdown" PCR targeting the internal transcribed spacer 1 of the ribosomal DNA (ITS1 TD PCR) that enables detection and discrimination of different Trypanosoma taxa in a single run due to variations in PCR product sizes. The assay achieves analytical sensitivity of 10 parasites per ml of blood for detection of T. congolense savannah type and T. brucei, and 100 parasites per ml of blood for detection of T. vivax in infected mouse blood. The ITS1 TD PCR was evaluated on cattle experimentally infected with T. congolense during an investigational new veterinary trypanocide drug efficacy study. ITS1 TD PCR demonstrated comparable performance to microscopy in verifying trypanocide treatment success, in which parasite DNA became undetectable in cured animals within two days post-treatment. ITS1 TD PCR detected parasite recrudescence three days earlier than microscopy and had a higher positivity rate than microscopy (84.85% versus 57.58%) in 66 specimens of relapsing animals collected after treatments. Therefore, ITS1 TD PCR provides a useful tool in assessment of drug efficacy against T. congolense infection in cattle. As the assay bears the potential for detection of mixed infections, it may be applicable for drug efficacy studies and diagnostic discrimination of T. vivax and T. congolense against other pathogenic trypanosomes, including T. brucei, T. evansi and T. equiperdum. PMID:24685024

Tran, Thao; Napier, Grant; Rowan, Tim; Cordel, Claudia; Labuschagne, Michel; Delespaux, Vincent; Van Reet, Nick; Erasmus, Heidi; Joubert, Annesca; Büscher, Philippe

2014-05-28

349

Drug deposition and distribution in healthy and atherosclerotic arteries and in models of atherosclerosis following bulk or stent-based drug delivery  

E-print Network

Drug eluting stents have revolutionized the practice of medicine and the landscape of medical devices. Yet, more than four years after introduction clinical trial data and clinical use have still not fully clarified what ...

Vukmirovic, Neda

2007-01-01

350

Cationic albumin nanoparticles for enhanced drug delivery to treat breast cancer: preparation and in vitro assessment.  

PubMed

Most anticancer drugs are greatly limited by the serious side effects that they cause. Doxorubicin (DOX) is an antineoplastic agent, commonly used against breast cancer. However, it may lead to irreversible cardiotoxicity, which could even result in congestive heart failure. In order to avoid these harmful side effects to the patients and to improve the therapeutic efficacy of doxorubicin, we developed DOX-loaded polyethylenimine- (PEI-) enhanced human serum albumin (HSA) nanoparticles. The formed nanoparticles were ~137?nm in size with a surface zeta potential of ~+15?mV, prepared using 20??g of PEI added per mg of HSA. Cytotoxicity was not observed with empty PEI-enhanced HSA nanoparticles, formed with low-molecular weight (25?kDa) PEI, indicating biocompatibility and safety of the nanoparticle formulation. Under optimized transfection conditions, approximately 80% of cells were transfected with HSA nanoparticles containing tetramethylrhodamine-conjugated bovine serum albumin. Conclusively, PEI-enhanced HSA nanoparticles show potential for developing into an effective carrier for anticancer drugs. PMID:22187654

Abbasi, Sana; Paul, Arghya; Shao, Wei; Prakash, Satya

2012-01-01

351

Radiation safety assessment of a system of small reactors for distributed energy.  

PubMed

A passively safe small reactor for a distributed energy system, PSRD, is an integral type of light-water reactor with a thermal output of 100 or 300 MW aimed to be used for supplying district heat, electricity to small grids, and so on. Candidate locations for the PSRD as a distributed energy source are on-ground, deep underground, and in a seaside pit in the vicinity of the energy consumption area. Assessments of the radiation safety of a PSRD were carried out for three cases corresponding to normal operation, shutdown and a hypothetical postulated accident for several siting candidates. Results of the radiation safety assessment indicate that the PSRD design has sufficient shielding performance and capability and that the exposure to the general public is very low in the case of a hypothetical accident. PMID:16381690

Odano, N; Ishida, T

2005-01-01

352

Assessing the power law hypothesis for the sizefrequency distribution of terrestrial and martian dust devils  

E-print Network

and martian dust devils A.V. Pathare a,*, M.R. Balme a , S.M. Metzger a , A. Spiga b,c , M.C. Towner d , N for the diameter dependence of terrestrial and martian dust devil frequency are assessed using new field observed dust devil size­frequency distributions are better fit by an exponential function than by a power

Spiga, Aymeric

353

In Vivo Assessment of Aqueous Humor Dynamics Upon Chronic Ocular Hypertension and Hypotensive Drug Treatment Using Gadolinium-Enhanced MRI  

PubMed Central

Purpose. Although glaucoma treatments alter aqueous humor (AH) dynamics to lower intraocular pressure, the regulatory mechanisms of AH circulation and their contributions to the pathogenesis of ocular hypertension and glaucoma remain unclear. We hypothesized that gadolinium-enhanced magnetic resonance imaging (Gd-MRI) can visualize and assess AH dynamics upon sustained intraocular pressure elevation and pharmacologic interventions. Methods. Gadolinium contrast agent was systemically administered to adult rats to mimic soluble AH components entering the anterior chamber (AC) via blood–aqueous barrier. Dynamic Gd-MRI was applied to examine the signal enhancement in AC and vitreous body upon microbead-induced ocular hypertension and unilateral topical applications of latanoprost, timolol maleate, and brimonidine tartrate to healthy eyes. Results. Gadolinium signal time courses in microbead-induced hypertensive eyes possessed faster initial gadolinium uptake and higher peak signals in AC than control eyes, reflective of reduced gadolinium clearance upon microbead occlusion. Opposite trends were observed in latanoprost- and timolol-treated eyes, indicative of their respective drug actions on increased uveoscleral outflow and reduced AH production. The slowest initial gadolinium uptake but strongest peak signals were found in AC of both brimonidine-treated and untreated fellow eyes. These findings drew attention to the systemic effects of topical hypotensive drug treatment. Gadolinium leaked into the vitreous of microbead-induced hypertensive eyes and brimonidine-treated and untreated fellow eyes, suggestive of a compromise of aqueous–vitreous or blood–ocular barrier integrity. Conclusions. Gadolinium-enhanced MRI allows spatiotemporal and quantitative evaluation of altered AH dynamics and ocular tissue permeability for better understanding the physiological mechanisms of ocular hypertension and the efficacy of antiglaucoma drug treatments. PMID:24764067

Ho, Leon C.; Conner, Ian P.; Do, Chi-Wai; Kim, Seong-Gi; Wu, Ed X.; Wollstein, Gadi; Schuman, Joel S.; Chan, Kevin C.

2014-01-01

354

Drug Absorption Principles  

Microsoft Academic Search

Pharmacokinetics describes drug absorption, distribution, metabolism, and excretion processes. Absorption is the rate and\\u000a extent at which drugs reach the systemic circulation from the site of administration. Distribution of a drug includes all\\u000a the processes that are involved from the time when the drug reaches the circulation to the time when it (or a metabolite of\\u000a the drug) leaves the

Xianhua Cao; Lawrence X. Yu; Duxin Sun

355

In vitro assessment of the adverse effects of antiretroviral drugs on the human male gamete.  

PubMed

This study was designed to investigate the in vitro effects of didanosine, zidovudine, saquinavir and indinavir, commonly used in highly active antiretroviral therapy, on human sperm fertility parameters. Thirty semen samples from healthy men were collected and prepared by gradient density method. Aliquots of 90% fractions with >80% motile spermatozoa were incubated for 1, 3, and 6h with different concentrations of the antiretroviral drugs (20, 40, and 80 ?g/ml). Sperm motility was evaluated by computer assisted sperm analysis system. Sperm mitochondrial potential was evaluated using 3,3'-dihexyloxacarbocyanine iodide (DIOC(6)) and the acrosome reaction was examined using pisum sativum agglutinin method. A dose-dependent decrease in sperm motility was observed with saquinavir. Saquinavir also induced a significant time and dose-dependent decrease in mitochondrial potential and an increase in spontaneous acrosome reaction. These findings indicate that, in vitro, higher doses of saquinavir have adverse effects on sperm motility, mitochondrial potential and acrosome reaction. PMID:21130153

Ahmad, G; Moinard, N; Jouanolou, V; Daudin, M; Gandia, P; Bujan, L

2011-03-01

356

Human Tumor Xenograft Models for Preclinical Assessment of Anticancer Drug Development  

PubMed Central

Xenograft models of human cancer play an important role in the screening and evaluation of candidates for new anticancer agents. The models, which are derived from human tumor cell lines and are classified according to the transplant site, such as ectopic xenograft and orthotopic xenograft, are still utilized to evaluate therapeutic efficacy and toxicity. The metastasis model is modified for the evaluation and prediction of cancer progression. Recently, animal models are made from patient-derived tumor tissue. The patient-derived tumor xenograft models with physiological characters similar to those of patients have been established for personalized medicine. In the discovery of anticancer drugs, standard animal models save time and money and provide evidence to support clinical trials. The current strategy for using xenograft models as an informative tool is introduced. PMID:24795792

2014-01-01

357

Soil texture distribution simulation and risk assessment using transition probability-based geostatistics  

NASA Astrophysics Data System (ADS)

Three dimensional soil textural structure in a township was conditionally simulated using a transition probability- based indicator geostatistical method based on 270 soil texture samples from 27 profiles. Additionally the distribution of soil profiles lacking clay interlayers (indicating high irrigation water and nutrient leaching risk) was analyzed using 500 realizations from the simulation. The results indicated that the simulation could predict the soil texture distribution with low uncertainties using the existing data, and the predicted soil map (0-10 cm) formed by the maximum probable soil textures also exhibited a good agreement with the legacy soil survey map. For water and nutrient leaching risk analysis, the areas lacking clay interlayer could be located; however, their distribution was still highly uncertain if based only on the existing sampling data. That means supplementary sampling in future is required for the risk assessment, and the existing study can help to optimise the sampling points and their distribution. Generally, the transition probability-based geostatistical simulation, as a stochastic conditional simulation method, exhibited its potential in soil texture spatial reproduction and related risk assessment.

