bluuebunny/crossref_metadata_2025 huggingface dataset:
The DAMASK trial protocol: a pragmatic randomised trial to evaluate whether GPs should have direct access to MRI for patients with suspected internal derangement of the knee
Authors: Brealey Stephen D , Atwell Christine , Bryan Stirling , Coulton Simon , Cox Helen , Cross Ben , Fylan Fiona , Garratt Andrew , Gilbert Fiona J , Gillan Maureen GC , Hendry Maggie , Hood Kerenza , Houston Helen , King David , Morton Veronica , Orchard Jo , Robling Michael , Russell Ian T , Torgerson David , Wadsworth Valerie , Wilkinson Clare
Published: October 2006

Background

Though new technologies like Magnetic Resonance Imaging (MRI) may be accurate, they often diffuse into practice before thorough assessment of their value in diagnosis and management, and of their effects on patient outcome and costs. MRI of the knee is a common investigation despite concern that it is not always appropriate. There is wide variation in general practitioners (GPs) access to, and use of MRI, and in the associated costs. The objective of this study was to resolve uncertainty whether GPs should refer patients with suspected internal derangement of the knee for MRI or to an orthopaedic specialist in secondary care.

Methods/Design

The design consisted of a pragmatic multi-centre randomised trial with two parallel groups and concomitant economic evaluation. Patients presenting in general practice with suspected internal derangement of the knee and for whom their GP was considering referral to an orthopaedic specialist in secondary care were eligible for inclusion. Within practices, GPs or practice nurses randomised eligible and consenting participants to the local radiology department for an MRI examination, or for consultation with an orthopaedic specialist. To ensure that the waiting time from GP consultation to orthopaedic appointment was similar for both trial arms, GPs made a provisional referral to orthopaedics when requesting the MRI examination. Thus we evaluated the more appropriate sequence of events independent of variations in waiting times. Follow up of participants was by postal questionnaires at six, twelve and 24 months after randomisation. This was to ensure that the evaluation covered all events up to and including arthroscopy.

Discussion

The DAMASK trial should make a major contribution to the development of evidence-based partnerships between primary and secondary care professionals and inform the debate when MRI should enter the diagnostic pathway.
Pseudo current density maps of electrophysiological heart, nerve or brain function and their physical basis
Authors: Haberkorn Wolfgang , Steinhoff Uwe , Burghoff Martin , Kosch Olaf , Morguet Andreas , Koch Hans
Published: October 2006

Background

In recent years the visualization of biomagnetic measurement data by so-called pseudo current density maps or Hosaka-Cohen (HC) transformations became popular.

Methods

The physical basis of these intuitive maps is clarified by means of analytically solvable problems.

Results

Examples in magnetocardiography, magnetoencephalography and magnetoneurography demonstrate the usefulness of this method.

Conclusion

Hardware realizations of the HC-transformation and some similar transformations are discussed which could advantageously support cross-platform comparability of biomagnetic measurements.
Reduction of Anion Reversal Potential Subverts the Inhibitory Control of Firing Rate in Spinal Lamina I Neurons: Towards a Biophysical Basis for Neuropathic pain
Authors: Prescott Steven A , Sejnowski Terrence J , De Koninck Yves
Published: October 2006

Background

Reduction of the transmembrane chloride gradient in spinal lamina I neurons contributes to the cellular hyperexcitability producing allodynia and hyperalgesia after peripheral nerve injury. The resultant decrease in anion reversal potential ( i.e. shift in Eanionto less negative potentials) reduces glycine/GABAAreceptor-mediated hyperpolarization, but the large increase in membrane conductance caused by inhibitory input can nonetheless shunt concurrent excitatory input. Without knowing the relative contribution of hyperpolarization and shunting to inhibition's modulation of firing rate, it is difficult to predict how much net disinhibition results from reduction of Eanion. We therefore used a biophysically accurate lamina I neuron model to investigate quantitatively how changes in Eanionaffect firing rate modulation.

