bluuebunny/crossref_metadata_2025 huggingface dataset:
Interpatient Variability: Genetic Predisposition and Other Genetic Factors
Authors: West William L. , Knight Enid M. , Pradhan Sikta , Hinds Tanya S.
Published: March 2013

Polymorphisms and other genetic factors related to enzymes metabolizing drugs and xenobiotic chemicals are well known. This article focuses on selected molecular mechanisms and introduces some of the clinical implications arising from genetically determined interpatient variability or expression in some of these enzymes. Selected are the polymorphic enzymes of cytochromes P‐450 (CYP) as examples of phase I enzymes and methyl transferases, n‐acetyl transferases, and glutathione‐s‐transferases as examples of phase II enzymes. The polymorphism surrounding arylhydrocarbon hydroxylase induction is briefly described. Phase I enzymatic reactions are predominantly oxidative, whereas phase II reactions often couple with the byproducts of phase I. Overall, in poor metabolizers, whether phase I or phase II, there is limited metabolism in most patients unless another major metabolic pathway involving other enzymes exists. Drug metabolism also depends on whether the parent compound is a prodrug that forms an active metabolite, and poor metabolizers under this condition will form only trace amounts of an active compound. Therefore, the clinical significance of genetic polymorphisms and other genetic factors may be related to substrate, metabolite, or the major elimination pathway.
Plasma Nitric Oxide Before and After Smoking Cessation with Nicotine Nasal Spray
Authors: Miller Virginia M. , Lewis Debra A. , Rud Kevin S. , Offord Kenneth P. , Croghan Ivana T. , Hurt Richard D.
Published: March 2013

Nicotine may affect cardiovascular function through release of neurotransmitters from autonomic nerves or release of vasoactive substances from the vascular endothelium. Nitric oxide is a neurotransmitter and endothelium‐derived factor that reduces tone of vascular smooth muscle. Experiments were designed to determine whether or not use of nicotine nasal spray for smoking cessation affects plasma levels of nitric oxide. Forty smokers self‐administered nicotine by nasal spray (one 0.5 mg spray to each nostril). Blood samples were taken before the use of the nasal spray and at treatment day 7 for the measurement of cotinine by high pressure liquid chromatography and nitric oxide (NOx) by chemiluminescence. Age‐comparable controls were never‐smokers nonnicotine users recruited from laboratory personnel. Mean plasma concentrations of NOx from smokers before treatment were significantly greater compared with nonsmokers (23 ± 10, n = 40 and 15 ± 6, n = 13 nmoles/mL [mean ± SD], respectively, P < 0.01). Plasma NOx in smokers was not significantly correlated with the average daily number of cigarettes smoked (r2 = 0.02, P > 0.05) but was positively and linearly correlated with plasma cotinine (r2 = 0.13, P < 0.02). In 32 self‐reported abstinent smokers (confirmed by expired carbon monoxide < 9 ppm) using nicotine nasal spray, cotinine decreased by 64% from pretreatment levels of 284 ± 103 to posttreatment levels of 90 ± 58 ng/mL. Plasma NOx was unchanged and went from 23.0 ± 10.1 at pretreatment to 21 ± 12 nmoles/mL with nicotine treatment. These results suggest that nicotine‐use, independent of cigarette smoking, affects plasma NOx.
Use of Chlorzoxazone as an In Vivo Probe of Cytochrome P450 2E1: Choice of Dose and Phenotypic Trait Measure
Authors: Frye Reginald F. , Adedoyin Adedayo , Mauro Kelly , Matzke Gary R. , Branch Robert A.
Published: March 2013

Chlorzoxazone is being developed and proposed for use as a probe to measure in vivo cytochrome P4502E1 activity, but the phenotypic trait measures that are used vary. Although the doses proposed for phenotyping range from 250 mg to 750 mg, the effect of dose on chlorzoxazone hydroxylation has not previously been evaluated. The purpose of this study was to characterize the pharmacokinetics of chlorzoxazone in normal healthy volunteers (N = 6) after single randomized oral doses of 250 mg and 750 mg. An additional 10 volunteers underwent a detailed pharmacokinetic study using the 250‐mg dose to further evaluate proposed phenotypic trait measures (N = 16). Timed blood and urine samples were obtained for 10 hours for chlorzoxazone and 6‐hydroxychlorzoxazone determination by HPLC. Pharmacokinetic parameter estimates were estimated using noncompartmental methods. Evaluation of phenotypic trait measures show that 6‐hydroxychlorzoxazone to chlorzoxazone plasma concentration ratios at 2 to 4 hours after drug administration demonstrated the highest correlations with metabolite formation clearance (r = 0.9; P < 0.001). Urine‐based parameters (e.g., total recovery) were not significantly related to formation clearance (r = 0.5; P > 0.05). Dose dependency in chlorzoxazone metabolism was shown by a 30% increase (P < 0.05) in the dose‐normalized area under the concentration‐time curve (AUC) of chlorzoxazone and lower incremental dose‐normalized urinary recovery of 6‐hydroxychlorzoxazone at early timepoints after the 750‐mg dose. In addition, the plasma ratio of 6‐hydroxychlorzoxazone to chlorzoxazone at 4 hours was reduced by 48% in 5 of 6 subjects after the 750‐mg dose (P > 0.05). These data suggest that 6‐hydroxylation was saturated at the higher dose and illustrate the importance of dose selection in phenotyping. The results of this study indicate that a chlorzoxazone dose of 250 mg should be used and that a single plasma ratio obtained 2 to 4 hours after dosing is reflective of chlorzoxazone 6‐hydroxylation and thus may serve as a cytochrome P4502E1 phenotypic trait measure.
Lack of Interaction Between Tramadol and Coumarins
Authors: Boeijinga Johan K. , van Meegen Erik , van den Ende Romana , Schook C. Edward , Cohen Adam F.
Published: March 2013

