Pharmaceutical preparations Research Papers - Academia.edu (original) (raw)

Background: Estimates of prevalence are known to be affected by the design of cross-sectional studies. A pan-European study provided an opportunity to compare the effect of two cross-sectional study designs on estimates of medicines use. Methods: A Service evaluation survey (SES) and a web-based point-prevalence study (PPS) were conducted as part of a European study of neonatal exposure to excipients. Neonatal units from all European Union countries plus Iceland, Norway, Switzerland and Serbia were invited to participate. All medicines prescribed to neonates were recorded during three-day and one-day study periods in the SES and PPS, respectively. In the PPS individual demographic and prescription data were also collected. To compare the probabilities that a particular medicine would be reported by each study multilevel mixed effects logistic regression models with crossed random effects were applied. The relationship between medicines exposure at the unit and individual levels in the PPS data was assessed using polynomial regression with square root transformation. Results: Of 31 invited countries 20 and 21 with 115 and 89 units joined the SES and PPS, respectively. Out of 5,572,859 live births in invited countries in 2010 a higher proportion was covered by units participating in the SES compared to the PPS (11% vs 6%, respectively; OR 1.89; 95% CI 1.87-1.89). A greater number of active pharmaceutical ingredients (API), manufacturers and trade names were registered in the SES compared to the PPS. High correlation between the two studies in frequency of use for each specified API was seen (R 2 = 0.86). The average probability of a department to use a given API was greater in the SES compared to the PPS (OR 2.36; 95% CI 2.05-2.73) with higher frequency of use and longer average duration of prescription further increasing the difference. The polynomial regression model described the correlation between APIs exposure on unit and individual level well (R 2 = 0.93). Conclusion: The simple data structure and longer study period of the SES resulted in improved recruitment and higher likelihood of capture for a given API. The frequency of use at the unit level appears a good surrogate of individual exposure rates.

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- Pharmacoepidemiology, Research Design, Biomedical Research, Data Collection

In the past decades, it has become increasingly apparent that in addition to therapeutic effect, drugs need to exhibit favourable absorption, distribution, metabolism and excretion (ADME) characteristics to produce a desirable response in vivo. As the recent progress in drug discovery technology enables rapid synthesis of vast numbers of potential drug candidates, robust methods are required for the effective screening of compounds synthesized within such programs, so that compounds with poor pharmacokinetic properties can be rejected at an early stage of drug development. Furthermore, a viable in silico method would save resources by enabling virtual screening of drug candidates already prior to synthesis. This review gives a general overview of the approaches aimed at predicting biological permeation, one of the cornerstones behind the ADME behaviour of drugs. The most important experimental and computational models are reviewed. Physicochemical factors underlying the permeation process are discussed.

- by Lasse Murtomaki
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- Algorithms, Physical Chemistry, Membranes, Prediction

It has been previously described that when a sample's particle size is determined using different sizing techniques, the results can differ considerably. The purpose of this study was to review several in-process techniques for particle size determination (Spatial Filtering Velocimetry, Focused Beam Reflectance Measurements, Photometric Stereo Imaging, and the Eyecon Ò technology) and compare them to well-known and widespread off-line reference methods (laser diffraction and sieve analysis). To start with, a theoretical explanation of the working mechanism behind each sizing technique is presented, and a comparison between them is established. Secondly, six batches of granules and pellets (i.e., spherical particles) having different sizes were measured using these techniques. The obtained size distributions and related D 10 , D 50 , and D 90 values were compared using the laser diffraction wet dispersion method as reference technique. As expected, each technique provided different size distributions with different D values. These dissimilarities were examined and explained considering the measurement principles behind each sizing technique. The particle property measured by each particle size analyzer (particle size or chord length) and how it is measured as well as the way in which size information is derived and calculated from this measured property and how results are presented (e.g., volume or mass distributions) are essential for the interpretation of the particle size data.

- by Tom van Den Kerkhof
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- Rheology, Pharmaceutical Technology, Pharmaceutical Chemistry, Lasers

Background Underlying systems factors have been seen to be crucial contributors to the occurrence of medication errors. By understanding the causes of these errors, the most appropriate interventions can be designed and implemented to minimise their occurrence. Objective This study aimed to systematically review and appraise empirical evidence relating to the causes of medication administration errors (MAEs) in hospital settings.

- by Richard Keers
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- Data Collection, Workload, Theoretical Models, Patient Care Team

Two simple, rapid, and selective analytical procedures were developed for the simultaneous determination of paracetamol (PR) and tramadol hydrochloride (TR) in a binary mixture using highperformance liquid chromatography with UV detection (HPLC-UV) and gas chromatography with mass spectrometry (GC-MS) techniques. HPLC resolved the two compounds on a Hypurity Advance column using a mobile phase consisting of phosphate buffer pH 6.3 and acetonitrile (90:10, v/v). PR and TR were detected by their UV absorption at 220 nm. GC-MS involved separation of the two compounds using 100% dimethylpolysiloxane (Rtx-1) column with temperature programming. The EI mass spectrum of PR was characterized by [M] + at 151 and a base peak at m/z 109 while TR mass spectrum was characterized by [M] + at 263 and a base peak at m/z 58. Quantification of the analytes in both methods was based on measuring the peak areas. The reliability and analytical performance of the proposed methods including linearity, ranges, precision, accuracy, detection, and quantification limits were statistically validated. Calibration curves were linear over the range 10-400 µg/mL for both PR and TR using the HPLC method and over the ranges of 75-500 and 25-350 µg/mL for PR and TR, respectively, using the GC-MS method. The proposed methods were successfully applied for the determination of the two compounds in laboratory-prepared mixtures and in commercially available tablet formulation. No interference peaks were observed from common pharmaceutical adjuvants. The results compared favorably with those obtained by a derivative spectrophotometric method.