Results

Simulations reveal that even a small reduction of Eanioncompromises inhibitory control of firing rate because reduction of Eanionnot only decreases glycine/GABAAreceptor-mediated hyperpolarization, but can also indirectly compromise the capacity of shunting to reduce spiking. The latter effect occurs because shunting-mediated modulation of firing rate depends on a competition between two biophysical phenomena: shunting reduces depolarization, which translates into reduced spiking, but shunting also shortens the membrane time constant, which translates into faster membrane charging and increased spiking; the latter effect predominates when average depolarization is suprathreshold. Disinhibition therefore occurs as both hyperpolarization- and shunting-mediated modulation of firing rate are subverted by reduction of Eanion. Small reductions may be compensated for by increased glycine/GABAAreceptor-mediated input, but the system decompensates ( i.e. compensation fails) as reduction of Eanionexceeds a critical value. Hyperexcitability necessarily develops once disinhibition becomes incompensable. Furthermore, compensation by increased glycine/GABAAreceptor-mediated input introduces instability into the system, rendering it increasingly prone to abrupt decompensation and even paradoxical excitation.

Conclusion

Reduction of Eaniondramatically compromises the inhibitory control of firing rate and, if compensation fails, is likely to contribute to the allodynia and hyperalgesia associated with neuropathic pain. These data help explain the relative intractability of neuropathic pain and illustrate how it is important to choose therapies not only based on disease mechanism, but based on quantitative understanding of that mechanism.
Diagnostic value and prognostic implications of serum procalcitonin after cardiac surgery: a systematic review of the literature
Authors: Sponholz Christoph , Sakr Yasser , Reinhart Konrad , Brunkhorst Frank
Published: October 2006

Introduction

Systemic inflammatory response syndrome is common after surgery, and it can be difficult to discriminate between infection and inflammation. We performed a review of the literature with the aims of describing the evolution of serum procalcitonin (PCT) levels after uncomplicated cardiac surgery, characterising the role of PCT as a tool in discriminating infection, identifying the relation between PCT, organ failure, and severity of sepsis syndromes, and assessing the possible role of PCT in detection of postoperative complications and mortality.

Methods

We performed a search on MEDLINE using the keyword 'procalcitonin' crossed with 'cardiac surgery,' 'heart,' 'postoperative,' and 'transplantation.' Our search was limited to human studies published between January 1990 and June 2006.

Results

Uncomplicated cardiac surgery induces a postoperative increase in serum PCT levels. Peak PCT levels are reached within 24 hours postoperatively and return to normal levels within the first week. This increase seems to be dependent on the surgical procedure and on intraoperative events. Although PCT values reported in infected patients are generally higher than in non-infected patients after cardiac surgery, the cutoff point for discriminating infection ranges from 1 to 5 ng/ml, and the dynamics of PCT levels over time may be more important than absolute values. PCT is superior to C-reactive protein in discriminating infections in this setting. PCT levels are higher with increased severity of sepsis and the presence of organ dysfunction/failure and in patients with a poor outcome or in those who develop postoperative complications. PCT levels typically remain unchanged after acute rejection but increase markedly after bacterial and fungal infections. Systemic infections are associated with greater PCT elevation than is local infection. Viral infections are difficult to identify based on PCT measurements.

Conclusion

The dynamics of PCT levels, rather than absolute values, could be important in identifying patients with infectious complications after cardiac surgery. PCT is useful in differentiating acute graft rejection after heart and/or lung transplantation from bacterial and fungal infections. Further studies are needed to define cutoff points and to incorporate PCT levels in useful prediction models.
Oxidative stress is increased in critically ill patients according to antioxidant vitamins intake, independent of severity: a cohort study
Authors: Abilés Jimena , de la Cruz Antonio Pérez , Castaño José , Rodríguez-Elvira Manuel , Aguayo Eduardo , Moreno-Torres Rosario , Llopis Juan , Aranda Pilar , Argüelles Sandro , Ayala Antonio , de la Quintana Alberto Machado , Planells Elena Maria
Published: October 2006

Introduction

Critically ill patients suffer from oxidative stress caused by reactive oxygen species (ROS) and reactive nitrogen species (RNS). Although ROS/RNS are constantly produced under normal circumstances, critical illness can drastically increase their production. These patients have reduced plasma and intracellular levels of antioxidants and free electron scavengers or cofactors, and decreased activity of the enzymatic system involved in ROS detoxification. The pro-oxidant/antioxidant balance is of functional relevance during critical illness because it is involved in the pathogenesis of multiple organ failure. In this study the objective was to evaluate the relation between oxidative stress in critically ill patients and antioxidant vitamin intake and severity of illness.