Li, Xiaopeng; Liu, Jianli; Zhang, Jiabao; Wang, Weipeng; Xin, Wenwen

2014-10-01

358

Validation of the human ozone challenge model as a tool for assessing anti-inflammatory drugs in early development.  

PubMed

This study aimed to test the utility of the ozone challenge model for profiling novel compounds designed to reduce airway inflammation. The authors used a randomized, double-dummy, double-blind, placebo-controlled 3-period crossover design alternating single orally inhaled doses of fluticasone propionate (inhaled corticosteroids, 2 mg), oral prednisolone (oral corticosteroids, 50 mg), or matched placebo. At a 2-week interval, 18 healthy ozone responders (>10% increase in sputum neutrophils) underwent a 3-hour ozone (250 ppb)/intermittent exercise challenge starting 1 hour after drug treatment. Airway inflammation was assessed at 2 hours (breath condensate) and 3 hours (induced sputum) after ozone challenge. Compared to placebo, pretreatment with inhaled corticosteroids or oral corticosteroids resulted in a significant reduction (mean [95% confidence interval]) of sputum neutrophils by 62% (35%, 77%) and 64% (39%, 79%) and of sputum supernatant myeloperoxidase by 55% (41%, 66%) and 42% (25%, 56%), respectively. The authors conclude that an optimized ozone challenge model (including ozone responders and ensuring adequate drug levels during exposure) may be useful for testing novel anti-inflammatory compounds in early development. PMID:15831772

Holz, Olaf; Tal-Singer, Ruth; Kanniess, Frank; Simpson, Kathy J; Gibson, Anthony; Vessey, Rupert S J; Janicki, Stanislawa; Magnussen, Helgo; Jörres, Rudolf A; Richter, Kai

2005-05-01

359

Comparative risk assessment of alcohol, tobacco, cannabis and other illicit drugs using the margin of exposure approach  

PubMed Central

A comparative risk assessment of drugs including alcohol and tobacco using the margin of exposure (MOE) approach was conducted. The MOE is defined as ratio between toxicological threshold (benchmark dose) and estimated human intake. Median lethal dose values from animal experiments were used to derive the benchmark dose. The human intake was calculated for individual scenarios and population-based scenarios. The MOE was calculated using probabilistic Monte Carlo simulations. The benchmark dose values ranged from 2?mg/kg bodyweight for heroin to 531?mg/kg bodyweight for alcohol (ethanol). For individual exposure the four substances alcohol, nicotine, cocaine and heroin fall into the “high risk” category with MOE < 10, the rest of the compounds except THC fall into the “risk” category with MOE < 100. On a population scale, only alcohol would fall into the “high risk” category, and cigarette smoking would fall into the “risk” category, while all other agents (opiates, cocaine, amphetamine-type stimulants, ecstasy, and benzodiazepines) had MOEs > 100, and cannabis had a MOE > 10,000. The toxicological MOE approach validates epidemiological and social science-based drug ranking approaches especially in regard to the positions of alcohol and tobacco (high risk) and cannabis (low risk). PMID:25634572

Lachenmeier, Dirk W.; Rehm, Jürgen

2015-01-01

360

Analysis of drugs of abuse by online SPE-LC high resolution mass spectrometry: Communal assessment of consumption.  

PubMed

An online SPE-LC-HRMS method was developed to monitor the consumption of 18 drugs of abuse (DOAs) including amphetamines, opioids, cocainics, cannabinoids, lysergics, and their corresponding metabolites in a well characterized college campus setting via wastewater analysis. Filtered and diluted (10×) sewage water samples (5mL inj.) were automatically pre-concentrated and analyzed in 15min using a Thermo EQuan MAX online SPE system equipped with a HyperSep™ Retain PEP (20×2.1mm×12?m) SPE column and a Hypersil Gold™ aQ (150×2.1mm×3?m) analytical column. A Q Exactive™ Hybrid Quadrupole-Orbitrap HRMS was used in full scan mode (R=140,000) for positive identification, and quantitation of target compounds. Method detection limits for all analytes ranged between 0.6 and 1.7ng/L in sewage. A total of 14 DOAs were detected from two different locations (dorms and main college campus) within a one-year period. Most frequently detected drugs throughout the entire study were amphetamine (>96%) and THC's metabolite 11-nor-9-carboxy-?-9-THC (>100%) with maximum concentrations of 5956 and 2413ng/L respectively. Daily doses per 1000 people were determined in order to assess consumption of THC, amphetamine, heroin and cocaine, in both dorms and main campus. PMID:25553546

Heuett, Nubia V; Ramirez, Cesar E; Fernandez, Adolfo; Gardinali, Piero R

2015-04-01

361

Comparative risk assessment of alcohol, tobacco, cannabis and other illicit drugs using the margin of exposure approach.  

PubMed

A comparative risk assessment of drugs including alcohol and tobacco using the margin of exposure (MOE) approach was conducted. The MOE is defined as ratio between toxicological threshold (benchmark dose) and estimated human intake. Median lethal dose values from animal experiments were used to derive the benchmark dose. The human intake was calculated for individual scenarios and population-based scenarios. The MOE was calculated using probabilistic Monte Carlo simulations. The benchmark dose values ranged from 2?mg/kg bodyweight for heroin to 531?mg/kg bodyweight for alcohol (ethanol). For individual exposure the four substances alcohol, nicotine, cocaine and heroin fall into the "high risk" category with MOE < 10, the rest of the compounds except THC fall into the "risk" category with MOE < 100. On a population scale, only alcohol would fall into the "high risk" category, and cigarette smoking would fall into the "risk" category, while all other agents (opiates, cocaine, amphetamine-type stimulants, ecstasy, and benzodiazepines) had MOEs > 100, and cannabis had a MOE > 10,000. The toxicological MOE approach validates epidemiological and social science-based drug ranking approaches especially in regard to the positions of alcohol and tobacco (high risk) and cannabis (low risk). PMID:25634572

Lachenmeier, Dirk W; Rehm, Jürgen

2015-01-01

362

Independent Orbiter Assessment (IOA): Analysis 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 approach features a top-down analysis of the hardware to determine failure modes, criticality, and potential critical items. To preserve independence, this analysis was accomplished without reliance upon the results contained within the NASA FMEA/CIL documentation. This report documents the independent analysis results corresponding to the Orbiter Electrical Power Distribution and Control (EPD and C) hardware. The EPD and C hardware performs the functions of distributing, sensing, and controlling 28 volt DC power and of inverting, distributing, sensing, and controlling 117 volt 400 Hz AC power to all Orbiter subsystems from the three fuel cells in the Electrical Power Generation (EPG) subsystem. Volume 2 continues the presentation of IOA analysis worksheets and contains the potential critical items list.

Schmeckpeper, K. R.

1987-01-01

363

Assessment of the effect of vasodilators on the distribution of cardiac output by whole-body Thallium imaging  

SciTech Connect

Vasodilator therapy (tx) of congestive heart failure (CHF) has been shown to be effective in increasing cardiac output (CO) and lowering vascular resistance. Unfortunately, these hemodynamic effects are not usually accompanied by improved peripheral circulation of exercise capacity. To assess the effect of a new vasodilator, Cl-914, on the redistribution of CO to the peripheral circulation, the authors performed testing whole-body thallium scanning (WB-Th) on 6 patients (pts) with severe CHF. Immediately following i.v. injection of 1.5 mCi Th-201, WB scanning was performed from anterior and posterior views. Regions of interest were defined for the peripheral (P) muscles (legs and arms), central torso (C), and splanchnic bed (S). The geometric mean of activity in these regions was calculated from both views. Each pt was studied before tx and again, after 1 week on tx. Invasive measurements revealed that all pts had significant improvements in resting cardiac output (mean increase 49%) and vascular resistance (mean decrease 30%). Unlike other vasodilators, all CI-914 pts had a significant improvement in treadmill exercise capacity (mean increase 54%). WB-Th revealed a significant shift in CO to the peripheral circulation with P:C increased 33.2% (rho= .001) and P:S increased 29% (rho=.01). Vasoactive drugs may significantly alter the relative distribution of cardiac output. WB-Th scanning provides a simple quantitative means of following such changes.