- by Tarek S. Belal
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- Analytical Chemistry, Mass Spectrometry, Quantitative analysis, GC-MS

Objective In the 6 years since the National Library of Medicine began monthly releases of RxNorm, RxNorm has become a central resource for communicating about clinical drugs and supporting interoperation between drug vocabularies. Materials and methods Built on the idea of a normalized name for a medication at a given level of abstraction, RxNorm provides a set of names and relationships based on 11 different external source vocabularies. The standard model enables decision support to take place for a variety of uses at the appropriate level of abstraction. With the incorporation of National Drug File Reference Terminology (NDF-RT) from the Veterans Administration, even more sophisticated decision support has become possible. Discussion While related products such as RxTerms, RxNav, MyMedicationList, and MyRxPad have been recognized as helpful for various uses, tasks such as identifying exactly what is and is not on the market remain a challenge.

- by John Kilbourne
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- Engineering, Computer Science, Natural Language Processing, Medicine

Introduction: Extracorporeal membrane oxygenation (ECMO) is a supportive therapy, with its success dependent on effective drug therapy that reverses the pathology and/or normalizes physiology. However, the circuit that sustains life can also sequester life-saving drugs, thereby compromising the role of ECMO as a temporary support device. This ex vivo study was designed to determine the degree of sequestration of commonly used antibiotics, sedatives and analgesics in ECMO circuits. Methods: Four identical ECMO circuits were set up as per the standard protocol for adult patients on ECMO. The circuits were primed with crystalloid and albumin, followed by fresh human whole blood, and were maintained at a physiological pH and temperature for 24 hours. After baseline sampling, fentanyl, morphine, midazolam, meropenem and vancomycin were injected into the circuit at therapeutic concentrations. Equivalent doses of these drugs were also injected into four polyvinylchloride jars containing fresh human whole blood for drug stability testing. Serial blood samples were collected from the ECMO circuits and the controls over 24 hours and the concentrations of the study drugs were quantified using validated assays. Results: Four hundred samples were analyzed. All study drugs, except meropenem, were chemically stable. The average drug recoveries from the ECMO circuits and the controls at 24 hours relative to baseline, respectively, were fentanyl 3% and 82%, morphine 103% and 97%, midazolam 13% and 100%, meropenem 20% and 42%, vancomycin 90% and 99%. There was a significant loss of fentanyl (p = 0.0005), midazolam (p = 0.01) and meropenem (p = 0.006) in the ECMO circuit at 24 hours. There was no significant circuit loss of vancomycin at 24 hours (p = 0.26). Conclusions: Sequestration of drugs in the circuit has implications on both the choice and dosing of some drugs prescribed during ECMO. Sequestration of lipophilic drugs such as fentanyl and midazolam appears significant and may in part explain the increased dosing requirements of these drugs during ECMO. Meropenem sequestration is also problematic and these data support a more frequent administration during ECMO.

- by Daniel Mullany and +1
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- Critical Care, Anti-Bacterial Agents, Swine, Analgesics

tests. This process is not only time consuming, but the solid dosage forms are destroyed. Tablets from the batch of formulation will normally be completed before the results of quantitative analysis for content uniformity of the tablets are known. If the analysis on unit dosage or content uniformity fails to satisfy the acceptance criteria, then no remedial action can be taken except to regrind, remix, and repress the tablets.

- by Michael Cima and +1
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- Fluorescence, Pharmaceutical Technology, Pharmaceutical Chemistry, Light

The preparative chromatographic resolution of racemic mixtures is rapidly becoming a standard approach for the generation of enantiomers in pharmaceutical R&D. This paper will discuss the optical resolution of a pharmaceutical intermediate as the separation is scaled up from the milligram to the kilogram scale. Difficulties encountered and their solutions at each scale will be discussed. In addition, the exploration of Simulated Moving Bed (SMB) for the separation will also be discussed. Finally, a comparison of the productivities and solvent consumption for each method and scale will be presented.

- by Carlos Orihuela
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- Engineering, Technology, Chromatography, Raw materials

The OECD guideline for studies on percutaneous penetration to be used in hazard and risk evaluations prescribes experimental conditions with optimal barrier integrity of the skin, which in many occupational settings probably is not true. Thus, workers may have compromised skin due to chemical or mechanical damage, due to different medical conditions (eczema, dermatitis, skin irritation) or related to occupational scenarios involving prolonged wet work. The present study used the OECD guideline procedures to study the in vitro percutaneous penetration through human skin of a number of model substances (glyphosat, caffeine, benzoic acid, malathion) covering a range of solubilities. Further, we studied the extent to which a slightly damaged skin would change the rate, the amount absorbed during dermal exposure and the distribution of chemical deposition between epidermis and dermis. The present study demonstrates that a limited damage to the skin significantly increases the permeability coefficient (K p) as well as total percutaneous penetration of chemicals, and most significantly for those compounds that due to their physicochemical characteristics (the most hydrophilic as well as the most lipophilic) have low penetration rates through intact skin. The present experiment not only confirms the proportionality between lipophilicity and potential for percutaneous penetration, but also illustrates that at a certain degree of lipophilicity of a model compound, the different skin compartments become more attractive for temporary deposition of model compounds. Moreover, a clear change from epidermal deposition towards a dominating dermis deposition of chemicals temporarily deposited within the skin is seen following damage to the skin barrier. Thus, the distribution of chemicals within the skin compartments is affected by the physicochemical characteristics of the chemicals as well as by the integrity of the skin. This observation may have implications when evaluating the possibility of removing chemicals from the skin through different cleansing procedures following unintended dermal exposures.