Methods

Spectrophotometry was used to measure in plasma the total antioxidant capacity and levels of lipid peroxide, carbonyl group, total protein, bilirubin and uric acid at two time points: at intensive care unit (ICU) admission and on day seven. Daily diet records were kept and compliance with recommended dietary allowance (RDA) of antioxidant vitamins (A, C and E) was assessed.

Results

Between admission and day seven in the ICU, significant increases in lipid peroxide and carbonyl group were associated with decreased antioxidant capacity and greater deterioration in Sequential Organ Failure Assessment score. There was significantly greater worsening in oxidative stress parameters in patients who received antioxidant vitamins at below 66% of RDA than in those who received antioxidant vitamins at above 66% of RDA. An antioxidant vitamin intake from 66% to 100% of RDA reduced the risk for worsening oxidative stress by 94% (ods ratio 0.06, 95% confidence interval 0.010 to 0.39), regardless of change in severity of illness (Sequential Organ Failure Assessment score).

Conclusion

The critical condition of patients admitted to the ICU is associated with worsening oxidative stress. Intake of antioxidant vitamins below 66% of RDA and alteration in endogenous levels of substances with antioxidant capacity are related to redox imbalance in critical ill patients. Therefore, intake of antioxidant vitamins should be carefully monitored so that it is as close as possible to RDA.
Prediction of trans-antisense transcripts in Arabidopsis thaliana
Authors: Wang Huan , Chua Nam-Hai , Wang Xiu-Jie
Published: October 2006

Background

Natural antisense transcripts (NATs) are coding or non-coding RNAs with sequence complementarity to other transcripts (sense transcripts). These RNAs could potentially regulate the expression of their sense partner(s) at either the transcriptional or post-transcriptional level. Experimental and computational methods have demonstrated the widespread occurrence of NATs in eukaryotes. However, most previous studies only focused on cis-NATs with little attention being paid to NATs that originate in trans.

Results

We have performed a genome-wide screen of trans-NATs in Arabidopsis thaliana and identified 1,320 putative trans-NAT pairs. An RNA annealing program predicted that most trans-NATs could form extended double-stranded RNA duplexes with their sense partners. Among trans-NATs with available expression data, more than 85% were found in the same tissue as their sense partners; of these, 67% were found in the same cell as their sense partners at comparable expression levels. For about 60% of Arabidopsis trans-NATs, orthologs of at least one transcript of the pair also had trans-NAT partners in either Populus trichocarpa or Oryza sativa. The observation that 430 transcripts had both putative cis- and trans-NATs implicates multiple regulations by antisense transcripts. The potential roles of trans-NATs in inducing post-transcriptional gene silencing and in regulating alternative splicing were also examined.

Conclusion

The Arabidopsis transcriptome contains a fairly large number of trans-NATs, whose possible functions include silencing of the corresponding sense transcripts or altering their splicing patterns. The interlaced relationships observed in some cis- and trans-NAT pairs suggest that antisense transcripts could be involved in complex regulatory networks in eukaryotes.
Gas Chromatography Electron Ionization Mass Spectrometric Analysis of Trimethylsilyl Derivatives of Bis(2-Hydroxyethylthio)Alkanes and Bis(2-Hydroxyethylsulfonyl)Alkanes
Authors: Kanaujia Pankaj K. , Tak Vijay , Pardasani Deepak , Gupta A.K. , Jain Rajiv , Dubeya D.K.
Published: October 2006

This communication describes the GC/MS analysis of the bis(trimethylsilyl) (bis-TMS) derivatives of bis(2-hydroxyethylthio)alkanes (BHETAs) and bis(2-hydroxyethylsulfonyl)alkanes (BHESAs) which are important markers of sulfur mustard class of chemical warfare agents. The study was undertaken with a view to develop a spectral database of these compounds for verification analysis of the Chemical Weapons Convention (CWC). Based on the obtained mass spectra of bis-TMS derivatives of BHETAs and BHESAs, the fragmentation routes are proposed, which explain most of the characteristic ions.
The Effect of Latent Hardening on the Texture of 3004 Aluminum Deformed in Plane Strain, Predicted by an Explicit Dynamic Finite Element Analysis
Authors: Young MJ , Choi SK , Thomson PF
Published: October 2006