The objective of this study was to investigate whether the central analgesic tramadol influences the effects of the coumarin anticoagulant phenprocoumon during multiple‐dose administration. Nineteen patients receiving long‐term anticoagulant therapy who had been in a stable hypothrombinemic state for at least 3 months completed a double‐blind, placebo‐controlled, crossover study. Tramadol was administered in the usual therapeutic dose of 50 mg three times daily. The average daily phenprocoumon dose was identical for individual patients in both treatment periods. The equivalence ratio (tramadol/placebo) of the international normalized ratio (INR) values was 0.99 (90% confidence interval 0.89‐1.10), thus fulfilling predetermined bioequivalence criteria (0.70‐1.43). Therefore, tramadol does not affect INR in patients being treated with phenprocoumon. These data suggest a lack of interaction between tramadol and coumarin anticoagulants.
Pharmacokinetics and Protein Binding of Eprosartan in Healthy Volunteers and in Patients with Varying Degrees of Renal Impairment
Authors: Martin David E. , Chapelsky Martha C. , Ilson Bernard , Tenero David , Boike Steven C. , Zariffa Névine , Jorkasky Diane K.
Published: March 2013

This was an open‐label, parallel group study to compare the pharmacokinetics of multiple oral doses of eprosartan in subjects with normal renal function (Clcr >80 mL/min; n = 8) and patients with mild (Clcr 60–80 mL/min; n = 8), moderate (Clcr 30–59 mL/min; n = 15), or severe (Clcr <30 mL/min; n = 3) renal insufficiency. Each subject received oral eprosartan 200 mg twice daily for 6 days and a single dose on day 7. Mean total maximum concentration (Cmax) and area under the concentration—time curve from 0 to 12 hours (AUC0–12) were similar for healthy subjects and those with mild renal impairment, but were an average of 25% to 35% and 51% to 55% greater for patients with moderate and severe renal impairment, respectively, compared with healthy subjects. Mean renal clearance (Clr), which was similar for healthy subjects and patients with mild renal impairment, was decreased an average of 41% and 95% in the groups with moderate and severe renal impairment, respectively, compared with normal subjects. Eprosartan was highly bound to plasma proteins in all groups; however, the unbound fraction was increased approximately two‐fold in the group with severe renal impairment. Mean unbound Cmax and AUC0–12 were an average of 53% to 61% and 185% to 210% greater for the patients with moderate and severe renal impairment, respectively, compared with healthy subjects. Headache was the most common adverse experience reported in all subgroups. Eprosartan was safe and well tolerated regardless of degree of renal impairment. Cmax and AUC were increased and renal clearance decreased in patients with moderate to severe renal impairment in comparison to healthy subjects and patients with mild renal impairment. However, based on the moderate renal clearance and known safety profile of eprosartan, it is not necessary to adjust the dose of eprosartan in patients with renal insufficiency.
Droperidol Elimination After Cardiopulmonary Bypass Surgery
Authors: Sawyer Catherine A. , Baker . A. Barry , Ramzan Iqbal , Regaglia Francesca
Published: March 2013

A high‐dose (0.75 to 2.8 mg/kg) pharmacokinetic study of droperidol was undertaken in patients during the recovery phase after cardiac surgery involving hypothermic cardiopulmonary bypass (CPB). The elimination half‐life of droperidol in these patients, determined from concentration—time data obtained after CPB, was significantly prolonged relative to previously reported mean values in younger surgical patients not undergoing CPB and receiving lower doses of the drug (0.05–0.20 mg/kg). On stratification of the patients by droperidol dose, there was an inverse correlation between the size of the dose and the elimination half‐life of droperidol: mean half‐life decreased as mean dose increased. This difference in elimination half‐life was not related to the duration of the CPB procedure, or the total anesthetic time, both of which were not significantly different between the patient groups receiving the three different doses of droperidol. The magnitude or duration of hypothermia after CPB did not differ between the three patient groups. The differences in half‐lives are more likely due to the clinical condition of the patients, such that the patients who received the higher doses of droperidol were also judged clinically to be less ill and thus eliminated droperidol more efficiently. This hypothesis, however, could not be supported due to the small number of patients studied. The results obtained in this study indicate that droperidol elimination is significantly prolonged after high‐dose administration to elderly patients undergoing hypothermic CPB procedures during cardiac surgery.
Steady‐State Pharmacokinetics of Zonisamide, an Antiepileptic Agent for Treatment of Refractory Complex Partial Seizures
Authors: Kochak Gregory M. , Page John G. , Buchanan Robert A. , Peters Richard , Padgett Claire S.
Published: March 2013

A 56‐day pharmacokinetic study of zonisamide was conducted in 24 healthy volunteers. Steady state was achieved in 29 days including two dose escalations, and in an average of 15 days from the last dose adjustment. Twice‐daily administration of 200 mg every 12 hours produced a 14% serum level fluctuation at steady state. After once‐daily administration of 400 mg, a 27% serum level fluctuation was observed. The terminal phase half‐life after the last dose was 63 to 69 hours, which is consistent with the half‐life of 52 to 60 hours found in single‐dose studies. This result demonstrates that zonisamide is not an autoinducer. Serum oral clearance of 0.60 to 0.71 L/hr (0.121–0.132 mL/min/kg) was similar to that observed in other multiple‐dose studies.
Efficacy of Intravenous Granisetron in Suppressing the Bradycardia and Hypotension Associated with a Rabbit Model of the Bezold‐Jarisch Reflex
Authors: White C. Michael , Chow Moses S. S. , Fan Chengde , Kluger Jeffrey , Bazunga Munama
Published: March 2013