- by Flemming Nielsen
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- Kinetics, Dermatology, In Vitro, Caffeine

New PVC membrane electrodes for the determination of sulfadiazine (SDZ) are presented. The electrodes are fabricated with conventional and tubular configurations with a graphite-based electrical contact, and no internal reference solution. The selective membranes consist of bis(triphenylphosphoranilidene)ammonium•SDZ (electrode A), tetraoctylammonium bromide (electrode B), or iron(II)-phthalocyanine (FePC) (electrode C) electroactive materials dispersed in a PVC matrix of o-nitrophenyl octyl ether (o-NPOE) plasticizer. The sensors A, B, and C displayed linear responses over the concentration ranges 1.0 ¥ 10-2-1.0 ¥ 10-5 , 1.0 ¥ 10-2-7.5 ¥ 10-6 , and 3.2 ¥ 10-2-7.0 ¥ 10-6 mol l-1 (detection limits of 1.09, 2.04 and 0.87 mg ml-1) with anionic slopes of-57.3 ± 0.1,-46.7 ± 0.5, and-65.1 ± 0.2 mV decade-1 , respectively. No effect from pH was observed within 4.0-5.5, 4.8-10, and 4.5-8, respectively, and good selectivity was found. The sensors were applied to the analysis of pharmaceuticals and biological fluids in steady state and in flow conditions.

- by Felismina Moreira
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- Chemistry, Analytical Chemistry, Medicine, Potentiometry

Pharmacogenomics is the study of the myriad interactions between genes and pharmacotherapy. Developments in pharmacogenomics have changed and will affect pharmaceutical research, drug development and the practice of medicine in a significant way. In this article, we make an inventory of the ethical implications that might arise as a result of possible developments in pharmacogenomics and investigate whether the present ethical framework will be able to adequately answer arising questions. We think that many of the questions related to the consequences of pharmacogenomics are answerable along the lines of present ethical thinking. We also believe, however, that many 'changes of degree' may result in a 'change of kind.' We therefore think that pharmacogenomics may potentially have such a profound influence on scientific research and the pharmaceutical industry, the practice of medicine and society at large, that this will generate its own unique dynamic, which will require new ethical research. We suggest that the notion of 'responsibility' will be a major focus of such research.

- by Johannes Van Delden
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- Philosophy, Ethics, Applied Ethics, Public Opinion

A method is described for the simultaneous profiling of sample lipophilicity, integrity, and purity. The method is rapid and is applicable to high throughput profiling of pharmaceutical properties in drug discovery. A short Polaris C column is used 18 with a rapid, wide-polarity mobile phase gradient, UV detection, and MS analysis. The lipophilicity of each component is estimated from a calibration curve using six drug or organic compounds and plotting their respective measured retention time versus Log D (literature). The correlation of Log D (literature) to Log D (HPLC) for 60 structurally diverse drugs has 7.4 7.4 7.4 2 a correlation coefficient r of 0.89. The method is applicable to compounds with MW.200 and retention time.1.5 min for rapid, initial pharmaceutical profiling in drug discovery.

Objective To examine the practice of concealing drugs in patients' foodstuff in nursing homes. Design Cross sectional study with data collected by structured interview. Setting All five health regions in Norway. Participants Professional carers of 1362 patients in 160 regular nursing home units and 564 patients in 90 special care units for people with dementia. Main outcome measures Frequency of concealment of drugs; who decided to conceal the drugs; how this practice was documented in the patients' records; and what types of drugs were given this way. Results 11% of the patients in regular nursing home units and 17% of the patients in special care units for people with dementia received drugs mixed in their food or beverages at least once during seven days. In 95% of cases, drugs were routinely mixed in the food or beverages. The practice was documented in patients' records in 40% (96/241) of cases. The covert administration of drugs was more often documented when the physician took the decision to hide the drugs in the patient's foodstuff (57%; 27/47) than when the person who made the decision was unknown or not recorded (23%; 7/30). Patients who got drugs covertly more often received antiepileptics, antipsychotics, and anxiolytics compared with patients who were given their drugs openly. Conclusions The covert administration of drugs is common in Norwegian nursing homes. Routines for such practice are arbitrary, and the practice is poorly documented in the patients' records.

- by O. Kirkevold
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- Dementia, Food, British medical history, Norway

During the production of air-filled albumin microspheres, to be used as an ultrasound contrast agent, it was observed that some albumin lots could not be used owing to albumin precipitation. In order to understand the reason for these lot-to-lot variations, 24 lots of 5 % (w/v) human albumin pharmaceutical preparations were analysed. The results revealed that the good albumin lots all contained <0.03 mol of free SH groups per mol of albumin. The precipitation observed with other lots was most probably due to higher amounts of free SH groups. The lower amount of free SH groups in the good lots correlated with: (i) a yellow colour of the solutions and a UV-visible spectrum similar to that observed for non-enzymatic glycosylation; (ii) a decreased fructosamine content; (iii) an increased mobility against the anode in isoelectric focusing; and (iv) an increased truncation of the two N-terminal amino acids. No, or only small, differences were observed for the amounts of albumin dimer, albumin aggregates and protein impurities, and these could not account for the albumin precipitation. The differences observed between the albumin lots were most probably due to varying storage times and/or storage conditions, and incubation experiments revealed changes in all parameters that differed between the good and bad lots. Increasing the storage temperature or exposing the solutions to light resulted in a faster decrease of free SH groups and increase of the yellow colouration. It is likely that at least some of the changes observed were due to reactive degradation products formed from the stabilizer N-acetyl-L-tryptophan. The results presented should also be of interest regarding the storage of monoclonal antibodies and other proteins used in pharmaceuticals.