Juni, J.E.; Wallis, J.; Diltz, E.; Nicholas, J.; Lahti, D.; Pitt, B.

1985-05-01

364

Religiosity and HIV-related drug risk behavior: a multidimensional assessment of individuals from communities with high rates of drug use  

PubMed Central

We examined the relationship between religiosity and HIV-related drug risk behavior among individuals from communities with high rates of drug use who participated in the SHIELD (Self-Help in Eliminating Life Threatening Disease) study. This analysis examined the dimensions of religious ideation, religious participation and religious support separately to further understand the relationship with risk taking. Results indicate that greater religious participation appeared to be the dimension most closely associated with drug behaviors. Specifically, we found that those with greater religious participation are significantly less likely to report recent opiates or cocaine use; injection drug use; crack use; needle, cotton or cooker sharing. Future work to understand the nature of these associations will assist in the development of interventions in communities with high rates of drug use. PMID:22399161

Billioux, Veena G.; Sherman, Susan G.; Latkin, Carl A.

2012-01-01

365

Development of an in vitro cytochrome P450 cocktail inhibition assay for assessing the inhibition risk of drugs of abuse.  

PubMed

Drugs of abuse are not tested for cytochrome P450 (CYP) inhibition potential before distribution. Therefore, a cocktail assay should be developed for testing the inhibition potential for all relevant CYPs. The following CYP test substrates and selective inhibitors were incubated in pooled human liver microsomes: phenacetin (alpha-naphthoflavone for CYP1A2), coumarin (tranylcypromine, CYP2A6), bupropion (sertraline, CYP2B6), amodiaquine (trimethoprim, CYP2C8), diclofenac (sulfaphenazole, CYP2C9), omeprazole (fluconazole, CYP2C19), dextromethorphan (quinidine, CYP2D6), chlorzoxazone (clomethiazole, CYP2E1), testosterone (verapamil, CYP3A). Samples were analyzed after protein precipitation using a Thermo Fisher Q-Exactive LC-high-resolution-MS/MS. The IC50 values were calculated by plotting the concentration of the formed metabolite, relative to the control sample, over the logarithm of the inhibitor concentration. They were determined either for single substrate or the cocktail incubation. Unfortunately, the cocktail assay had to be split because of interferences during incubation caused by substrates or metabolites, but the mixture of both incubates could be analyzed in one analytical run. The IC50 values determined in the single substrate or both cocktail incubations were comparable among themselves and with published data. In conclusion, the new inhibition cocktail assay was reproducible and applicable for testing the inhibition potential of drugs of abuse as exemplified for 2,5-dimethoxy-4-iodo-amfetamine (DOI). PMID:25111188

Dinger, Julia; Meyer, Markus R; Maurer, Hans H

2014-10-01

366

Drug pharmacokinetics and pharmacodynamics: Technological considerations  

SciTech Connect

Additionally, the use of PET to examine drug pharmacokinetics and pharmacadynamics and the relationship of these properties to the behavioral, therapeutic and toxic properties of drugs and substances of abuse is emerging as a powerful new scientific tool. The pharmacokinetic properties of a drug, which comprises all of the biological processes which determine the fraction of the drug available, can be measured using the labeled drug itself. For example, the labeled drug can be used to measure the absolute uptake, regional distribution and kinetics of a drug at its site of action in the body. Additionally the labeled drug and whole body its labeled metabolites and thus provide information an potential toxic effects as well as tissue half lives. On the other hand, different labeled tracers can be used to assess drug pharmacodynamics which include the biological Processes involved in the drug`s effects. For example, with appropriate radiotracers, the effects of a drug on metabolism, neurotransmitter activity, blood flew, enzyme activity or other processes can be probed.

Fowler, J.S.; Volkow, N.D.; Wolf, A.P.

1992-12-31

367

Assessment of New Immunosuppressive Drugs in a Rat Cardiac Allograft Heterotopic Model  

Microsoft Academic Search

We assessed FK506 (FK) and rapamycin (RPM) in a heterotopic abdominal rat heart transplant model using a major histocompatibility mismatch (DA to LEW). The end point of our study was histologic grading of rejection (Billingham and working formulation) at 1 week. Two doses of FK (2.0 and 8.0mg\\/kg p.o., q.d.) and RPM (1.5 and 6.0mg\\/kg i.p., q.d.) were compared to

B. Walpoth; J. Galdikas; T. Vorburger; H. J. Altermatt; T. Schaffner; U. Althaus; M. Billingham; R. Morris

1992-01-01

368

High frequency resonant waveguide grating imager for assessing drug-induced cardiotoxicity  

NASA Astrophysics Data System (ADS)

We report a high-frequency resonant waveguide grating imager for assessing compound-induced cardiotoxicity. The imager sweeps the wavelength range from 823 nm to 838 nm every 3 s to identify and monitor compound-induced shifts in resonance wavelength and then switch to the intensity-imaging mode to detect the beating rhythm and proarrhythmic effects of compounds on induced pluripotent stem cell-derived cardiomyocytes. This opens possibility to study cardiovascular biology and compound-induced cardiotoxicity.

Ferrie, Ann M.; Wu, Qi; Deichmann, Oberon D.; Fang, Ye

2014-05-01

369

A novel QSAR model of Salmonella mutagenicity and its application in the safety assessment of drug impurities  

SciTech Connect

As indicated in ICH M7 draft guidance, in silico predictive tools including statistically-based QSARs and expert analysis may be used as a computational assessment for bacterial mutagenicity for the qualification of impurities in pharmaceuticals. To address this need, we developed and validated a QSAR model to predict Salmonella t. mutagenicity (Ames assay outcome) of pharmaceutical impurities using Prous Institute's Symmetry?, a new in silico solution for drug discovery and toxicity screening, and the Mold2 molecular descriptor package (FDA/NCTR). Data was sourced from public benchmark databases with known Ames assay mutagenicity outcomes for 7300 chemicals (57% mutagens). Of these data, 90% was used to train the model and the remaining 10% was set aside as a holdout set for validation. The model's applicability to drug impurities was tested using a FDA/CDER database of 951 structures, of which 94% were found within the model's applicability domain. The predictive performance of the model is acceptable for supporting regulatory decision-making with 84 ± 1% sensitivity, 81 ± 1% specificity, 83 ± 1% concordance and 79 ± 1% negative predictivity based on internal cross-validation, while the holdout dataset yielded 83% sensitivity, 77% specificity, 80% concordance and 78% negative predictivity. Given the importance of having confidence in negative predictions, an additional external validation of the model was also carried out, using marketed drugs known to be Ames-negative, and obtained 98% coverage and 81% specificity. Additionally, Ames mutagenicity data from FDA/CFSAN was used to create another data set of 1535 chemicals for external validation of the model, yielding 98% coverage, 73% sensitivity, 86% specificity, 81% concordance and 84% negative predictivity. - Highlights: • A new in silico QSAR model to predict Ames mutagenicity is described. • The model is extensively validated with chemicals from the FDA and the public domain. • Validation tests show desirable high sensitivity and high negative predictivity. • The model predicted 14 reportedly difficult to predict drug impurities with accuracy. • The model is suitable to support risk evaluation of potentially mutagenic compounds.

Valencia, Antoni; Prous, Josep; Mora, Oscar [Prous Institute for Biomedical Research, Rambla de Catalunya, 135, 3-2, Barcelona 08008 (Spain); Sadrieh, Nakissa [Office of Pharmaceutical Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993-0002 (United States); Valerio, Luis G., E-mail: luis.valerio@fda.hhs.gov [Office of Pharmaceutical Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993-0002 (United States)

2013-12-15

370

Nitroxide derivatives for imaging of hypercholesterolemia-induced kidney dysfunction and assessing the effectiveness of antilipidemic drugs.  