This study investigated whether granisetron, a 5‐HT3 receptor antagonist, can alter the Bezold‐Jarisch reflex (i.e., hypotension and inappropriate heart rate slowing). A hemorrhagic rabbit model that has been shown to induce the Bezold‐Jarisch reflex was used. In 11 rabbits (3.8 kg), catheters were placed in the carotid arteries one day before experimental hemorrhage. On the day of the study, the rabbits were given intravenous granisetron (50 μg/kg) or an equal volume of saline. Five minutes after administration of granisetron or saline, hemorrhage was induced by continuous blood withdrawal at 5 mL/min and blood pressure (BP) and heart rates were obtained at frequent intervals until systolic BP declined to 80 mmHg. Six rabbits received saline and five granisetron. An average of 77.6 mL ± 16.4 mL of blood was removed in the group receiving granisetron (compared with 56.5 mL ± 13.1 mL for the saline group) before achieving the target systolic BP of 80 mmHg. The group receiving granisetron demonstrated the same ability to increase their heart rate from baseline as the saline group. However, the granisetron group had a final heart rate that was closer to their maximal heart rate than the saline group. In this animal model, granisetron was significantly more effective at preventing inappropriate heart rate slowing and allowed significantly more blood to be removed before reaching the target blood pressure. This implies that granisetron may be effective in preventing vasovagal syncope, although further study should be carried out to verify these potentially interesting findings.
Effect of Troglitazone on Steady‐State Pharmacokinetics of Digoxin
Authors: Loi Cho‐Ming , Knowlton Philip W. , Stern Ralph , Randinitis Edward J. , Vassos Artemios B. , Koup Jeffrey R. , Sedman Allen J.
Published: March 2013

Twelve healthy subjects participated in a study to determine the effect of multiple doses of troglitazone on the steady‐state pharmacokinetics of digoxin. Subjects received digoxin 0.25 mg orally once daily on days 1 through 20 and 400 mg of troglitazone orally once daily on days 11 through 20. Serial plasma samples and 24‐hour urine samples collected before and after the doses on days 10 and 20 were analyzed for digoxin using a radioimmunoassay method. Eleven subjects completed the study. Administration of multiple oral doses of digoxin and troglitazone was well tolerated. Mean values for maximum concentration (Cmax), time to Cmax (tmax), and area under the concentration—time curve from 0 to 24 hours (AUC0–24) of digoxin on day 10 were similar to those on day 20. Mean day 10 digoxin values for minimum concentration (Cmin), apparent oral clearance (Cl/F), total urinary excretion from 0 to 24 hours (Ae0–24), and renal clearance (Clr) were also similar to corresponding values on day 20. Thus, concomitant administration of multiple‐dose troglitazone does not alter the steady‐state pharmacokinetics of digoxin.
Evaluation of the Potential Interaction Between Felbamate and Erythromycin in Patients with Epilepsy
Authors: Sachdeo Rajesh C. , Narang‐Sachdeo Satinder , Montgomery Paul A. , Shumaker Robert C. , Perhach James L. , Lyness William H. , Rosenberg Alberto
Published: March 2013

Effects of erythromycin on hepatic CYP450 3A4 isozymes can profoundly influence the metabolism of many therapeutic agents. An open‐label, randomized, two‐period, crossover study was therefore conducted to evaluate the pharmacokinetics of felbamate before and after a concurrent 10‐day regimen (333 mg three times daily) of erythromycin. Patients were receiving either 3,000 or 3,600 mg/day felbamate monotherapy for treatment of epilepsy. Mean dose‐normalized values for maximum concentration (Cmax) and area under the concentration—time curve (AUCr) of felbamate were not statistically different in patients taking felbamate as monotherapy than in patients after erythromycin coadministration. Estimates of time to Cmax (tmax), minimum concentration (Cmin), apparent clearance (Cl/kg), average concentration (Cav), and degree of fluctuation (DFss) were likewise unchanged. The incidence of mild and moderate adverse events increased during coadministration of the two drugs. Because patients with epilepsy can not be treated with erythromycin alone, it could not be determined whether the adverse events were attributable to erythromycin or to the combination of the two drugs. Steady‐state pharmacokinetic parameters of felbamate were not influenced by erythromycin coadministration.
Performance of Human Mass Balance Studies with Stable Isotope‐Labeled Drug and Continuous Flow‐Isotope Ratio Mass Spectrometry: A Progress Report
Authors: Browne Thomas R. , Szabo George K. , Ajami Alfred , Browne David G.
Published: March 2013

We propose performing human mass balance studies by administering stable isotope labeled (13C or 15N) drug and quantitating excess (above background) 13C or 15N in urine, serum, and feces by continuous flow‐isotope ratio mass spectrometry (CF‐IRMS). Theoretical calculations and empirical data (dynamic range, linearity, sensitivity, precision, accuracy) are presented to establish that commercially available CF‐IRMS instruments can quantitate stable isotope labeled (one or two 15N or 13C labels) drug concentrations of 1.0 μg/mL or greater in urine, serum (15N), or feces. More than two 13C labels may be necessary to quantitate 1.0 μg/mL of drug in serum. Three volunteers received 650 mg of 15N13C2‐acetaminophen, and urine was collected for 72 hours. Percent of administered label recovered in urine from the three subjects was 97.4, 78.9, and 95.4 for 13C and 90.3, 77.0, and 90.6 for 15N. Fecal recovery of label for one subject was 0.9% (13C2) and 1.1% (15N). Serum pharmacokinetic values obtained by counting 13C or 15N in one subject were as expected for acetaminophen. This method appears to be promising, and further validation is ongoing.
A Phase I/II Evaluation of Oral L‐2‐Oxothiazolidine‐4‐Carboxylic Acid in Asymptomatic Patients Infected with Human Immunodeficiency Virus
Authors: Barditch‐Crovo Patricia , Noe Dennis , Skowron Gail , Lederman Michael , Kalayjian Robert C. , Borum Peggy , Buier Rose , Rowe W. Bruce , Goldberg Dennis , Lietman Paul
Published: March 2013