Simulating plane strain compression of polycrystalline 3004 aluminum, representing a metal of high stacking fault energy (sfe), to 60% reduction by a finite element model permits prediction of the observed texture, in which the copper, S, and brass components co-exist (predicted by neither the Taylor nor the Sachs models). Modeling the rate of hardening on individual slip planes and latent hardening introduces additional shear strains and increases the volume fraction of the brass component, showing how the brass texture may develop in metals of high sfe, in the absence of twinning and shear banding as suggested by Leffers and Pedersen and by Engler.
Schubert's Sonata Forms and the Poetics of the Lyric
Authors: MAK SU YIN
Published: October 2006

Although recent scholarship has witnessed a welcome disavowal of the view that Schubert's formal and tonal designs in sonata form compositions bespeak the song composer's inability to master large-scale instrumental genres, it remains a commonplace to characterize Schubert's unorthodox practice as “lyrical.” Yet the historical, theoretical, and aesthetic bases of this lyricism have received little critical attention. A systematic and historically grounded approach to the notion of lyrical form in Schubert may be established by appealing to the rhetorical distinction between hypotaxis and parataxis, which pervaded late 18th-century discussions of both music and language. In particular, parataxis, a style that deliberately omits syntactical connections and relies instead on juxtaposition and parallelism, offers a suggestive technical link between Schubert's instrumental practice and the discursive techniques of contemporaneous lyric poetry. There are also aesthetic connections between idealist views of the lyric and the composer's own artistic beliefs, as confirmed by biographical documents. Schubert's approach to form was as much informed by these literary sensibilities as by the Classical compositional tradition. Like poets for whom the lyric served both as an Arcadian ideal of song and as an alternative to the prosaic realities of the present, Schubert evoked the lyric within the context of the sonata as a means of reunifying the dissociated sensibility of the Enlightenment. In so doing, he secured a place for the poetic imagination in instrumental music.
Diagnosing the educational needs of the chronically ill
Authors: Davis Wayne K. , Hull Alan L. , Boutagh Michele L.
Published: October 2006

Procedures for developing a diabetes educational profile to assess the educational needs of patients with a chronic illness can help others in constructing similar instruments.
Formative evaluation as model building
Authors: Eggert John D.
Published: October 2006

If you know the questions, you may no longer need the answers. Formative evaluation is examined as a process of developing consensus within a volunteer agency.
Uses of educational technology for formative evaluation
Authors: Huber Vandra L. , Gay Geri
Published: October 2006

Advances in educational technology are helping decision makers acquire the information necessary for formative evalution. Results can include better programming, diagnosis, and monitoring.
The potential of program monitoring
Authors: Wright Joan
Published: October 2006

As an early‐warning system, monitoring can alert program staff to adverse conditions in time to make adjustments and improvements before disaster occurs.
Self‐directed learning in a graduate adult education program
Authors: Bauer Barbara A.
Published: October 2006

Can self‐directed learning principles form the core of a total doctoral program in adult and continuing education within a traditional graduate school?
Interorganizational collaboration in continuing professional education
Authors: Hohmann Lillian
Published: October 2006

Interorganizational collaboration in continuing professional education is a fact of life. A knowledge of the process can prove useful in building more effective linkages.
Professional preparation of adult educators
Authors: Keyi Jiang , Weihua Lin
Published: October 2006

To meet the needs of the field, ten normal schools in adult higher education have been established throughout China for the special purpose of training teachers and administrators of adult education.
Paradoxes of staff development in a research hospital
Authors: Watkins Karen
Published: October 2006

Staff development in the complex, turbulent environment of a research hospital may be undermined by counterproductive, tacit learning norms that allow no critical reflection on practice.
Community‐based training for reentry women in nontraditional occupations
Authors: Howell Ruth S. , Schwartz Helen
Published: October 2006

Community‐based organizations are in a unique position to offer client‐focused basic education and training to returning women.
Women from special populations: The challenge of reentry
Authors: Safman Phyllis C.
Published: October 2006