PubMed

The present study was designed to clarify the possibility for application of nitroxide derivatives in magnetic resonance imaging (MRI) of hypercholesterolemia-mediated renal dysfunction in mice, as well as to assess the effectiveness of antilipidemic drugs (cholestyramine and ezetimibe). The mice were separated in four groups: (i) on a normal diet (ND) without medication (control); (ii) on a high cholesterol diet (CD) without medication; (iii) CD mice receiving cholestyramine; and (iv) CD mice receiving ezetimibe. In CD mice without medication, a hypercholesterolemia was developed, detected by the increasing of total plasma cholesterol and non-HDL cholesterol, and decreasing of HDL cholesterol. The hypercholesterolemia compromised renal function: blood urea nitrogen, creatine and uric acid increased significantly, accompanied with development of glomerulosclerosis, enhancement of the amount of neutrophils and overexpression of metalloproteinase-9. The mice were subjected to anesthesia and MR imaging was performed on 7 T magnet (T1-weighted incoherent gradient-echo sequence; fast low-angle shot). The region-of-interest was selected within the kidney. The images were obtained before and after injection of contrast probe [carbamoyl-PROXYL (CMP) or Gd-DTPA]. In the kidney of ND mice, the MRI signal intensity increased after injection of CMP, reached a maximum (very well-defined renal filtration peak) and decreased to the baseline level within 14 min. In kidney of CD mice, the CMP-mediated enhancement of MRI signal was not detected. Antilipidemic drugs patially abolished the effect of hypercholesterolemia on CMP-enhanced MRI in the kidney. The kinetic curves of Gd-enhanced MRI signal had also different profiles in the kidney of ND and CD mice. They were similar to the profiles of the kinetic curves, obtained from MR urography of healthy human and human with renal pathology, respectively. The present study suggests that CMP is a suitable MRI contrast probe for visualization of hypercholesterolemia-induced renal dysfunction in intact animals and the assessment of the efficacy of antilipidemic drugs. The probe was applied at a concentration that was 3 times lower than the LD50 for intravenous administration in mice. Since the probe is excreted by the kidney, it could be considered harmless for mammalians in the selected dose and appropriate candidate for translational research. PMID:21744874

Tomizawa, Atsuyuki; Hadjidekov, George; Ishii, Itsuko; Bakalova, Rumiana; Zhelev, Zhivko; Aoki, Ichio; Saga, Tsuneo; Kitada, Mitsukazu

2011-10-01

371

Assessment trials of the therapeutic efficacy of the drug "Zovirax" in some recurrent ocular and genital herpetic infections.  

PubMed

In this work are reported the results of the researches performed by the authors more than a decade ago, aimed at assessing the clinical benefit of the introduction of the drug "Zovirax" in the treatment of recurrent herpetic infections with genital or ocular location. The results of the treatment carried out on a restricted group of patients were positive both in cases of genital herpes and of herpetic keratitis. The clinical benefit consisted in the reduction of the mean duration of the disease, in the shortening of the period of the infective virus elimination from the lesion, as well as in the decrease of the intensity and duration of the clinical symptomatology as a whole. With respect to these clinical parameters, the observations of the authors performed on a low number of cases are consistent with the data obtained by other authors in the framework of more extensive studies. The renewed discussion of these clinical and laboratory observations carried out by the authors during the first years after the introduction in our country of this drug in the therapeutic arsenal of herpetic infections is aimed at establishing a landmark for the comparison with more recent results of similar studies, starting from the idea of the opportunity of assessing periodically the sensitivity of herpes simplex virus strains, circulating among the autochthonous population, to the inhibitory action of some antiviral drugs. In other words, the in vitro testing of the susceptibility of these strains to the chemotherapeutic agents in current use is predictive for the efficacy degree of these drugs in the treatment of some forms of herpetic infections. This evaluation represents at the same time, undoubtedly, a useful epidemiological surveillance means of the circulation of human herpes viruses among the population. We refer especially to the risk of appearance of pharmacoresistant mutants, a risk possible under the conditions of the increased access of patients to the antiviral chemotherapeutic medication, which implicitly augments the probability of a fortuitous administration of treatments insufficient as regards the dose or the duration. In this work there are also shown the results regarding some experimental aspects related to the immune control mechanisms of the herpetic infection, which may complement the chemotherapeutic action. Under the treatment with acycloguanosine the synthesis of herpetic antigens is kept at a level sufficient for the circulating antibody synthesis induction and the HSV infected cells treated with the drug are recognized and lysed by effectors of the cell-mediated immune response of the host. Hence, it may be asserted that, in some clinical cases of recurrent herpes with frequent episodes, it is useful to perform immunostimulating treatments, able to potentiate the cell-mediated immune mechanisms possibly involved in the limitation of the herpetic infection at the peripheral level and of its spreading in the central nervous system. PMID:10892424

Mu?iu, A; Sahnazarov, N; Cri?an, I

1998-01-01

372

A unique drug distribution process for radium Ra 223 dichloride injection and its implication for product quality, patient privacy, and delineation of professional responsibilities.  

PubMed

On May 15, 2013, Bayer Healthcare Pharmaceuticals announced that it had received marketing approval for the therapeutic radioactive medication radium Ra 223 dichloride injection (Xofigo; Ra 223). The product acquisition and distribution process for hospital-based nuclear pharmacies and nuclear medicine services is unlike any other. The product is distributed as a low-risk compounded sterile preparation through a single compounding nuclear pharmacy located in Denver, Colorado, pursuant to a prescription. This model for drug distribution and delivery to the user institution has implications for product quality, patient privacy, and delineation of professional responsibilities. PMID:25301826

Dansereau, Raymond N

2014-11-01

373

Effect of sampling and diagnostic effort on the assessment of schistosomiasis and soil-transmitted helminthiasis and drug efficacy: a meta-analysis of six drug efficacy trials and one epidemiological survey.  

PubMed

SUMMARY It is generally recommended to perform multiple stool examinations in order to improve the diagnostic accuracy when assessing the impact of mass drug administration programmes to control human intestinal worm infections and determining efficacy of the drugs administered. However, the collection and diagnostic work-up of multiple stool samples increases costs and workload. It has been hypothesized that these increased efforts provide more accurate results when infection and drug efficacy are summarized by prevalence (proportion of subjects infected) and cure rate (CR, proportion of infected subjects that become egg-negative after drug administration), respectively, but not when these indicators are expressed in terms of infection intensity and egg reduction rate (ERR). We performed a meta-analysis of six drug efficacy trials and one epidemiological survey. We compared prevalence and intensity of infection, CR and ERR based on collection of one or two stool samples that were processed with single or duplicate Kato-Katz thick smears. We found that the accuracy of prevalence estimates and CR was lowest with the minimal sampling effort, but that this was not the case for estimating infection intensity and ERR. Hence, a single Kato-Katz thick smear is sufficient for reporting infection intensity and ERR following drug treatment. PMID:24725546

Levecke, Bruno; Brooker, Simon J; Knopp, Stefanie; Steinmann, Peter; Sousa-Figueiredo, Jose Carlos; Stothard, J Russell; Utzinger, Jürg; Vercruysse, Jozef

2014-12-01

374

Pharmaceutical characterization and thermodynamic stability assessment of a colloidal iron drug product: iron sucrose.  

PubMed

The study objective was to evaluate the thermodynamic stability of iron sucrose complexes as determined by molecular weight (m.w.) changes. The first part of the study focused on the effect of thermal stress, pH, electrolyte or excipient dilution on the stability of a colloidal iron drug product. Part two focused on the physical and chemical evaluation of the colloidal nature of iron sucrose using a series of characterization experiments: ultracentrifugation, dialysis, particle size, zeta potential, and osmotic pressure analysis. A validated Taguchi-optimized high performance gel permeation chromatography method was used for m.w. determinations. Results indicate m.w. of the iron sucrose complex remained unchanged after excipient dilution, ultracentrifugation, dialysis, and electrolyte dilution. Electrolyte dilution studies indicated the lyophilic nature of the iron sucrose colloid with a particle size of 10nm and zeta potential of 0 mV. The complex deformed at low pH and reformed back at the formulation pH. The complex is stable under mild-to-moderate temperature <50°C but aggregates following prolonged exposure to high temperatures >70°C. In conclusion, the resistance of the complex to breakdown by electrolytic conditions, excipient dilution, ultracentrifugation and the reversible complexation after alteration of formulation pH suggest iron sucrose is a lyophilic colloid in nature and lyophilic colloidals are thermodynamically stable. PMID:24440404

Shah, Rakhi B; Yang, Yongsheng; Khan, Mansoor A; Raw, Andre; Yu, Lawrence X; Faustino, Patrick J

2014-04-10

375

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. 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.

2012-01-01

376

Time-of-flight secondary ion mass spectrometry study on the distribution of alendronate sodium in drug-loaded ultra-high molecular weight polyethylene.  