A randomized double‐blind, placebo‐controlled study was conducted in 37 asymptomatic HIV‐infected individuals (mean CD4 count 707 cells/mm3) to characterize the safety, pharmacokinetics, and effect on blood thiols of three dosage levels of a cysteine prodrug, L‐2‐oxothiazolidine‐4‐carboxylic acid (OTC; Procysteine; Clintec Technologies, Deerfield, IL). Single‐dose administration of OTC resulted in measurable plasma levels at all dosages, with a mean peak plasma concentration of 734 ± 234 nmol/mL at the highest dosage studied. After 4 weeks of administration three times daily, a statistically significant increase was seen in whole blood glutathione in the 1,500 mg and 3,000 mg dose groups compared with the placebo group. A significant increase in whole blood cysteine and peripheral blood mononuclear cell (PBMC) glutathione was not seen during the study period.
The Sodium‐Calcium Ion Membrane Exchanger: Physiologic Significance and Pharmacologic Implications
Authors: Yashar Payam R. , Fransua Mesfin , Frishman William H.
Published: March 2013

The Na+‐Ca2+ exchanger is a non‐ATP—dependent protein that, under steady‐state conditions, extrudes Ca2+ from the interior of the cell into the extracellular space via facilitated transport. The activity of the exchanger seems to be reduced in myocardial ischemia, leading to increased intracellular Ca2+ in the ischemic heart, which can result in arrhythmia, myocardial stunning, and necrosis. In contrast, congestive heart failure and myocardial hypertrophy are associated with increased exchanger activity and a decreased inotropic state. Pharmacologic agents are being developed to modulate sodium ion levels in the cell, which could enhance or reduce sodium‐calcium exchange as needed in various pathophysiologic states. At this time there are no available drugs that act specifically on the Na+‐Ca2+ exchanger itself. The exchanger has been cloned, and inhibitory peptides of the exchanger may soon be available for possible use in treatment of congestive heart failure.
The Effects of Gender on Adrenergic Receptor Responsiveness
Authors: Luzier Aileen Bown , Nawarskas James J. , Añonuevo John , Wilson Michael F. , Kazierad David J.
Published: March 2013

This study was conducted to determine whether gender differences exist in adrenergic receptor sensitivity and baroreflex response. Adrenergic receptor sensitivity was assessed by administering sequentially increasing intravenous doses of phenylephrine and isoproterenol. Baroreflex sensitivity was determined from the slope of pulse intervals plotted against phenylephrine‐induced rise in systolic blood pressure (SBP). Drug‐induced changes in heart rate, blood pressure, and brachial artery diameter were measured and statistically compared. Women required a lower infusion rate of phenylephrine to increase SBP by 20 mmHg from baseline. There were no statistically significant gender‐related differences in baroreflex sensitivity. The dose of isoproterenol needed to increase heart rate by 25 beats per minute from baseline also did not differ significantly between groups. Percent changes from baseline in brachial artery diameters in response to phenylephrine also were similar between groups. These data suggest that women may have greater α1‐adrenergic receptor sensitivity than men, whereas β‐adrenergic receptor sensitivity is similar between genders. A trend toward a greater baroreflex sensitivity in men than in women was also observed. This study also provides evidence for a possible relationship between adrenergic receptor sensitivity and baroreflex sensitivity.
Effect of Hepatic Impairment on the Pharmacokinetics of Zolmitriptan
Authors: Dixon R. , French S. , Kemp J. , Sellers M. , Leclerc V. , Delvaux M. , Rautureau J.
Published: March 2013

Zolmitriptan, an oral 5HT1D agonist for the acute treatment of migraine, is cleared from the systemic circulation mainly by hepatic metabolism. Consequently, changes in hepatic function may result in changes in the pharmacokinetics of zolmitriptan. This open, parallel‐group study was conducted to compare the pharmacokinetics and tolerability of a single 10‐mg dose of zolmitriptan in healthy subjects and patients with hepatic impairment. A total of 37 participants entered and completed the study, including 10 healthy volunteers, 11 patients with moderate hepatic impairment, 10 patients with severe hepatic impairment without ascites, and 6 patients with severe hepatic impairment with ascites. The metabolism of zolmitriptan was reduced in patients with severe hepatic impairment compared with healthy subjects, resulting in higher peak plasma concentrations (47%), increased exposure (226%), and prolonged half‐life (157%). The changes were similar in the presence and absence of ascites. Smaller changes were observed in patients with moderate hepatic impairment. Plasma concentrations of the three major metabolites of zolmitriptan were reduced in the patients with hepatic impairment. Patients with moderate hepatic impairment require no dosage adjustment, but the recommended daily intake of zolmitriptan may need to be reduced in patients with severe hepatic impairment.
Plasma Protein Binding of Letrozole, a New Nonsteroidal Aromatase Enzyme Inhibitor
Authors: Colussi Danielle M. , Parisot Carole Y. , Lefèvre Gilbert Y.
Published: March 2013