- by Cath Christiansen
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- Engineering, Technology, Biological Sciences, Albumin
- by Diana Gomez
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- Neurodegenerative Diseases, Stroke, Blood brain barrier, Intranasal Administration

Transdermal drug delivery systems (TDDS), also known as ''patches,'' are dosage forms designed to deliver a therapeutically effective amount of drug across a patient's skin. The adhesive of the transdermal drug delivery system is critical to the safety, efficacy and quality of the product. In the Drug Quality Reporting System (DQRS), the United States Food and Drug Administration (FDA) has received numerous reports of ''adhesion lacking'' for transdermal drug delivery systems. This article provides an overview of types of transdermals, their anatomy, the role of adhesion, the possible adhesion failure modes and how adhesion can be measured. Excerpts from FDA reports on the lack of adhesion of transdermal system products are presented. Pros and cons of in vitro techniques, such as peel adhesion, tack and shear strength, in vivo techniques used to evaluate adhesive properties are discussed. To see a decrease in ''adhesion lacking'' reports, adhesion needs to become an important design parameter and suitable methods need to be available to assess quality and in vivo performance. This article provides a framework for further discussion and scientific work to improve transdermal adhesive performance.

- by Bill Doub
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- Drug delivery, Pharmaceutical Chemistry, Adhesion, Quality Control
- by edzard E Ernst
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- Homeopathy, Forecasting, Medicine, Pharmaceutical preparations

Characterization and treatment of a real pharmaceutical wastewater containing 775 mg dissolved organic carbon per liter by a solar photo-Fenton/biotreatment were studied. There were also many inorganic compounds present in the matrix. The most important chemical in this wastewater was nalidixic acid (45 mg/L), an antibiotic pertaining to the quinolone group. A Zahn-Wellens test demonstrated that the real bulk organic content of the wastewater was biodegradable, but only after long biomass adaptation; however, the nalidixic acid concentration remained constant, showing that it cannot be biodegraded. An alternative is chemical oxidation (photo-Fenton process) first to enhance biodegradability, followed by a biological treatment (Immobilized Biomass Reactor-IBR). In this case, two studies of photo-Fenton treatment of the real wastewater were performed, one with an excess of H 2 O 2 (kinetic study) and another with controlled H 2 O 2 dosing (biodegradability and toxicity studies). In the kinetic study, nalidixic acid completely disappeared after 190 min. In the other experiment with controlled H 2 O 2 , nalidixic acid degradation was complete at 66 mM of H 2 O 2 consumed. Biodegradability and toxicity bioassays showed that photo-Fenton should be performed until total degradation of nalidixic acid before coupling a biological treatment. Analysis of the average oxidation state (AOS) demonstrated the formation of more oxidized intermediates. With this information, the photo-Fenton treatment time (190 min) and H 2 O 2 dose (66 mM) necessary for adequate biodegradability of the wastewater could be determined. An IBR operated in batch mode was able to reduce the remaining DOC to less than 35 mg/L. Ammonium consumption and NO 3 À generation demonstrated that nitrification was also attained in the IBR. Overall DOC degradation efficiency of the combined photo-Fenton and biological treatment was over 95%, of which 33% correspond to the solar photochemical process and 62% to the biological treatment.

- by A. Agüera
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- Water, Kinetics, Water Purification, Minerals

Concepts of pharmacokinetics including kinetic models, first order processes, apparent volume of distribution, half-life, clearance, duration of drug action, dose schedules and plasma drug concentration monitoring are briefly outlined.

- by richard ogilvie
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- Kinetics, DISTRIBUTION, Kidney, Liver

Benzophenones (BP) and related aryl ketone photophores have become established as the photoactivatable group of choice for high-efficiency covalent modification of hydrophobic regions of binding proteins, including enzymes and receptors that recognize peptide hormones, (oligo)nucleotides and nucleosides, phosphoinositides, inosi-to1 polyphosphates and a wide variety of therapeutic molecules. This review presents the advantages of BP as photoaffinity labels and provides specific examples from the last 3 years of applications of BP-containing ligands used in biochemistry.

- by Glenn Prestwich
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- Photochemistry, Photobiology, Biological Sciences, Physical sciences
- by Alan Boobis
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- Genetics, Polymorphism, Experience Design, Pharmacokinetics
- by Tuula Tuhkanen
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- Environmental Science, Performance, Filtration, Water Pollution

In 1994, the US Food and Drug Administration (FDA) proposed an approach, based on extrapolation of efficacy findings from adults to the pediatric population, to maximize the use of adult data and other data when designing pediatric drug-development programs. We examined the experience of the FDA in using extrapolation to evaluate how and when it was used and any changes in scientific assumptions over time. We reviewed 370 pediatric studies submitted to the FDA between 1998 and 2008 in response to 159 written requests (166 products) issued under the Pediatric Exclusivity Provision. We identified cases in which efficacy was extrapolated from adult data or other data, we categorized the type of pediatric data required to support extrapolation, and we determined whether the data resulted in new pediatric labeling. Extrapolation of efficacy from adult data occurred for 82.5% of the drug products (137 of 166). Extrapolation was defined as complete for 14.5% of the products (24 of 166) and...