PubMed

The aim of this study was to investigate the drug distribution in ultra-high molecular weight polyethylene (UHMWPE) loaded with alendronate sodium (ALN), which was developed to treat particle-induced osteolysis after artificial joint replacements, since the drug distribution in UHMWPE could play a key role in controlling drug release. A mixture of UHMWPE powder and ALN was dried and hot pressed to prepare UHMWPE loaded with ALN (UHMWPE-ALN). Fourier transform infrared spectroscopy analysis demonstrated that the hot press had no effect on the functional groups of ALN in UHMWPE-ALN. X-ray diffraction indicated that there was no phase change of the UHMWPE after hot pressing. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) spectra revealed the existence of characteristic elements and functional groups from ALN in UHMWPE-ALN, such as Na+, C3H8N+, PO3(-) and PO3H(-). In addition, SIMS images suggested that ALN did not agglomerate in UHMWPE-ALN. A small punch test and hardness test were carried out and the results indicated that ALN did not affect the mechanical properties at the present content level. The present study demonstrated that it was feasible to fabricate the un-agglomerated distributed drug in UHMWPE with good mechanical properties. This ALN loaded UHMWPE would have potential application in clinics. PMID:19966382

Liu, Xiaomin; Qu, Shuxin; Lu, Xiong; Ge, Xiang; Leng, Yang

2009-12-01

377

Assessing the Spatial Scale Effect of Anthropogenic Factors on Species Distribution  

PubMed Central

Patch context is a way to describe the effect that the surroundings exert on a landscape patch. Despite anthropogenic context alteration may affect species distributions by reducing the accessibility to suitable patches, species distribution modelling have rarely accounted for its effects explicitly. We propose a general framework to statistically detect the occurrence and the extent of such a factor, by combining presence-only data, spatial distribution models and information-theoretic model selection procedures. After having established the spatial resolution of the analysis on the basis of the species characteristics, a measure of anthropogenic alteration that can be quantified at increasing distance from each patch has to be defined. Then the distribution of the species is modelled under competing hypotheses: H0, assumes that the distribution is uninfluenced by the anthropogenic variables; H1, assumes the effect of alteration at the species scale (resolution); and H2, H3 … Hn add the effect of context alteration at increasing radii. Models are compared using the Akaike Information Criterion to establish the best hypothesis, and consequently the occurrence (if any) and the spatial scale of the anthropogenic effect. As a study case we analysed the distribution data of two insular lizards (one endemic and one naturalised) using four alternative hypotheses: no alteration (H0), alteration at the species scale (H1), alteration at two context scales (H2 and H3). H2 and H3 performed better than H0 and H1, highlighting the importance of context alteration. H2 performed better than H3, setting the spatial scale of the context at 1 km. The two species respond differently to context alteration, the introduced lizard being more tolerant than the endemic one. The proposed approach supplies reliably and interpretable results, uses easily available data on species distribution, and allows the assessing of the spatial scale at which human disturbance produces the heaviest effects. PMID:23825669

Mangiacotti, Marco; Scali, Stefano; Sacchi, Roberto; Bassu, Lara; Nulchis, Valeria; Corti, Claudia

2013-01-01

378

Distribution and quantitative assessment of world crude oil reserves and resources  

USGS Publications Warehouse

World Demonstrated Reserves of crude oil are approximately 723 billion barrels of oil (BBO). Cumulative production is 445 BBO and annual production is 20 BBO. Demonstrated Reserves of crude-oil have declined over the past 10 years consistent with discoveries lagging production over the same period. The assessment of Undiscovered Resources shows a 90 percent probability that the amount discoverable lies between 321 and 1,417 BBO, 550 BBO being the most likely value. The most likely value for Ultimate recoverable resources is 1,718 BBO. The distribution of Ultimate Resources of crude oil will remain highly skewed toward the Middle East; no frontier areas that have potentials large enough to significantly affect present distribution are recognized. Rates of discovery have continued to decline over the past 20 years even though exploration activity has increased in recent years. Prudence dictates, therefore, that the low side of the assessment of Undiscovered Resources be responsibly considered and that alternate energy sources be a part of future planning. Extra-heavy oil and bitumen are assessed separately, with Reserves being figured as the annual productive capacity of installed facilities times 25 years. The annual production of extra-heavy oil is about 8 million barrels and of bitumen about 60 million barrels.

Masters, Charles D.; Root, David H.; Dietzman, William D.

1983-01-01

379

Hospital distribution in a metropolitan city: assessment by a geographic information system grid modelling approach.  

PubMed

Grid models were used to assess urban hospital distribution in Seoul, the capital of South Korea. A geographical information system (GIS) based analytical model was developed and applied to assess the situation in a metropolitan area with a population exceeding 10 million. Secondary data for this analysis were obtained from multiple sources: the Korean Statistical Information Service, the Korean Hospital Association and the Statistical Geographical Information System. A grid of cells measuring 1 × 1 km was superimposed on the city map and a set of variables related to population, economy, mobility and housing were identified and measured for each cell. Socio-demographic variables were included to reflect the characteristics of each area. Analytical models were then developed using GIS software with the number of hospitals as the dependent variable. Applying multiple linear regression and geographically weighted regression models, three factors (highway and major arterial road areas; number of subway entrances; and row house areas) were statistically significant in explaining the variance of hospital distribution for each cell. The overall results show that GIS is a useful tool for analysing and understanding location strategies. This approach appears a useful source of information for decision-makers concerned with the distribution of hospitals and other health care centres in a city. PMID:24893031

Lee, Kwang-Soo; Moon, Kyeong-Jun

2014-05-01

380

Thoughts on the current assessment of Polo-like kinase inhibitor drug discovery.  

PubMed

The Polo-like kinase 1 (Plk1) plays a key role in regulating a broad spectrum of critical cell cycle events. Plk1 is a marker of cellular proliferation and has prognostic potential in different types of human tumors. In a series of preclinical studies, Plk1 has been validated as a cancer target. This prompted many pharmaceutical companies to develop small-molecule inhibitors targeting the classical ATP-binding site of Plk1 for anticancer drug development. Recently, FDA has granted a Breakthrough Therapy designation to the Plk inhibitor BI 6727 (volasertib), which provided a survival benefit for patients suffering from acute myeloid leukemia. Remarkably, a new generation of Plk1 inhibitors that target the second druggable domain of Plk1, the Polo-box domain, is currently being tested preclinically. Since various ATP-competitive compounds of Plk1 inhibit also the activities of Plk2 and Plk3, which act as tumor suppressors, the roles of closely related Plk-family members in cancer cells need to be considered carefully. In this article, the authors highlight recent insights into the biology of Plks in cancer cells and discuss the progress in the development of small-molecule Plk1 inhibitors. The authors believe that the greatest therapeutic benefit might come through leukemic cells that are in direct contact with the inhibitor in the blood stream. The identification of biomarkers and studies that document Plk activities in treated patients would also be beneficial to better understand the role of Plk inhibition in tumor development and anticancer therapy. PMID:25263688

Strebhardt, Klaus; Becker, Sven; Matthess, Yves

2015-01-01

381

Drug-protein interactions assessed by fluorescence measurements in the real complexes and in model dyads  

NASA Astrophysics Data System (ADS)

In the present work, a systematic fluorescence study on supramolecular systems using two serum albumins (HSA or BSA) as hosts and the nonsteroidal antiinflammatory drugs carprofen (CPF) or naproxen (NPX) as guests has been undertaken. In parallel, model dyads containing Tyr or Trp covalently linked to CPF or NPX have also been investigated. In HSA/(S)-CPF and BSA/(S)-CPF ( ?exc = 266 nm), at 1:1 M ratio, an important degree (more than 40%) of singlet-singlet energy transfer (SSET) was observed to take place. The distance ( r) calculated for energy transfer from the SAs to (S)-CPF through a FRET mechanism was found to be ca. 21 Å. In the case of HSA/(S)-NPX and BSA/(S)-NPX, energy transfer occurred to a lower extent (ca. 7%), and r was determined as ca. 24 Å. In order to investigate the possible excited state interactions between bound ligands and the relevant amino acids present in the protein binding sites, four pairs of model dyads were designed and synthesised, namely ( S, S)-TyrCPF, ( S, R)-TyrCPF, ( S, S)-TrpCPF, ( S, R)-TrpCPF, ( S, S)-TyrNPX, ( S, R)-TyrNPX, ( S, S)-TrpNPX and ( S, R)-TrpNPX. A complete SSET was observed from Tyr or Trp to CPF, since no contribution from the amino acids was present in the emission of the dyads. Likewise, a very efficient Tyr or Trp to NPX energy transfer was observed. Remarkably, in ( S, S)-TrpNPX and ( S, R)-TrpNPX a configuration-dependent reduction in the emission intensity was observed, revealing a strong and stereoselective intramolecular quenching. This effect can be attributed to exciplex formation and is dynamic in nature, as the fluorescence lifetimes were much shorter in ( S, R)- and ( S, S)-TrpNPX (1.5 and 3.1 ns, respectively) than in (S)-NPX (11 ns).

Vayá, Ignacio; Pérez-Ruiz, Raúl; Lhiaubet-Vallet, Virginie; Jiménez, M. Consuelo; Miranda, Miguel A.