The protein binding characteristics of the nonsteroidal aromatase inhibitor letrozole were determined using 14C‐labeled letrozole. The binding of letrozole in human serum was 60.1 ± 2.9% as a mean obtained in six individual sera and was similar in human plasma. The binding in human serum remained constant at concentrations of letrozole ranging from 10 to 500 ng/mL. A similar binding value in human serum was obtained using equilibrium dialysis and ultrafiltration technique. Albumin (binding 55.1 ± 1.4%) is the main protein involved in the drug binding to plasma proteins. Increases in letrozole concentration (10–500 ng/mL) had no effect on binding. Albumin binding appeared to be nonsaturable with a binding capacity of 2 L/mmol. Binding to α1‐acid glycoprotein and to gamma globulins was lower than 10%. The fraction in erythrocytes with a hematocrit of 0.4 was found to be 35.2 ± 2.7%. Letrozole binding to serum proteins of rat, dog, mouse, and rabbit was approximately 10% lower than that in human serum and approximately 20% lower than that in baboons. Tamoxifen (100‐1,500 ng/mL) had no effect on the in vitro binding of letrozole. Ex vivo binding in plasma from patients after repeated administration of letrozole alone (61.4 ± 2.6%) was the same as after combined administration of letrozole and tamoxifen (60.0 ± 3.2%).
Tissue growth into three‐dimensional composite scaffolds with controlled micro‐features and nanotopographical surfaces
Authors: Tamjid Elnaz , Simchi Arash , Dunlop John W. C. , Fratzl Peter , Bagheri Reza , Vossoughi Manouchehr
Published: March 2013

Controlling topographic features at all length scales is of great importance for the interaction of cells with tissue regenerative materials. We utilized an indirect three‐dimensional printing method to fabricate polymeric scaffolds with pre‐defined and controlled external and internal architecture that had an interconnected structure with macro‐ (400–500 μm) and micro‐ (∼25 μm) porosity. Polycaprolactone (PCL) was used as model system to study the kinetics of tissue growth within porous scaffolds. The surface of the scaffolds was decorated with TiO2 and bioactive glass (BG) nanoparticles to the better match to nanoarchitecture of extracellular matrix (ECM). Micrometric BG particles were also used to reveal the effect of particle size on the cell behavior. Observation of tissue growth and enzyme activity on two‐dimensional (2D) films and three‐dimensional (3D) scaffolds showed effects of nanoparticle inclusion and of surface curvature on the cellular adhesion, proliferation, and kinetics of preosteoblastic cells (MC3T3‐E1) tissue growth into the pore channels. It was found that the presence of nanoparticles in the substrate impaired cellular adhesion and proliferation in 3D structures. Evaluation of alkaline phosphate activity showed that the presence of the hard particles affects differentiation of the cells on 2D films. Notwithstanding, the effect of particles on cell differentiation was not as strong as that seen by the curvature of the substrate. We observed different effects of nanofeatures on 2D structures with those of 3D scaffolds, which influence the cell proliferation and differentiation for non‐load‐bearing applications in bone regenerative medicine. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 101A:2796–2807, 2013.
DBU Promoted Facile Synthesis of New Thieno[2,3‐b]pyridine/quinoline Derivatives and Their Antimicrobial Evaluation
Authors: Kumar Chebolu Naga Sesha Sai Pavan , Srihari Ejjirothu , Ravinder Mettu , Kumar Koochana Pranay , Murthy U. S. N. , Rao Vaidya Jayathirtha
Published: March 2013

Several new thieno[2,3‐b]pyridine and thieno[2,3‐b]quinoline derivatives are synthesized in an efficient manner catalyzed by DBU as a base. Simple workup procedure, good yields, and mild reaction conditions are the salient features of this method. All the synthesized compounds are screened for antimicrobial activity against several organisms.
1,3‐Dipolar Cycloaddition of 4‐Chlorobenzonitrile Oxide with Some Dipolarophiles: Theoretical Analysis of Regioselectivity
Authors: Bakavoli Mehdi , Moeinpour Farid , Sardashti‐Birjandi Arezoo , Davoodnia Abolghasem
Published: March 2013

Reaction of 4‐chlorobenzonitrile oxide (2) which was generated in situ with acrylo nitrile (3), vinyl acetate (4) and allyl bromide (5) as dipolarphile afforded the new cycloadducts 6a, 7a, and 8a compounds, respectively. Reactivity and regiochemistry of these reactions were investigated using activation energy calculations and density functional theory‐based reactivity indexes. The theoretical 13C NMR chemical shifts of the cycloadducts which were obtained by gauge‐invariant atomic orbital method were comparable with the observed values.
Strategies for improving family engagement during family‐centered rounds
Authors: Kelly Michelle M. , Xie Anping , Carayon Pascale , DuBenske Lori L. , Ehlenbach Mary L. , Cox Elizabeth D.
Published: March 2013

BACKGROUND

Family‐centered rounds (FCR) are recommended as standard practice in the pediatric inpatient setting; however, limited data exist on best practices promoting family engagement during rounds.

OBJECTIVE

To identify strategies to enhance family engagement during FCR using a recognized systems engineering approach.

METHODS

In this qualitative study, stimulated recall interviews using video‐recorded rounding sessions were conducted with participants representing the various stakeholders on rounds (15 parents/children and 22 healthcare team [HCT] members) from 4 inpatient services at a children's hospital in Wisconsin. On video review, participants were asked to provide strategies that would increase family engagement on FCR. Qualitative content analysis of interview transcripts was performed in an iterative process.

RESULTS

We identified 21 categories of strategies corresponding to 2 themes related to the structure and process of FCR. Strategies related to the structure of FCR were associated with all five recognized work system elements: people (HCT composition), tasks (HCT roles), organization (scheduling of rounds and HCT training), environment (location of rounds and HCT positioning), and tools and technologies (computer use). Strategies related to the FCR process were associated with three rounding phases: before (HCT and family preparation), during (eg, introductions, presentation content, communication style), and after (follow‐up) FCR.