Displaced homemakers and rural, minority, and disabled women bring to their education and pretraining programs particular needs that require specific accommodations.
Continuing education in colleges of further education
Authors: Piper Laurie S.
Published: October 2006

Further education in the United Kingdom has been increasingly affected by the actiuities of the Manpower Sewices Commission: the commission and the Department of Education and Science haue a relationship that is both collaboratiue and competitive. The system has been subjected to frequent change, and further dramatic change is imminent.
Educational initiatives with the unemployed
Authors: Walters Nicholas
Published: October 2006

Throughout the late 1970s and 1980s, Britain, along with other western European countries, experienced structural unemployment on a large scale. Adult education has responded to this new situation with initiatives that embrace ideas of both vocational and liberal traditions.
Open learning and continuing education
Authors: Tight Malcolm
Published: October 2006

Open learning offers both a coherent methodology and an adaptable range of practical techniques for developing continuing education.
Learning about planning from success and failure
Authors: Sork Thomas J.
Published: October 2006

Making mistakes in the design and delivery of programs is inevitable, but learning from those mistakes requires deliberate reflection and systematic analysis.
A rationale for certificate programs
Authors: Holt Margaret E.
Published: October 2006

Certificate programs began to flourish in the 1970s as a response to specific technological and professional demands for concise and concentrated studies.
Heuristics for planning and presenting effective certificate programs
Authors: Bratton Barry D.
Published: October 2006

Using information from the fields of instructional design and technology, educational psychology, training, and evaluation, this chapter presents heuristics that can be applied to certificate programs.
The economics of certificate programs
Authors: Robinson Jane Hoopes
Published: October 2006

Favorable cost‐benefit ratios of certificate programs in part explain the popularity and growth of this new enterprise among colleges, universities, and professional groups.
Selected interviews with certificate program students
Authors: Rutkowski Thomas M. , Holt Margaret E. , Lopos George J.
Published: October 2006

Semistructured interviews with certificate program students emphasized more positive than negative assessments, especially with respect to the career‐related values of such studies. Nonetheless, the marginality of and limited receptivity to many certificate programs within larger university structures raise concerns.
The influence of affective processing in education and training
Authors: Ferro Trenton R.
Published: October 2006

Learning is not just the acquisition and manipulation of content; how and how well we learn is influenced by the affective realm—our emotions and feelings—as well as by the cognitive domain.
Staff development: Addressing issues of race and gender
Authors: Amstutz Donna D.
Published: October 2006

How can staff development be used to address issues of race and gender in adult education settings?
Enhancing self‐direction in the adult learner: Instructional techniques for teachers and trainers
Authors: Slusarski Susan B.
Published: October 2006

Adult educators may use a variety of techniques in formal learning situations to overcome learner—and teacher—resistance to self‐direction in learning.
Workplace learning: Changing times, changing practices
Authors: Watkins Karen E.
Published: October 2006

This chapter offers a brief history of the field, a portrait of workplace learning today, contrasting definitions, and emerging issues that are changing workplace learning practices.
Book groups: Communities of learners
Authors: Kerka Sandra
Published: October 2006

Hundreds of thousands of adults participate in book discussion groups, satisfying lifelong learning needs informally and in community.
Part three: Should the knowledge base come from theory & from practice?. Professionalization comes from theory and research: The why instead of the how to
Authors: Chalofsky Neal E.
Published: October 2006

Without a solid theory and research base the discipline will never become a valid field of study but will forever remain a collection of anecdotes and speculation.
Carbon‐Nanotube‐Based Hybrid Materials: Nanopeapods
Authors: Kitaura Ryo , Shinohara Hisanori
Published: October 2006

This review article focuses on the structures and properties of novel hybrid nanocarbon materials, which are created by incorporating atoms and molecules into the hollow spaces of carbon nanotubes (CNTs); thus they are called nanopeapods. After dealing with synthesis procedures, we discuss the structures and electronic properties of the hybrid materials based on high‐resolution transmission electron microscopy (HRTEM), electron energy‐loss spectroscopy (EELS), X‐ray and electron diffraction, scanning tunneling microscopy (STM), and field‐effect transistor transport measurements. Utilization of the low‐dimensional nanosized spaces of CNTs to produce novel low‐dimensional nanocluster, nanowire, and nanotube materials is also discussed.
Plasma levels of chlorodesmethyldiazepam in humans
Authors: Bo L. Dal , Marcucci F. , Mussini E. , Perbellini D. , Castellani A. , Fresia P.
Published: October 2006

Chlorodesmethyldiazepam (I) concentrations were followed for 72 h in the plasma of four volunteers given 2 mg of the drug orally. The drug appears to be well absorbed, reaching peak plasma levels of 20–30 ng ml−1 1–2 h after administration; 72 h after administration, plasma concentrations are still measurable (5 ng ml−1).