2010-02-01

382

Investigation of uniform biomaterial-based microspheres with precisely controlled size and size distribution for development of advanced drug delivery systems  

NASA Astrophysics Data System (ADS)

Uniform microspheres (MS) of biocompatible polymers were investigated for use as advanced drug delivery vehicles. Novel methods of fabricating the precision particles (i.e., precision particle fabrication (PPF) techniques) of biomaterials were developed utilizing mechanical, hydrodynamic, and electric forces, where the drug release kinetics could be accurately controlled without uncertainties resulting from uncontrolled size distribution of the MS. Monodisperse MS of EC with two different polymer viscosities (4- and 45-cp) were fabricated by the PPF method. The drugs encapsulated in the EC MS tended to concentrate near the surface depending on their hydrophilicity. The 30- and 35-mum MS exhibited more even distribution of the drug than the larger ones and showed almost linear release during the first 24 h. To fabricate uniform MS of a hydrophilic polymer, an electric force was utilized to separate the uniformly generated drops. Both direct and indirect drop charging were incorporated, resulting in coulombic repulsion among the drops. Because no surfactant was involved, the method became nontoxic. For chitosan and starch, the dry MS were obtained by solvent evaporation at a high temperature (140 ˜ 160°C). However, due to their degradation at such high temperature, the gelatin solution drops were gelled at a low temperature (0 ˜ 4°C). Uniform gelatin MS (GMS) were crosslinked using glutaraldehyde solutions with different concentrations. An acidic drug was introduced to form polyion complex with GMS. As a result of glutaraldehyde concentration gradient in the MS, heterogeneous crosslinking seemed to exist. The amount of complexed drug near the surface decreased as the glutaraldehyde concentration increased. In situ study of the degradation profiles of the GMS with higher glutaraldehyde concentrations revealed faster erosion at the center than near the surface. Uniform chitosan MS (CMS) were employed for precisely controlled delivery of acidic drug, where colon-specific delivery could be realized without any additive polymers or toxic process. For strong acidic drug, the smaller the CMS, the more drugs could be contained until the colonic site hence the better candidate for colon-specific delivery. Weak acidic drug preferred the larger CMS due to the smaller amount of release at the gastric fluid.

Choy, Young Bin

383

HIV Incidence Among Injection Drug Users in New York City, 1990 to 2002: Use of Serologic Test Algorithm to Assess Expansion of HIV Prevention Services  

Microsoft Academic Search

Objectives. We sought to estimate HIV incidence among injection drug users (IDUs) in New York City from 1990 to 2002 to assess the impact of an expansion of syringe exchange services. Syringe exchange increased greatly during this period, from 250 000 to 3 000 000 syringes exchanged annually. Methods. Serum samples were obtained from serial cross-sectional surveys of 3651 IDUs.

Theresa Perlis; Kamyar Arasteh; Lucia V. Torian; Sara Beatrice; Judith Milliken; Donna Mildvan; Samuel R. Friedman

384

Examining the Relationship between Gender and Drug-Using Behaviors in Adolescents: The Use of Diagnostic Assessments and Biochemical Analyses of Urine Samples.  

ERIC Educational Resources Information Center

Examines the relationship between gender and drug use among adolescents using diagnostic assessments and biochemical analyses of urine samples. Statistical significance was found in the relationship between gender and marijuana use. The study confirms that more research is needed in this area. (Author/MKA)

James, William H.; Moore, David D.

1999-01-01

385

Assessment of the therapeutic potential of cytokines, cytotoxic drugs and effector cell populations for the treatment of multiple myeloma using the 5T33 murine myeloma model  

Microsoft Academic Search

The therapeutic potential of six cytokines, eight cytotoxic drugs and two effector cell populations for the treatment of multiple myeloma was assessed in vitro using the 5T33 murine myeloma model. The efficacy of combination IFN-? and melphalan therapy was also evaluated in vitro and in vivo. Of the cytokines tested in vitro using the MTT assay, only IFN-? demonstrated significant

Linda S Manning; Narelle L Chamberlain; Michael F Leahy; Frank T Cordingley

1995-01-01

386

Establishing an Alcohol and Other Drug Assessment and Intervention Program Within an On-Site Counselor Education Research and Training Clinic.  

ERIC Educational Resources Information Center

The authors describe the Substance Information Program, a university alcohol and other drug assessment and intervention program. The program is housed in a counseling department's on-site training and research clinic and gives counselors-in-training an opportunity to gain practical addictions training. (Author)

Juhnke, Gerald A.; Huffman, Shirley B.; Nilsen, Keith A.; Adams, Jennifer R.; Dew, Brain J.; Jordan, Joseph P.; Charkow, Wendy B.; Curtis, Russell C.; Gmutza, Brian M.; Long, Jolie A.; Booth, Caroline S.; Hagedorn, William Bryce; Rubio, Paula; Schroat, David A.

2002-01-01

387

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

388

The features of the landslide distribution and assessment of landslide susceptibility in Japan  

NASA Astrophysics Data System (ADS)

Many landslides occur in the place which the landslide generated in the past, or its surrounding area. The causes are considered to be formation of slipping surface, the moving mass which becomes vulnerable by deformation or destruction and geological structures in which a slipping surface is easily formed. Therefore, it is very important for prevention and mitigation of the landslide damages to create the landslide inventory map which is shown the place which the landslide generated in the past. National Research Institute for Earth Science and Disaster Prevention (NIED), Japan, have published the landslide inventory map "landslide distribution maps" for preventing and mitigating landslide disasters. The landslide distribution map have mapped the 380,000 or more landslide topographies in whole Japan by interpretation of aerial photographs. The individual landslide not less than 150 m wide is drawn in the landslide distribution map. The objects of this research are to clarify geological and geomorphological features of landslide distributions by analyzing the landslide distribution map and to make the landslide susceptibility map for the assessment of landslide in whole Japan. The landside distribution in whole Japan is not equal and there is a difference in the density. I propose the method of the wide area landslide assessment used by the features and distributions according to of geological setting. I calculate the landslide body ratio in each geological unit. The landslide body ratio is that the rate of the landslide body area in each geological unit and the whole area in each geological unit. The landslide body ratio can be considered that landslide susceptibility (occurrence probability of landslides) in each geological unit. As a result, an average of the landslide body ratio is about 5.2 % in whole Japan. The area consist of the accretionary complex based on volcanic rocks and plutonic rocks have comparatively high-risk landslide susceptibility, and the area of Neogene rocks and Paleogene rocks have the high-risk too. On the other hand, the area of plutonic rocks and Quaternary rocks have low-risk landslide susceptibility. The results show that the landslide susceptibility is greatly different according to geological unit. Landslide body ratio map

Doshida, S.

2013-12-01

389

Schistosomiais and Soil-Transmitted Helminth Control in Niger: Cost Effectiveness of School Based and Community Distributed Mass Drug Administration  

PubMed Central

Background In 2004 Niger established a large scale schistosomiasis and soil-transmitted helminths control programme targeting children aged 5–14 years and adults. In two years 4.3 million treatments were delivered in 40 districts using school based and community distribution. Method and Findings Four districts were surveyed in 2006 to estimate the economic cost per district, per treatment and per schistosomiasis infection averted. The study compares the costs of treatment at start up and in a subsequent year, identifies the allocation of costs by activity, input and organisation, and assesses the cost of treatment. The cost of delivery provided by teachers is compared to cost of delivery by community distributers (CDD). The total economic cost of the programme including programmatic, national and local government costs and international support in four study districts, over two years, was US$ 456,718; an economic cost/treatment of $0.58. The full economic delivery cost of school based treatment in 2005/06 was $0.76, and for community distribution was $0.46. Including only the programme costs the figures are $0.47 and $0.41 respectively. Differences at sub-district are more marked. This is partly explained by the fact that a CDD treats 5.8 people for every one treated in school. The range in cost effectiveness for both direct and direct and indirect treatments is quantified and the need to develop and refine such estimates is emphasised. Conclusions The relative cost effectiveness of school and community delivery differs by country according to the composition of the population treated, the numbers targeted and treated at school and in the community, the cost and frequency of training teachers and CDDs. Options analysis of technical and implementation alternatives including a financial analysis should form part of the programme design process. PMID:22022622

Leslie, Jacqueline; Garba, Amadou; Oliva, Elisa Bosque; Barkire, Arouna; Tinni, Amadou Aboubacar; Djibo, Ali; Mounkaila, Idrissa; Fenwick, Alan

2011-01-01

390

DASMIweb: online integration, analysis and assessment of distributed protein interaction data  

PubMed Central

In recent years, we have witnessed a substantial increase of the amount of available protein interaction data. However, most data are currently not readily accessible to the biologist at a single site, but scattered over multiple online repositories. Therefore, we have developed the DASMIweb server that affords the integration, analysis and qualitative assessment of distributed sources of interaction data in a dynamic fashion. Since DASMIweb allows for querying many different resources of protein and domain interactions simultaneously, it serves as an important starting point for interactome studies and assists the user in finding publicly accessible interaction data with minimal effort. The pool of queried resources is fully configurable and supports the inclusion of own interaction data or confidence scores. In particular, DASMIweb integrates confidence measures like functional similarity scores to assess individual interactions. The retrieved results can be exported in different file formats like MITAB or SIF. DASMIweb is freely available at http://www.dasmiweb.de. PMID:19502495

Blankenburg, Hagen; Ramírez, Fidel; Büch, Joachim; Albrecht, Mario

2009-01-01

391

Drug pharmacokinetics and pharmacodynamics: Technological considerations  

SciTech Connect

Additionally, the use of PET to examine drug pharmacokinetics and pharmacadynamics and the relationship of these properties to the behavioral, therapeutic and toxic properties of drugs and substances of abuse is emerging as a powerful new scientific tool. The pharmacokinetic properties of a drug, which comprises all of the biological processes which determine the fraction of the drug available, can be measured using the labeled drug itself. For example, the labeled drug can be used to measure the absolute uptake, regional distribution and kinetics of a drug at its site of action in the body. Additionally the labeled drug and whole body its labeled metabolites and thus provide information an potential toxic effects as well as tissue half lives. On the other hand, different labeled tracers can be used to assess drug pharmacodynamics which include the biological Processes involved in the drug's effects. For example, with appropriate radiotracers, the effects of a drug on metabolism, neurotransmitter activity, blood flew, enzyme activity or other processes can be probed.