CONCLUSIONS

We identified a range of strategies to enhance family engagement during FCR. These strategies both confirm prior work on the importance of the content and style of communication on rounds and highlight other factors within the hospital work system, like scheduling and computer use, which may affect family engagement in care. Journal of Hospital Medicine 2013;8:201–207. © 2013 Society of Hospital Medicine
‐corrected water–fat imaging using compressed sensing and parallel imaging
Authors: Wiens Curtis N. , McCurdy Colin M. , Willig‐Onwuachi Jacob D. , McKenzie Charles A.
Published: March 2013

Purpose

To demonstrate an approach to water–fat separation with
correction using compressed sensing and parallel imaging.

Methods

Acquisition times for chemical shift based water–fat separation imaging are lengthy, and many applications rely on image acceleration techniques. In this study, we present an integrated compressed sensing, parallel imaging,
corrected water–fat separation technique for water–fat imaging of highly accelerated acquisitions. Reconstruction times are reduced using coil compression.

Results

The proposed technique is demonstrated using a customized IDEAL‐SPGR pulse sequence to acquire retrospectively and prospectively undersampled datasets of the liver, calf, knee, and abdominal cavity. This technique is shown to offer comparable image quality relative to fully sampled reference images for a range of acceleration factors. At high acceleration factors, this technique is shown to offer improved image quality over parallel imaging.

Conclusion

A technique is described that uses compressed sensing and parallel imaging to reconstruct
‐corrected water and fat images from accelerated datasets. Acceleration factors as high as 7.0 are shown with excellent image quality. These high acceleration factors enable water–fat separation with higher resolution or greater anatomical coverage in breath‐hold applications. Magn Reson Med 71:608–616, 2014. © 2013 Wiley Periodicals, Inc.
Intramolecular zero‐quantum‐coherence 2D NMR spectroscopy of lipids in the human breast at 7 T
Authors: de Graaf Robin A. , Klomp Dennis W. J. , Luijten Peter R. , Boer Vincent O.
Published: March 2013

Purpose

Intramolecular zero‐quantum‐coherences (ZQCs) are intrinsically insensitive toward magnetic field inhomogeneity. This fact is used to quantify and characterize lipid signals in the human breast at 7 T despite the presence of severe magnetic field inhomogeneity caused by water–lipid susceptibility boundaries.

Methods

A novel 3D localized 2D ZQC method is presented. The combination of cardiac/respiratory triggering and post‐acquisition navigator echo correction provides high‐quality 2D NMR spectra in vivo.

Results

The lipid profile of the human breast could be quantified by 2D ZQC NMR in 100% of the subjects despite a wide range of magnetic field homogeneity. With conventional 1D 1H MRS, the magnetic field homogeneity was only adequate in 60% of the subjects. The results from 2D ZQC NMR and 1D NMR are in good correspondence, both in vitro and in vivo.

Conclusion

It has been demonstrated that high quality and quantitative 2D ZQC NMR spectra can be acquired from human breast tissue at 7 T. While the simplicity and sensitivity of 1D MRS are preferable when the magnetic field homogeneity is adequate, the 2D ZQC method provides a viable alternative in cases where this requirement cannot be met. Magn Reson Med 71:451–457, 2014. © 2013 Wiley Periodicals, Inc.
Automatic detection of small bowel contraction frequencies in motility plots using lomb‐scargle periodogram and sinus‐fitting method—initial experience
Authors: Bickelhaupt Sebastian , Cattin Roger , Froehlich Johannes M. , Raible Stephan , Bouquet Hanspeter , Bill Urs , Patak Michael A.
Published: March 2013

Purpose

Contraction frequencies are an important parameter for the analysis of bowel motility in MRI. The contraction curve can be rather noisy and the frequency‐evaluation might be difficult. The aim was to evaluate manual calculations of small bowel contraction frequency in comparison with automatic calculations using two mathematically established methods.

Methods

The institutional‐review‐board approved study consisted of 48 segmental small‐bowel motility‐plots out of a previous study with 25 patients (15 men/10 women; mean 39 years, standard deviation ± 14.67) undergoing MRI (1.5 T, GE‐Medical Systems; two‐dimensional‐Fiesta, pulse repetition time 2.91, echo time 1.25, flip‐angle 45°, matrix 256 × 256, slice thickness 10 mm) were evaluated. Calculations of contraction frequency was performed either manually or using Lomb‐Scargle‐periodograms and Sinus‐Fitting method. The results were compared using intraclass correlation coefficient, Friedman's‐test and Wilcoxon‐matched‐paired‐signed‐rank‐test (P < 0.05 considered statistically significant).

Results

Mean contraction frequency was 5.69 (standard deviation ± 1.99) for manual calculations showing moderate interreader reliability (intraclass correlation coefficient 0.72; 95% confidence‐interval: 0.59;0.82). No significant difference (P = 0.776) was found to Lomb‐Scargle‐periodograms (5.34 contractions‐per‐minute [cpm], standard deviation ± 2.47; P = 0.174) and to the sinus‐fitting‐method (5.47 cpm; standard deviation ± 2.57; P = 0.0779). For the latter calculations failed in 3/48 plots, while manual and Lomb‐Scargle‐periodograms could be performed successfully in all 48/48 plots.