The analytical method involved a single extraction of I from the plasma into benzene followed by centrifugation, evaporation, and gas‐chromatographic analysis of the samples.
The effect of displacement from protein binding on serum and tissue fluid levels of cephazolin
Authors: Polacek I. , Mühlbauer H.
Published: October 2006

Displacement of cephazolin, a highly protein‐bound β‐lactam antibiotic, by sulpha‐phenazole was studied in vitro and in vivo. In vitro, the sulphonamide was effective in displacing the antibiotic from its binding sites at the concentration 100–1000 μmol I−1. In vivo, both the serum and the tissue fluid concentration of free cephazolin increased significantly in rats concomitantly treated with sulphaphenazole.
Pharmacokinetics of isosorbide dinitrate after intravenous infusion in human subjects
Authors: Taylor T. , Chasseaud L. F. , Doyle E. , Darragh A. , O'Kelly D. A. , Fitzgerald D.
Published: October 2006

Plasma concentrations of isosorbide dinitrate have been measured after intravenous infusion of drug at a rate of 5·0 mg h−1 for 150 min and after single equal oral doses of 12·5 mg of drug in solution to two normal human subjects. During the infusion, uneven plateau concentrations were approached after 30 min. The calculated average steady‐state plasma levels were 258 ng ml−1 and 514 ng ml−1 in the two subjects respectively. The half‐life of elimination of isosorbide dinitrate after termination of the infusion was 9–10 min. After oral doses, peak plasma levels of 26·6 ng ml−1 and 12·7 ng ml−1 occurred at 10 min and 20 min in the two subjects respectively. The terminal half‐life of drug after the oral doses was much longer than the elimination half‐life (about 10 min), and was associated with the absorption phase. Fairly good agreement was obtained between the observed concentrations and those predicted by a one‐compartment open model.

The systemic availability of isosorbide dinitrate after the oral doses was up to only 3 per cent of the equal doses infused, indicating that presystemic elimination processes accounted for very large proportions of the oral doses. The systemic clearances of drug after infusion of 0·32 1 min−1 and 0·161 min−1 were unexpectedly low for a drug of reported high liver extraction ratio.
A propranolol radioimmunoassay and its use in the study of its pharmaco‐kinetics following low doses
Authors: Mould G. P. , Clough J. , Morris B. A. , Stout G. , Marks V.
Published: October 2006

A radioimmunoassay has been developed for propranolol with a sensitivity of 2.37nmol l−1 in unextracted plasma using a 50 μl sample. Plasma concentration measurements were made on samples from volunteers for up to 8 h after they had been given 5, 10, or 40 mg of propranolol by mouth. Analysis of the results showed that mean elimination half‐lives and total body clearances were similar following each of the doses and that the area under the curve was proportional to the dose. Steady‐state propranolol concentrations in 17 patients on regular propranolol treatment were linearly related to the dose over the range 20.640 mg d −1; the regression line extrapolated to the origin. These data indicate non‐saturable kinetics for the hepatic metabolism of propranolol within the dose ranges investigated and lead us to believe that there is no ‘oral‐threshold’ dose for propranolol. The radioimmunoassay may be useful in clinical practice for monitoring plasma propranolol concentrations and for detecting patient compliance.
Concentrations of N‐descyclopropyl‐methylprazepam in whole‐blood, plasma, and milk after administration of prazepam to humans
Authors: Brodie R. R. , Chasseaud L. F. , Taylor T.
Published: October 2006

After oral doses of 30 mg of prazepam to humans, N‐descyclopropylmethylprazepam (desalkylprazepam, N‐desmethyldiazepam) is the only major drug‐related compound in plasma. Neither the parent drug, nor its major urinary metabolites were detected in plasma. The overall concentration‐time profile of desalkylprazepam