Fowler, J.S.; Volkow, N.D.; Wolf, A.P.

1992-01-01

392

Assessment of the integration capability of system architectures from a complex and distributed software systems perspective  

NASA Astrophysics Data System (ADS)

Procurement and design of system architectures capable of network centric operations demand for an assessment scheme in order to compare different alternative realizations. In this contribution an assessment method for system architectures targeted at the C4ISR domain is presented. The method addresses the integration capability of software systems from a complex and distributed software system perspective focusing communication, interfaces and software. The aim is to evaluate the capability to integrate a system or its functions within a system-of-systems network. This method uses approaches from software architecture quality assessment and applies them on the system architecture level. It features a specific goal tree of several dimensions that are relevant for enterprise integration. These dimensions have to be weighed against each other and totalized using methods from the normative decision theory in order to reflect the intention of the particular enterprise integration effort. The indicators and measurements for many of the considered quality features rely on a model based view on systems, networks, and the enterprise. That means it is applicable to System-of-System specifications based on enterprise architectural frameworks relying on defined meta-models or domain ontologies for defining views and viewpoints. In the defense context we use the NATO Architecture Framework (NAF) to ground respective system models. The proposed assessment method allows evaluating and comparing competing system designs regarding their future integration potential. It is a contribution to the system-of-systems engineering methodology.

Leuchter, S.; Reinert, F.; Müller, W.

2014-06-01

393

A Phylogeographic Study of the Tiger (Panthera tigris): Using Holocene Distribution Models to Assess Late Pleistocene Range Shifts   

E-print Network

Assessing tiger distributions through the Late Pleistocene can provide insight to the evolutionary histories of currently recognized tiger subspecies. If global tiger ranges have been continuous, and not sufficiently isolated through glacial...

Cooper, David Matthew

2013-11-28

394

Assessment of HIV antiretroviral therapy adherence by measuring drug concentrations in hair among children in rural Uganda.  

PubMed

Current tools for measuring medication adherence have significant limitations, especially among pediatric populations. We conducted a prospective observational study to assess the use of antiretroviral (ARV) drug levels in hair for evaluating antiretroviral therapy (ART) adherence among HIV-infected children in rural Uganda. Three-day caregiver recall, 30-day visual analog scale (VAS), Medication Event Monitoring System (MEMS), and unannounced pill counts and liquid formulation weights (UPC) were collected monthly over a one-year period. Hair samples were collected quarterly and analyzed for nevirapine (NVP) levels, and plasma HIV RNA levels were collected every six months. Among children with at least one hair sample collected, we used univariable random intercept linear regression models to compare log transformed NVP concentrations with each adherence measure, and the child's age, sex, and CD4 count percentage (CD4%). One hundred and twenty-one children aged 2-10 years were enrolled in the study; 74 (61%) provided at least one hair sample, and the mean number of hair samples collected per child was 1.9 (standard deviation [SD] 1.0). Three-day caregiver recall, VAS, and MEMS were found to be positively associated with increasing NVP concentration in hair, although associations were not statistically significant. UPC was found to have a nonsignificant negative association with increasing hair NVP concentration. In conclusion, NVP drug concentrations in hair were found to have nonsignificant, although generally positive, associations with other adherence measures in a cohort of HIV-infected children in Uganda. Hair collection in this population proved challenging, suggesting the need for community education and buy-in with the introduction of novel methodologies. PMID:25483955

Olds, Peter K; Kiwanuka, Julius P; Nansera, Denis; Huang, Yong; Bacchetti, Peter; Jin, Chengshi; Gandhi, Monica; Haberer, Jessica E

2015-03-01

395

An integrative pharmacological approach to radio telemetry and blood sampling in pharmaceutical drug discovery and safety assessment  

PubMed Central

Background A successful integration of the automated blood sampling (ABS) and telemetry (ABST) system is described. The new ABST system facilitates concomitant collection of physiological variables with blood and urine samples for determination of drug concentrations and other biochemical measures in the same rat without handling artifact. Method Integration was achieved by designing a 13 inch circular receiving antenna that operates as a plug-in replacement for the existing pair of DSI's orthogonal antennas which is compatible with the rotating cage and open floor design of the BASi Culex® ABS system. The circular receiving antenna's electrical configuration consists of a pair of electrically orthogonal half-toroids that reinforce reception of a dipole transmitter operating within the coil's interior while reducing both external noise pickup and interference from other adjacent dipole transmitters. Results For validation, measured baclofen concentration (ABST vs. satellite (?M): 69.6 ± 23.8 vs. 76.6 ± 19.5, p = NS) and mean arterial pressure (ABST vs. traditional DSI telemetry (mm Hg): 150 ± 5 vs.147 ± 4, p = NS) variables were quantitatively and qualitatively similar between rats housed in the ABST system and traditional home cage approaches. Conclusion The ABST system offers unique advantages over traditional between-group study paradigms that include improved data quality and significantly reduced animal use. The superior within-group model facilitates assessment of multiple physiological and biochemical responses to test compounds in the same animal. The ABST also provides opportunities to evaluate temporal relations between parameters and to investigate anomalous outlier events because drug concentrations, physiological and biochemical measures for each animal are available for comparisons. PMID:21244682

2011-01-01

396

Assessing the availability of the teratogenic drug isotretinoin outside the pregnancy prevention programme: a survey of e-pharmacies†  

PubMed Central

Purpose The increase in online purchasing of medications raises safety concerns regarding teratogenic drugs. The use of the teratogenic drug ‘isotretinoin’ for women of childbearing age requires strict adherence to the Pregnancy Prevention Programme (PPP), a risk minimisation measure imposed on prescribers and users. We sought to determine how readily consumers can purchase isotretinoin online and the associated safety procedures and information. Methods A descriptive cross-sectional survey was conducted of 50 e-pharmacies identified from commonly used search engines. E-pharmacy characteristics and isotretinoin PPP specific criteria were evaluated. Purchases of isotretinoin from seven e-pharmacies not bearing authentication logos and not requiring a prescription were assessed for PPP policy adherence, purchasing procedures and compound quality. Results Forty-three (86%) of the e-pharmacies did not have an authentication seal/logo. Isotretinoin could be purchased from 42 sites without a valid prescription. Information on isotretinoin causing birth defects was lacking in 25 of the 50 sites, on not taking isotretinoin in pregnancy in 24 sites and not taking isotretinoin if planning or at risk of a pregnancy in 33 sites. Of the eight attempted purchases, seven arrived, all without any patient information leaflet. All were verified as isotretinoin. Conclusion The Internet provides a loophole for purchasing of medications known to cause congenital abnormalities, which needs to be addressed by medicines regulatory agencies worldwide. The current PPP for isotretinoin may be failing to protect mothers and babies from preventable harm—clinicians need to be aware of this, and the public needs to be educated about the potential risks. PMID:24493556

Lagan, Briege M; Dolk, Helen; White, Bronagh; Uges, Donald R A; Sinclair, M

2014-01-01

397

Assessment of function and clinical utility of alcohol and other drug web sites: An observational, qualitative study  

PubMed Central

Background The increasing popularity and use of the internet makes it an attractive option for providing health information and treatment, including alcohol/other drug use. There is limited research examining how people identify and access information about alcohol or other drug (AOD) use online, or how they assess the usefulness of the information presented. This study examined the strategies that individuals used to identify and navigate a range of AOD websites, along with the attitudes concerning presentation and content. Methods Members of the general community in Brisbane and Roma (Queensland, Australia) were invited to participate in a 30-minute search of the internet for sites related to AOD use, followed by a focus group discussion. Fifty one subjects participated in the study across nine focus groups. Results Participants spent a maximum of 6.5 minutes on any one website, and less if the user was under 25 years of age. Time spent was as little as 2 minutes if the website was not the first accessed. Participants recommended that AOD-related websites should have an engaging home or index page, which quickly and accurately portrayed the site's objectives, and provided clear site navigation options. Website content should clearly match the title and description of the site that is used by internet search engines. Participants supported the development of a portal for AOD websites, suggesting that it would greatly facilitate access and navigation. Treatment programs delivered online were initially viewed with caution. This appeared to be due to limited understanding of what constituted online treatment, including its potential efficacy. Conclusions A range of recommendations arise from this study regarding the design and development of websites, particularly those related to AOD use. These include prudent use of text and information on any one webpage, the use of graphics and colours, and clear, uncluttered navigation options. Implications for future website development are discussed. PMID:21545748

2011-01-01

398

Assessment of the safety, targeting, and distribution characteristics of a novel pH-sensitive hydrogel.  