Conclusion

Herein, we could show that Lomb‐Scargle‐periodograms and Sinus‐Fitting are fast and reliable methods to automatically measure small‐bowel contraction frequencies even in noisy small bowel motility plots. Magn Reson Med 71:628–634, 2014. © 2013 Wiley Periodicals, Inc.
Partial input to output impacts in DEA: Production considerations and resource sharing among business subunits
Authors: Imanirad Raha , Cook Wade D. , Zhu Joe
Published: March 2013

Data envelopment analysis (DEA) is a methodology for evaluating the relative efficiencies of peer decision‐making units (DMUs), in a multiple input/output setting. Although it is generally assumed that all outputs are impacted by all inputs, there are many situations where this may not be the case. This article extends the conventional DEA methodology to allow for the measurement of technical efficiency in situations where only partial input‐to‐output impacts exist. The new methodology involves viewing the DMU as a business unit, consisting of a set of mutually exclusive subunits, each of which can be treated in the conventional DEA sense. A further consideration involves the imposition of constraints in the form of assurance regions (AR) on pairs of multipliers. These AR constraints often arise at the level of the subunit, and as a result, there can be multiple and often inconsistent AR constraints on any given variable pair. We present a methodology for resolving such inconsistencies. To demonstrate the overall methodology, we apply it to the problem of evaluating the efficiencies of a set of steel fabrication plants. © 2013 Wiley Periodicals, Inc. Naval Research Logistics, 2013
Uncertainty quantification of high‐dimensional complex systems by multiplicative polynomial dimensional decompositions
Authors: Yadav Vaibhav , Rahman Sharif
Published: March 2013

The central theme of this paper is multiplicative polynomial dimensional decomposition (PDD) methods for solving high‐dimensional stochastic problems. When a stochastic response is dominantly of multiplicative nature, the standard PDD approximation, predicated on additive function decomposition, may not provide sufficiently accurate probabilistic solutions of a complex system. To circumvent this problem, two multiplicative versions of PDD, referred to as factorized PDD and logarithmic PDD, were developed. Both versions involve a hierarchical, multiplicative decomposition of a multivariate function, a broad range of orthonormal polynomial bases for Fourier‐polynomial expansions of component functions, and a dimension‐reduction or sampling technique for estimating the expansion coefficients. Three numerical problems involving mathematical functions or uncertain dynamic systems were solved to corroborate how and when a multiplicative PDD is more efficient or accurate than the additive PDD. The results show that indeed, both the factorized and logarithmic PDD approximations can effectively exploit the hidden multiplicative structure of a stochastic response when it exists. Since a multiplicative PDD recycles the same component functions of the additive PDD, no additional cost is incurred. Finally, the random eigensolutions of a sport utility vehicle comprising 40 random variables were evaluated, demonstrating the ability of the new methods to solve industrial‐scale problems. Copyright © 2013 John Wiley & Sons, Ltd.
Structure and performance of poly(vinylidene fluoride) membrane with temperature‐sensitive poly(n‐isopropylacrylamide) homopolymers in membrane pores
Authors: Chen Xi , Shi Congcong , Wang Zeya , He Yang , Bi Shiyin , Feng Xia , Chen Li
Published: March 2013

The poly(vinylidene fluoride) (PVDF)/poly(N‐isopropylacrylamide) (PNIPAM) blend membranes with different PNIPAM contents are prepared by phase inversion of PNIPAM and PVDF in aqueous medium. The membranes are characterized by thermal gravimetric analyses, elemental analysis, Fourier transform infrared spectrometer, X‐ray photoelectron spectroscopy, and scanning electron microscope photographs. The results indicate that PNIPAM chains are largely distributed in membrane pore other than membrane surface, and furthermore, with the increase of PNIPAM content, the porous size, porosity, and water flux through the membrane increase, the hydrophilicity and antiprotein fouling are enhanced. The blend membrane exhibits temperature‐sensitive permeability to aqueous solutions, with the most drastic change being observed at the lower critical solution temperature (LCST) of PNIPAM (around 32°C). Below the LCST, the blend membrane shows a high protein rejection and a low water flux; above the LCST, the blend membrane shows a low protein rejection and a high water flux. POLYM. COMPOS., 2013. © 2013 Society of Plastics Engineers
Mechanical and morphological properties of wood plastic composites based on municipal plastic waste
Authors: Kazemi Yasamin , Cloutier Alain , Rodrigue Denis
Published: March 2013

Production and characterization of wood plastic composites (WPC) from the light fraction of municipal plastic wastes (post‐consumer) and wood processing residues (sawdust) were investigated. Composition analysis revealed the presence of polyethylene (PE) and polypropylene (PP) as the two main components of the matrix. In order to improve compatibility and adhesion between all the phases, an ethylene–octene copolymer was used to compatibilize the polymer phases and was also acting as an impact modifier, while the addition of maleated polyethylene and maleated polypropylene (MAPP) were acting as coupling agents between the polymer matrix and the wood flour. The combined effect of all the components was found to produce composites with interesting morphological (dispersion and adhesion) and mechanical properties (tension, torsion, flexion, and impact) after optimization of the additive package (blend of coupling agents). POLYM. COMPOS., 2013. © 2013 Society of Plastics Engineers
Evaluating the introduction of a computerized prior‐authorization system on the completeness of drug exposure data
Authors: Gamble John‐Michael , Johnson Jeffrey A. , Majumdar Sumit R. , McAlister Finlay A. , Simpson Scot H. , Eurich Dean T.
Published: March 2013

Purpose

Administrative databases that only capture records for benefit‐approved prescriptions may underestimate exposure because they do not capture non‐benefit prescriptions. Using a natural experiment, we illustrate the impact of automating a prior‐authorization policy on the completeness of drug exposure.