Desalkylprazepam is used as a simplified name for N‐descyclopropylmethylprazepam.

in the plasma of females was lower than, and significantly different (p< 0.001) from that in the plasma of males. However, the mean peak desalkylprazepam concentrations in the plasma of females (265 ng ml−1 ±60 S.D.) were not significantly different (p >0.05) from those in males (342ngml−1 ±60 S.D.). Concentrations declined in the plasma of either sex with similar half‐lives (mean 60 h, range 37–93 h). Apparent plasma desalkylprazepam clearances were also similar (mean 1.09 1 h−1, range 0.74–1.84 1 h−1).

At 12 h after the last of multiple doses of prazepam (60 mg d−1 for 3 days) to lactating women, mean plasma concentrations of desalkylprazepam were 823 ng ml−1 ±200 S.D. and declined with a mean half‐life of about 60 h over the time‐course studied. There was only slight uptake of desalkylprazepam into blood cells; plasma : whole blood concentration ratios were constant at about 1.6. Concentrations of desalkylprazepam in milk were low at about 10 percent of the corresponding plasma levels (e.g. 86 ng ml−1 ±37 S.D. at 12 h). The data suggest that, expressed on a mg kg−1 basis, exposed neonates could receive about 4 per cent of the maternal dose of prazepam as desalkylprazepam.
The effect of antacid, metoclopramide, and propantheline on the bioavailability of metoprolol and atenolol
Authors: Regardh Carl G. , Lundborg Per , Persson Bengt A.
Published: October 2006

Concomitant administration of antacid increased the maximum concentration (Cpmax) and the area under the plasma concentration‐time curve (AUC) of 100 mg oral dose of metoprolol by 25 per cent (p< 0.05) and 11 per cent (p < 0.1) respectively. For atenolol the opposite effect was observed and Cpmax and AUC were decreased by 37 and 33 per cent respectively (p< 0.02). In both cases the antacid did not affect the time‐course of the drug in the plasma. Pretreatment with metoclopramide did not affect the time‐course of atenolol in the plasma or its bioavailability. Propantheline prolonged the absorption phase of atenolol and the time of peaking (tmax) was shifted from 2.1 to 4.5 h. Cpmax of atenolol was essentially unchanged by propantheline pretreatment while the AUC was increased by 36 per cent. It is concluded that the negative effect of the antacid on the bioavailability of atenolol is caused by a reduction in the in vivo dissolution rate due to increased gastric pH. The positive effect of propantheline might be due either to more efficient absorption of atenolol in the upper part of the intestine or more extensive dissolution of the drug as a result of prolonged contact with gastric juice or a combination of these factors.
Pharmacokinetic evaluation of noreximide in rats
Authors: Koch Heinrich P. , Pischek Gertrude , Holzbecher Margarete , Ritschel Wolfgang A.
Published: October 2006

The pharmacokinetics of noreximide in the rat after i.v., p.o., and i.p. administration was studied. The biologic half‐life of approximately 8 h was found almost the same for all three routes. Upon p.o. administration the fraction of drug absorbed is 85 per cent, and the peak concentration in the blood is reached within approximately 4.5 h. Additional pharmaco‐kinetic parameters are listed.
Plasma propranolol concentrations in rats with adjuvant‐induced arthritis
Authors: Bishop Hilary , Schneider R. E. , Welling P. G.
Published: October 2006

Previous work has shown that after a single oral dose, plasma propranolol concentrations in patients with active inflammatory disease are significantly higher than those in healthy subjects.

After oral administration of propranolol (2 mg) to arthritic rats, the area under the mean drug concentration‐time curve in plasma was approximately 10 times greater than that in control animals. After intravenous administration (0.25 mg) the area in arthritic rats was approximately doubled compared with that in controls.