- by Gilbert Burckart
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- Pediatrics, Quality Control, Child, Program Development

by guest on July 28, 2016 http://toxsci.oxfordjournals.org/ Downloaded from 198 NAUMANN ET AL. by guest on July 28, 2016 http://toxsci.oxfordjournals.org/ Downloaded from 200 NAUMANN ET AL. by guest on July 28, 2016 http://toxsci.oxfordjournals.org/ Downloaded from FIG. 2. Dose-normalized mean plasma concentrations (ngÁml À1 /mgÁkg À1 ) of MK-0679 for 0-6 h after administration of drug by the iv, it, po, and in routes. USE OF BIOAVAILABILITY DATA TO ADJUST OELS 201 by guest on July 28, 2016 http://toxsci.oxfordjournals.org/ Downloaded from a Total dose, Dose ET , and Dose LUNG (TB þ P) were estimated based upon exposure dose and regional deposition fraction. b Computed using the trapezoidal rule (SigmaPlot, version 8.0; SPSS, Inc.). USE OF BIOAVAILABILITY DATA TO ADJUST OELS 205 by guest on July 28, 2016 http://toxsci.oxfordjournals.org/ Downloaded from 210 NAUMANN ET AL. by guest on July 28, 2016 http://toxsci.oxfordjournals.org/ Downloaded from

- by Patricia Weideman
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- Pharmaceutical, Absorption, Bioavailability, Rats

Successful drug discovery relies on the selection of drug candidates with good in vivo pharmacokinetic (PK) properties as well as appropriate preclinical efficacy and safety profiles. In vivo PK profiling is often a bottleneck in the discovery process. In this review, we focus on the tiered in vivo PK approaches implemented at the Genomics Institute of the Novartis Research Foundation (GNF), which includes snapshot PK, rapid PK and full PK studies. These in vivo PK approaches are well integrated within discovery research, allow tremendous flexibility and are highly efficient in supporting the diverse needs and increasing demand for in vivo profiling. The tiered in vivo PK studies expedite compound profiling and help guide the selection of more desirable compounds into efficacy models and for progression into development.

- by Tove Tuntland
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- Drug Discovery, Pharmacokinetics, Drug Design, Pharmaceutical preparations

Individualized drug dosage regimens cannot be developed without first setting an individualized, specific goal for each patient. Serum drug concentrations have commonly been described in terms of therapeutic ranges in which most patients have a therapeutic effect and a low incidence of toxicity. It is generally held that the serum concentrations of patients should be within this therapeutic range. Clinicians look at serum concentrations to see if they are in the socalled therapeutic range, and often adjust the dose if they are not. However, they often do this without looking carefully to see if the patient is tolerating that concentration or not, or if a higher or a lower level might actually be more desirable. Often, if the level is "therapeutic", that is the end of the analysis, and no further thought is given as to whether or not a different serum level might be better. In addition, there is definitely a greater effect of the drug at the top of the therapeutic range than at the bottom, and it increases steadily throughout the range. This is often not considered clinically. 20 10 0 0 50 100 THERAP EFFECTS TOXIC EFFECTS

- by Roger Jelliffe
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- Analytical Chemistry, Individuality, Pharmacokinetics, Therapeutic drug monitoring

In the context of drug discovery, drug target interactions (DTIs) can be predicted based on observed topological features of a semantic network across the chemical and biological space. In a semantic network, the types of the nodes and links are different. In order to take into account the heterogeneity of the semantic network, meta-path-based topological patterns were investigated for link prediction. Supervised machine learning models were constructed based on meta-path topological features of an enriched semantic network, which was derived from Chem2Bio2RDF, and was expanded by adding compound and protein similarity neighboring links obtained from the PubChem databases. The additional semantic links significantly improved the predictive performance of the supervised learning models. The binary classification model built upon the enriched feature space using the Random Forest algorithm significantly outperformed an existing semantic link prediction algorithm, Semantic Link Associa...

- by abhik Seal
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- Computer Science, Machine Learning, Data Mining, Medicine

The two-part article aimed to investigate poloxamer 407-based microspheres as a novel platform for enhancing and controlling the delivery of atenolol across the oromucosal tissue. In the Part I of the work, atenolol-loaded poloxamers 407 microparticles were prepared by the solvent free spray congealing technology. This approach was feasible upon the high viscosity of the systems allowing for high loaded (20% w/w) non-aggregated microspheres. Several formulations were studied and the results demonstrated that the drug release patterns, solubility data, mucoadhesion to buccal tissue and gelling properties in saliva could be modified by adding different amount of an amphiphilic polymer-lipid excipient (Gelucire(®) 50/13) to poloxamer 407. Particularly, microspheres based only on poloxamer 407 exhibited very high solubility, mucoadhesive strength and gelling behaviour. To assess their potential as matrix for buccal application, the gelling property and the drug release from tablets obta...