Methods

Using Saskatchewan (Canada) databases, weekly counts of benefit‐approved and total prescription records in 2006 for new users of antidiabetic agents were examined across four categories: thiazolidinediones (TZDs), metformin, glyburide, and insulin. On July 1, 2006, Saskatchewan's public drug plan implemented an automated, online‐adjudicated, prior‐authorization process for TZDs; previously, prior approval was paper based. No such policy changes occurred for other drugs. We estimated the effect of this policy change on drug exposure using interrupted time‐series analyses.

Results

We examined 223 552 prescription records: 19% were for TZDs, 48% for metformin, 20% for glyburide, and 13% for insulin. Prior to automation, there were, on average, 571 benefit‐approved TZD records per week; however, the number of benefit‐approved TZD records increased immediately after the automated process was introduced by 240 prescriptions per week (95% CI 200–280, p < 0.001). The average proportion of TZD benefit‐approved records was 73% before and increased to 93% immediately following policy change (20% absolute change, 95% CI 18.7–20.4%). No changes were observed for metformin, glyburide, or insulin (p > 0.1 for all).

Conclusions

Automating prior authorization for TZDs immediately increased the proportion of captured TZD records, suggesting in our study that one‐fifth of TZD exposure was previously misclassified. If replicable, this indicates that even subtle changes in reimbursement policy may affect the validity of drug exposure data. Copyright © 2013 John Wiley & Sons, Ltd.
Laser Ignition of Nano‐Composite Energetic Loose Powders
Authors: Stacy Shawn C. , Pantoya Michelle L.
Published: March 2013

Laser ignition experiments were conducted to better understand parameters that influence ignition of energetic materials. A Nd:YAG laser (10 ms, 1.5 J, 3 mm spot diameter) was used to heat the top surface of an energetic powder composed of nanometric aluminum (Al) combined stoichiometrically with an oxidizer (copper oxide (CuO), iodine pentoxide (I2O5), polytetrafluoroethylene (C2F4), molybdenum trioxide (MoO3) or iron oxide (Fe2O3)). Ignition delay time was calculated as the difference between first light of the laser’s flash lamp and the energetic material. Results show that laser energy required for ignition is dependent on pre‐ignition reactions, phase change/decomposition temperatures, confinement, and laser absorbance.
Theoretical Investigation of Several 1,2,3,4‐Tetrazine‐Based High‐Energy Compounds
Authors: Tan Bisheng , Huang Ming , Huang Hui , Long Xinping , Li Jinshan , Nie Fude , Huang Jinglun
Published: March 2013

The enthalpies of formation of six 1,2,3,4‐tetrazine‐based compounds were calculated according to the Density Functional Theory BOP/TNP method and by using homodesmotic reaction designs. Their detonation performances, including detonation velocity and pressure, were predicted in terms of the Stine equations. The 1,2,3,4‐Tetrazine‐based compounds labeled A, B, C, D, and F are powerful high‐energy compounds. The detonation performances of A and B, including detonation velocity, and detonation pressure, are superior to that of the current high‐energy explosive CL‐20. The detonation velocity, detonation pressure, and oxygen balance of 1,2,3,4‐tetrazine related oxo derivatives can be improved by partial oxidation of the nitrogen atoms in the tetrazine ring, but further oxidation causes reduction of the enthalpies and specific impulses of the oxo derivatives. Calculation of the molecular resonance energies indicated that E [C6N12] and F have more negative values, i.e, the ring strain energies of their configurations are high, whereas the resonance energies of C and D are low, only compound B has a very positive resonance energy. Considering energy and stability, B is a promising compound for practical use with both high energy and low sensitivity.
Identifying Kondo orbitals through spatially resolved STS
Authors: Antipov Andrey E. , Ribeiro Pedro , Kroha Johann , Kirchner Stefan
Published: March 2013

We study the influence of angular degrees of freedom of magnetic adatoms on metallic surfaces onto scanning tunneling spectra. Kondo scattering of electrons off the adatom changes the local density of states near the Fermi level. The spatial dependence of this correction is set by the orbital structure of the local moment localized on the adatom. By considering a multilevel Anderson model with non‐degenerate orbitals of differing orbital structure, we demonstrate that the spatial dependence of the scanning tunneling spectrum contains sufficient information to infer the orbital degrees of freedom of the magnetic adatom.
Efficiency of automated peak identification with daily used commercial software for X‐ray photoelectron spectra ‐ report from VAMAS/TWA 2/A 9 project
Authors: Suzuki Mineharu , Fukushima Sei , Tanuma Shigeo
Published: March 2013

In the first step of X‐ray photoelectron spectroscopy (XPS) analysis, photoelectron peaks in a survey spectrum for the specimen of interest are generally identified as arising from particular elements and electron energy levels. This peak identification is performed using sophisticated software on commercial XPS instruments. For the Versailles Project on Advanced Materials and Standards (VAMAS)/Technical Working Area (TWA) 2/A 9 project, automated peak‐identification efficiency using commercial software utilities has been investigated with simulated test XPS spectra. This efficiency has been investigated with reference peaks that were detected by eye in our previous work [SIA, 2008, 40, 1337]. We found (i) one software that identified the binding energy (BE) at the peak maximum for a fitted curve in the peak region, a second that reported the BE stored in its database, and a third that reported the BE as the local maximum, (ii) software does not identify some weak peaks even though they were obviously detected by analysts, (iii) only one major peak of a doublet appeared to be in software database when the energy separation is less than about 4 eV such as 3.6 eV for Au 4f, and (iv) the identification efficiency is larger than 90% when the ratio between peak height and noise amplitude is greater than 10. We suggest several things for improving software design to assist non‐expert analysts. Copyright © 2013 John Wiley & Sons, Ltd.