PubMed

In our previous study, we synthesized a pH-sensitive hydrogel based on poly (?-caprolactone) (PCL), Pluronic (Poloxamer) and methacrylic acid (MAA) using UV-initiated free-radical polymerization. In the present study, we evaluated the safety of the obtained GMA-PCFC-GMA copolymer and a P(CFC-MAA-MEG) hydrogel both in vitro and in vivo. The pharmacokinetics study and distribution characteristics of dexamethasone in rat blood and mouse colon were investigated in detail. The in vitro toxicity of the GMA-PCFC-GMA copolymer was evaluated using a cell viability assay with HEK293 cells. An acute oral toxicity test was conducted by orally administering mice with a total of 10,000mg/kg body weight of the P(CFC-MAA-MEG) hydrogel. The mice were then observed continuously for 14 days. After which, they were sacrificed and their blood collected for routine blood and serum chemistry tests. Pharmacokinetic and colonic tissue distribution studies were conducted using high-performance liquid chromatography to detect the concentration of dexamethasone in rat blood and mouse colon tissue. All of the results indicated that both the GMA-PCFC-GMA copolymer and P(CFC-MAA-MEG) hydrogel were nontoxic. Moreover, the hydrogel significantly enhanced the colon-targeting behavior of dexamethasone. These results suggested that the novel hydrogel has great potential in colon-targeted drug delivery. PMID:25465751

Dong, Kai; Dong, Yalin; You, Cuiyu; Xu, Wei; Huang, Xiaoyan; Yan, Yan; Zhang, Lu; Wang, Ke; Xing, Jianfeng

2014-11-01

399

Ecosystem classification for EU habitat distribution assessment in sandy coastal environments: an application in central Italy.  

PubMed

Many recent developments in coastal science have gone against the demands of European Union legislation. Coastal dune systems which cover small areas of the earth can host a high level of biodiversity. However, human pressure on coastal zones around the world has increased dramatically in the last 50 years. In addition to direct habitat loss, the rapid extinction of many species that are unique to these systems can be attributed to landscape deterioration through the lack of appropriate management. In this paper, we propose to use of an ecosystem classification technique that integrates potential natural vegetation distribution as a reference framework for coastal dune EU Habitats (92/43) distribution analysis and assessment. As an example, the present study analyses the EU Habitats distribution within a hierarchical ecosystem classification of the coastal dune systems of central Italy. In total, 24 land elements belonging to 8 land units, 5 land facets, 2 land systems and 2 land regions were identified for the coastal dunes of central Italy, based on diagnostic land attributes. In central Italy, coastal dune environments including all the beach area, mobile dunes and all the fixed-dune land elements contain or could potentially hold at least one EU habitat of interest. Almost all dune slack transitions present the potentiality for the spontaneous development of EU woodlands of interest. The precise information concerning these ecosystems distribution and ecological relationships that this method produces, makes it very effective in Natura 2000 European network assessment. This hierarchical ecosystem classification method facilitates the identification of areas to be surveyed and eventually bound, under the implementation of EU Habitat directive (92/43) including areas with highly disturbed coastal dune ecosystems. PMID:17624597

Carranza, Maria Laura; Acosta, Alicia T R; Stanisci, Angela; Pirone, Gianfranco; Ciaschetti, Giampiero

2008-05-01

400

Metrological assessment of a portable analyzer for monitoring the particle size distribution of ultrafine particles.  

PubMed

Adverse health effects caused by worker exposure to ultrafine particles have been detected in recent years. The scientific community focuses on the assessment of ultrafine aerosols in different microenvironments in order to determine the related worker exposure/dose levels. To this end, particle size distribution measurements have to be taken along with total particle number concentrations. The latter are obtainable through hand-held monitors. A portable particle size distribution analyzer (Nanoscan SMPS 3910, TSI Inc.) was recently commercialized, but so far no metrological assessment has been performed to characterize its performance with respect to well-established laboratory-based instruments such as the scanning mobility particle sizer (SMPS) spectrometer. The present paper compares the aerosol monitoring capability of the Nanoscan SMPS to the laboratory SMPS in order to evaluate whether the Nanoscan SMPS is suitable for field experiments designed to characterize particle exposure in different microenvironments. Tests were performed both in a Marple calm air chamber, where fresh diesel particulate matter and atomized dioctyl phthalate particles were monitored, and in microenvironments, where outdoor, urban, indoor aged, and indoor fresh aerosols were measured. Results show that the Nanoscan SMPS is able to properly measure the particle size distribution for each type of aerosol investigated, but it overestimates the total particle number concentration in the case of fresh aerosols. In particular, the test performed in the Marple chamber showed total concentrations up to twice those measured by the laboratory SMPS-likely because of the inability of the Nanoscan SMPS unipolar charger to properly charge aerosols made up of aggregated particles. Based on these findings, when field test exposure studies are conducted, the Nanoscan SMPS should be used in tandem with a condensation particle counter in order to verify and correct the particle size distribution data. PMID:24817159

Stabile, Luca; Cauda, Emanuele; Marini, Sara; Buonanno, Giorgio

2014-08-01

401

New concept for HPTLC peak purity assessment and identification of drugs in multi-component mixtures.  

PubMed

Simple methods for HPTLC peak purity assessment and identification of the HPTLC peaks were presented. The spectrodensitograms - selected at different time intervals across the elution time of the HPTLC peak - were extracted and digital algorithms for manipulating the data were carried out in the wavelength domain. Three different methods were developed for testing the HPTLC peak purity using the mathematically transformed data of the spectrodensitograms. These included the method of relative absorption, the method of logA versus the wavelength plots and the derivative (first, second, third and fourth) method. The identification of the HPTLC peaks was based on the use of the derivative profile of the spectrodensitogram and the derivative ratios as fingerprints for the compounds. The wavelengths of absorbance and derivative (first, second, third and fourth) optima of the extracted spectrodensitograms were allocated. The data were compared with those obtained using the corresponding reference standard. The validity of the proposed methods was performed by chromatography of a mixture containing mebendazole and methylparaben as a model versus the winCATS(®) spectral correlation method as a reference method. The study indicated that the proposed concept is a reliable non-confusing valuable tool for testing the purity and identity of the HPTLC peaks as the results are easily and rigorously interpreted. PMID:22265550

Hewala, Ismail I; Bedair, Mona M; Shousha, Sherif M

2012-01-15

402

An Oxycodone Conjugate Vaccine Elicits Drug-Specific Antibodies that Reduce Oxycodone Distribution to Brain and Hot-Plate Analgesia  

PubMed Central

Opioid conjugate vaccines have shown promise in attenuating the behavioral effects of heroin or morphine in animals. The goal of this study was to extend this approach to oxycodone (OXY), a commonly abused prescription opioid. Haptens were generated by adding tetraglycine (Gly)4 or hemisuccinate (HS) linkers at the 6-position of OXY. Immunization of rats with OXY(Gly)4 conjugated to the carrier proteins bovine serum albumin (BSA) or keyhole limpet hemocyanin (KLH) produced high-titer antibodies to OXY and its metabolite oxymorphone with substantially lower affinities for other structurally related opioid agonists and antagonists. There was no measurable binding of antibody by the (Gly)4 linker alone or off-target opioids methadone and buprenorphine. OXY(HS) conjugates were less immunogenic despite achieving protein haptenation ratios comparable to OXY(Gly)4-BSA. In rats given a single intravenous dose of OXY, immunization with OXY(Gly)4-KLH increased OXY protein binding and retention in serum while decreasing its unbound (free) concentration in plasma and distribution to brain. Vaccine efficacy correlated with serum antibody titers, and it was greatest in rats given the lowest OXY dose (0.05 mg/kg) but was significant even after a larger OXY dose (0.5 mg/kg), equivalent to the high end of the therapeutic range in humans. These effects of OXY(Gly)4-KLH on drug disposition were comparable to those of nicotine or cocaine vaccines that are in clinical trials as addiction treatments. Immunization with OXY(Gly)4-KLH also reduced OXY analgesia in a thermal nociception test. These data support further study of vaccination with the OXY(Gly)4-KLH immunogen as a potential treatment option for OXY abuse or addiction. PMID:22262924

Le Naour, M.; Harmon, T. M.; Tucker, A. M.; Portoghese, P. S.; Pentel, P. R.

2012-01-01