The brain is a delicate organ, and nature has very efficiently protected it. The brain is shielded against potentially toxic substances by the presence of two barrier systems: the blood brain barrier (BBB) and the blood cerebrospinal fluid barrier (BCSFB). Unfortunately, the same mechanisms that protect it against intrusive chemicals can also frustrate therapeutic interventions. Despite aggressive research, patients suffering from fatal and/or debilitating central nervous system (CNS) diseases, such as brain tumours, HIV encephalopathy, epilepsy, cerebrovascular diseases and neurodegenerative disorders, far outnumber those dying of all types of systemic cancers or heart diseases. The abysmally low number of potential therapeutics reaching commercial success is primarily due to the complexity of the CNS drug development. The clinical failure of many probable candidates is often, ascribable to poor delivery methods which do not pervade the unyielding BBB. It restricts the passive diffusion of many drugs into the brain and constitutes a significant obstacle in the pharmacological treatment of central nervous system (CNS) disorders. General methods that can enhance drug delivery to the brain are, therefore, of great pharmaceutical interest. Various strategies like non-invasive methods, including drug manipulation encompassing transformation into lipophilic analogues, prodrugs, chemical drug delivery, carrier-mediated drug delivery, receptor/vector mediated drug delivery and intranasal drug delivery, which exploits the olfactory and trigeminal neuronal pathways to deliver drugs to the brain, are widely used. On the other hand the invasive methods which primarily rely on disruption of the BBB integrity by osmotic or biochemical means, or direct intracranial drug delivery by intracerebroventricular, intracerebral or intrathecal administration after creating reversible openings in the head, are recognised. Extensive review pertaining specifically, to the patents relating to drug delivery across the CNS is currently available. However, many patents e.g. US63722506, US2002183683 etc., have been mentioned in a few articles. It is the objective of this article to expansively review drug delivery systems for CNS by discussing the recent patents available.

- by Nitin Jain
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- Pharmaceutical Technology, Drug delivery, Drug development, Drug Delivery System

Health care providers (HCPs) are increasingly aware of pressures on funding for health care services, including high cost medicines (HCMs). Allocating resources to innovative and expensive medications is particularly challenging and the decisionmaking processes and criteria used to allocate resources to HCMs have not been widely described in the literature. This case study aimed to describe the operations of the first reported High Cost Drug Sub-Committee (HCD-SC) in a public hospital in Australia. In addition the study also evaluated the decision-making process using Daniel and Sabin's ethical framework of "accountability for reasonableness". Some lessons emerged from the description of the operations of the HCD-SC. Decisions were not solely based on effectiveness and cost. Additional factors such as "clinical need" and the lack of an alternative treatment were involved in decisions about access to HCMs. Members of the HCD-SC also considered it was important to have consistency in the way decisions were being made. The findings from this study provide an evidence base for developing strategies to improve this hospital's decision-making process regarding access to HCMs.

- by Gisselle Gallego
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- Decision Making, Health Policy, Priority Setting, Pharmaceuticals

High-throughput screening of physical, genetic and chemical-genetic interactions brings important perspectives in the Systems Biology field, as the analysis of these interactions provides new insights into protein/gene function, cellular metabolic variations and the validation of therapeutic targets and drug design. However, such analysis depends on a pipeline connecting different tools that can automatically integrate data from diverse sources and result in a more comprehensive dataset that can be properly interpreted. We describe here the Integrated Interactome System (IIS), an integrative platform with a web-based interface for the annotation, analysis and visualization of the interaction profiles of proteins/genes, metabolites and drugs of interest. IIS works in four connected modules: (i) Submission module, which receives raw data derived from Sanger sequencing (e.g. two-hybrid system); (ii) Search module, which enables the user to search for the processed reads to be assembled...

- by Ramon Vidal
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- Engineering, Physics, Chemistry, Systems Biology

Many hospital-based studies throughout Europe have shown that a substantial number of children receive off-label prescribed drugs that lack marketing authorisation for paediatric use. Since information about the extent and characteristics of this prescribing pattern in paediatric primary health care is limited, we assessed the proportion of off-label drug prescribing for paediatric outpatients in a reference population of 350,000 children using a computerised prescription database. We also determined the adherence to a treatment guideline provided by the Stockholm county council as a quality of prescribing indicator. All drugs prescribed for children younger than 16 years of age in the Stockholm county in the year 2000 were ranked by the number of prescription items. The retrospective, descriptive analysis was restricted to those drugs that accounted for 90% of total prescribing. We calculated the proportion of off-label drug prescribing for different age and therapeutic groups with...

- by Ulf Bergman
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- Primary Health Care, Adolescent, Sweden, Child

This review article focuses on the speciflcities of chiral liquid chromatography, with particular emphasis on stability, stereoconversion, enantiomeric separation, recovery and drug concentration determinations. In addition, the paper presents an overview of the different steps which have to be followed for a chiral method to be validated. Sensitivity, selectivity, linearity, precision and accuracy all have to be ensured for three chemical entities, the two enantiomers and the racemate.

- by Amnon Hoffman
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- Chemistry, Medicine, SEM, AFM

Forensic analysis of pharmaceutical preparations requires a comparative analysis with a standard of the suspected drug in order to identify the active ingredient. Purchasing analytical standards can be expensive or unattainable from the drug manufacturers. Direct Analysis in Real Time (DART ) is a novel, ambient ionization technique, typically coupled with a JEOL AccuTOF  (accurate mass) mass spectrometer. While a fast and easy technique to perform, a drawback of using DART  is the lack of component separation of mixtures prior to ionization. Various in-house pharmaceutical preparations were purified using thin-layer chromatography (TLC) and mass spectra were subsequently obtained using the AccuTOF -DART  technique. Utilizing TLC prior to sample introduction provides a simple, low-cost solution to acquiring mass spectra of the purified preparation. Each spectrum was compared against an in-house molecular formula list to confirm the accurate mass elemental compositions. Spectra of purified ingredients of known pharmaceuticals were added to an in-house library for use as comparators for casework samples. Resolving isomers from one another can be accomplished using collision-induced dissociation after ionization. Challenges arose when the pharmaceutical preparation required an optimized TLC solvent to achieve proper separation and purity of the standard. Purified spectra were obtained for 91 preparations and included in an in-house drug standard library. Primary standards would only need to be purchased when pharmaceutical preparations not previously encountered are submitted for comparative analysis. TLC prior to DART  analysis demonstrates a time efficient and cost saving technique for the forensic drug analysis community.

- by Jessica Wood
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- Analytical Chemistry, Forensic Science, Forensic Sciences, Time of Flight
- by Heather Neville
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- Primary Health Care, Hospital Pharmacy, Hospitalization, Clinical
- by Narayana Narasimhan
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- Genetics, Microbiology, Mass Spectrometry, Taxonomy

We describe the identification of novel rapamycin derivatives present as low-level impurities in active pharmaceutical ingredients using an integrated, multidisciplinary approach. Rapamycin, a fermentation-derived natural product is itself used clinically and provides the starting material for several rapamycin analog drugs, typically used in oncology. LC-MS proved a sensitive means to analyze impurity profiles in batches of rapamycin. MS fragmentation was used to gain structural insight into these impurities, usually fermentation by-products, structurally very similar to rapamycin. In cases where MS fragmentation was unable to provide unambiguous structural identification, the impurities were isolated and purified using orthogonal HPLC methods. Using the higher mass sensitivity of small-volume NMR microprobes, submilligram amounts of isolated impurities were sufficient for further characterization by multidimensional NMR spectroscopy. Full assignment of the 1 H and 13 C NMR signals revealed the structure of these impurities at an atomic level. This systematic workflow enabled the identification of several novel rapamycin congeners from active pharmaceutical ingredient without the need for large-scale isolation of impurities. For illustration, two novel rapamycin derivatives are described in this study: 12-ethyl-rapamycin and 33-ethyl-rapamycin, which exemplify previously unreported modifications on the carbon skeleton of the rapamycin macrocycle. The methodologies described here can be of wide use for identification of closely related structures found; for example as fermentation by-products, metabolites or degradants of natural product-based drugs.

- by Stephan Zech
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- Genetics, Microbiology, Mass Spectrometry, Taxonomy

Models for drugs exhibiting target-mediated drug disposition (TMDD) play an important role in the investigation of biological products (Mager and Jusko 2001). These models are often overparameterized and difficult to converge. A simpler quasi-equilibrium (QE) approximation of the general model has been suggested (Mager and Krzyzanski 2005), but even this simpler form can be overparameterized when, for example, drug target level is not available. This work (a) introduces quasisteady-state (QSS) and Michaelis-Menten (MM) approximations of the TMDD model, (b) derives the relationships between the parameters of the TMDD, QE, QSS and MM models, (c) investigates the parameter ranges where the simplified approximations are equivalent to the TMDD model, (d) proposes an algorithm for establishing identifiability of these models, and (e) tests this algorithm on simulated datasets. The proposed QSS approximation is more general than the QE approximation: it degenerates into the QE approximation when the internalization rate of the drug-target complex is much smaller than its dissociation rate. The proposed identifiability analysis algorithm may be applied to provide justification for use of simplified approximations, avoiding use of incorrect parameter estimates of over-parameterized TMDD models while simultaneously saving time and resources required for the pharmacokinetics analysis of drugs with TMDD. The utility of the derived approximations and of the identifiability algorithm was demonstrated on the examples of the simulated data sets. The simulation examples indicated that the QSS model may be preferable to the QE model L. Gibiansky (B)

- by tony kakkar
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- Computer Science, Algorithms, Nonlinear dynamics, Pharmacokinetics

Poor-quality medicines present a serious public health problem, particularly in emerging economies and developing countries, and may have a significant impact on the national clinical and economic burden. Attention has largely focused on the increasing availability of deliberately falsified drugs, but substandard medicines are also reaching patients because of poor manufacturing and quality-control practices in the production of genuine drugs (either branded or generic). Substandard medicines are widespread and represent a threat to health because they can inadvertently lead to healthcare failures, such as antibiotic resistance and the spread of disease within a community, as well as death or additional illness in individuals. This article reviews the different aspects of substandard drug formulation that can occur (for example, pharmacological variability between drug batches or between generic and originator drugs, incorrect drug quantity and presence of impurities). The possible means of addressing substandard manufacturing practices are also discussed. A concerted effort is required on the part of governments, drug manufacturers, charities and healthcare providers to ensure that only drugs of acceptable quality reach the patient. Definitions In 2009, the World Health Organization (WHO) defined 'substandard' drugs (also called 'out of specification products') as 'genuine medicines produced by manufacturers authorized by the NMRA [national medicines regulatory

- by Atholl Johnston
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- Regulation, Quality Control, Inspection, Falsification

Brazil is blessed with a great biodiversity, which constitutes one of the most important sources of biologically active compounds, even if it has been largely underexplored. As is the case of the Amazon and Atlantic rainforests, the Brazilian marine fauna remains practically unexplored in the search for new biologically active natural products. Considering that marine organisms have been shown to be one of the most promising sources of new bioactive compounds for the treatment of different human diseases, the 8000 km of the Brazilian coastline represents a great potential for finding new pharmacologically active secondary metabolites. This review presents the status of marine natural products chemistry in Brazil, including results reported by different research groups with emphasis on the isolation, structure elucidation, and evaluation of biological activities of natural products isolated from sponges, ascidians, octocorals, and Opistobranch mollusks. A brief overview of the first Brazilian program on the isolation of marine bacteria and fungi, directed toward the production of biologically active compounds, is also discussed. The current multidisciplinary collaborative program under development at the Universidade de Sã o Paulo proposes to establish a new paradigm toward the management of the Brazilian marine biodiversity, integrating research on the species diversity, ecology, taxonomy, and biogeography of marine invertebrates and microorganisms. This program also includes a broad screening program of Brazilian marine bioresources, to search for active compounds that may be of interest for the development of new drug leads.

- by Ana Cristina de Souza
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- Marine Biology, Natural Products, Brazil, Porifera

We have used a Bayesian neural network to distinguish between drugs and nondrugs. For this purpose, the CMC acts as a surrogate for drug-like molecules while the ACD is a surrogate for nondrug-like molecules. This task is performed by using two different set of 1D and 2D parameters. The 1D parameters contain information about the entire molecule like the molecular weight and the the 2D parameters contain information about specific functional groups within the molecule. Our best results predict correctly on over 90% of the compounds in the CMC while classifying about 10% of the molecules in the ACD as drug-like. Excellent generalization ability is shown by the models in that roughly 80% of the molecules in the MDDR are classified as drug-like. We propose to use the models to design combinatorial libraries. In a computer experiment on generating a drug-like library of size 100 from a set of 10 000 molecules we obtain at least a 3 or 4 order of magnitude improvement over random methods. The neighborhoods defined by our models are not similar to the ones generated by standard Tanimoto similarity calculations. Therefore, new and different information is being generated by our models, and so it can supplement standard diversity approaches to library design.

- by Mark Murcko
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- Organic Chemistry, Medicinal Chemistry, Drug Design, Bayes Theorem

The perormance of two groups of hospitalized mentally ill patients (schizophrenia and major depression) and two groups of non-mentally-ill patients (patients hospitalized for ischemic heart disease and non-ill primary care patients) was compared on a standardized, objective instrument for assessing patients' understanding of information relevant for patient decision making (consent) about treatment with medication. Generally, hospitalized schizophrenic patients manifested significantly poorer understanding of “informed consent” disclosures about potential medication than did the other groups. Considerable variance, however, was apparent within the schizophrenic group and was related to a number of clinical and demographic variables. The results are interpreted with reference to issues of compatence to consent to or refuse treatment.

- by Thomas Grisso
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- Psychology, Cognitive Science, Law, Primary Care
- by James Armstrong
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- Pediatrics, Information Management, Anesthesiology, Cell Phones

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / c h r o m b Fast liquid chromatography-quadrupole linear ion trap-mass spectrometry analysis of polyunsaturated fatty acids and eicosanoids in human plasma ଝ Available online xxx Keywords: Mass spectrometry Fast liquid chromatography Linear ion trap On-line solid-phase extraction Eicosanoids Polyunsaturated fatty acid metabolism a b s t r a c t

- by Francesc Ventura
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- Engineering, Analytical Chemistry, Technology, Mass Spectrometry
- by María Vicent
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- Engineering, Technology, Nanomedicine, Polymers

In this paper we describe the hyphenation of high temperature liquid chromatography with ICP-MS and ESI-MS for the characterization of halogen containing drug metabolites. The use of temperature gradients up to 200 • C enabled the separation of metabolites with low organic modifier content. This specific property allowed the use of detection methods that suffer from (significant) changes in analyte response factors as a function of the organic modifier content such as ICP-MS. Metabolites of two kinase inhibitors (SB-203580-Iodo and MAPK inhibitor VIII) produced by bacterial cytochrome P450 BM3 mutants and human liver microsomes were identified based on high resolution MS n data. Quantification was done using their normalized and elemental specific response in the ICP-MS. The importance of these kinds of quantification strategies is stressed by the observation that the difference of the position of one oxygen atom in a structure can greatly affect its response in ESI-MS and UV detection.

- by Martin Giera
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- Analytical Chemistry, Mass Spectrometry, Drug metabolism, ICP-MS

The occurrence of 28 pharmaceuticals and 10 estrogens has been investigated in waters from the lower part of the Llobregat River basin, where the main intakes for production of drinking water for Barcelona (Spain) are located. Sampling was programmed to monitor the same mass of water on its way down the river to reflect inputs from discharges, contribution from subsidiaries plus persistence of the compounds in the surface water. Analysis of pharmaceuticals was performed by off-line solid phase extraction (SPE) followed by liquid chromatography-tandem mass spectrometry with a triple quadrupole analyzer (LC-QqQ-MS/MS). Further analysis by ultra performance liquid chromatography-mass spectrometry with a time-of-flight analyzer (UPLC-TOF-MS) has been proposed and applied for confirmation of several of these target compounds. Estrogens have been analysed by on-line SPE-LC-QqQ-MS/MS. Within the class of pharmaceuticals, 23 out of the 28 compounds investigated, were detected in at least one sample. The highest concentrations were observed for the b-blockers metoprolol (8042 ng L À1 ) and sotalol (788 ng L À1 ), the antibiotic ofloxacin (1904 ng L À1 ), and the lipid regulator gemfibrozil (1014 ng L À1 ). Within the group of estrogens, only estrone and estrone-3-sulfate were positively identified, with concentrations for the former (0.82-5.81 ng L À1 ) close in some locations to those considered sufficient to induce estrogenic effects in aquatic organisms (1-10 ng L À1 ). As a general pattern, concentration of target compounds increases along the river flow as expected.

- by Miren López de Alda
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- Mass Spectrometry, Environmental Monitoring, Rivers, Multidisciplinary