The mechanisms causing these changes are not known, but it is probable that increased drug binding to an acute phase reactant in plasma, together with decreased first‐pass hepatic clearance in arthritic rats after oral dosing, are involved.
Evidence for route dependent biotransformation of cyclobenzaprine hydrochloride
Authors: Till Alice E. , Constanzer Marvin L. , Demetriades Joan , Irvin John D. , Lee Robyn B. , Ferguson Roger K.
Published: October 2006

Cyclobenzaprine hydrochloride was administered to healthy volunteers as a 10mg oral tablet, 10mg and 20mg intramuscular injections, and a 10mg intravenous injection. Urinary excretion and plasma level data for cyclobenzaprine together provide evidence for route dependent biotransformation. Urinary excretion of total cyclobenzaprine (unchanged plus the glucuronide conjugate) was greater for the oral treatment than for the parenteral treatments (i.m. and i.v.). Area under the plasma concentration‐time curve for unchanged cyclobenzaprine, however, was less for the oral treatment than for the parenteral treatments. Based on area calculations, the bioavailability of the 10 mg oral tablet, 10 mg i.m. and 20 mg i.m. injection was 0.33, 0.76, and 0.56, respectively, when compared to the 10mg i.v. injection of cyclobenzaprine hydrochloride. The four treatments were well tolerated and no clinically adverse effects were observed.
The pharmacokinetics and metabolism of 14C‐carprofen in man
Authors: Ray John E. , Wade Denis N.
Published: October 2006

Three healthy male subjects received single 100mg oral doses of carprofen containing 20 μCi of 14C‐carprofen. Venous blood samples were drawn during the first 48 h after the dose and urine and feces were collected for 120h. Concentrations of carprofen and its metabolites in body fluids were determined by TLC and mass spectral analysis. After a lag time of 0.3±0.41h (mean ±S.D.), carprofen was absorbed rapidly and peak concentrations in the plasma were reached in 2.7 ± 1.3 h. The 14C plasma concentrations declined in a biphasic fashion. The mean half‐lives of the initial (α) and terminal (β) phases were 1.1 h and 20.6 ± 6.1 h, respectively. Biotransformation to a glucuronide metabolite appeared to be the major mechanism of carprofen clearance. In 48 h 74.0 per cent of administered radioactivity was recovered in urine and 14.1 per cent was recovered in feces. A glucuronide of carprofen comprised 85.0 per cent of the radiolabelled compounds in urine. The remaining radioactivity was comprised of parent drug (12.0 per cent) and un unidentified acid‐labile conjugate of the parent drug (3.0 per cent). This pattern of metabolism and excretion is different from that in the dog and rat and may explain species differences in drug activity and toxicity.
Comparison of gentamicin and tobramycin nephrotoxicity in patients receiving individualized‐pharmacokinetic dosing regimens
Authors: Pancorbo Salvador , Compty Christina , Heissler Joseph
Published: October 2006

The incidence of nephrotoxicity has been studied in 175 patients who received either gentamicin or tobramycin. All patients received individualized dosing regimens of the drugs based on pharmacokinetic parameters measured after the initial dose. Subsequent doses were calculated from the pharmacokinetic data to produce peak aminoglycoside levels of between 6 and 8 μg ml−1 and trough levels that were below 2 μg ml−1. Renal toxicity was defined as a 30 per cent or greater increase in the serum creatinine level above the baseline value. Five of the 125 patients (4 per cent) who received gentamicin, and 1 of the 39 patients (2.6 per cent) who received tobramycin developed signs of nephrotoxicity. This difference was not statistically significant.
The assessment of fractional drug removal by extracorporeal dialysis
Authors: Lee Ching‐San C.
Published: October 2006

It is generally concurred that the effectiveness of extracorporeal dialysis is best evaluated by fractional drug removal, i.e. the proportion of body burden of drug removed during the period of dialysis treatment. Two equations reported in the literature and five equations proposed in this article are examined for their validity in the assessment of fractional drug removal. Potential limitations and applicable conditions of these equations are discussed and compared. Calculations of fractional drug removal are demonstrated using both simulated and experimental data of ethambutol. Depending on the available kinetic measurements during dialysis and post dialysis, one may apply each equation separately or in conjunction with others to the calculation of fractional drug removal.
Pharmacokinetics of valproic acid and metabolites in mouse plasma and brain following constant‐rate application of the drug and its unsaturated metabolite with an osmotic delivery system
Authors: Nau Heinz , Zierer Rainer
Published: October 2006

Human therapeutic valproic acid (VPA) levels could be maintained in the mouse for a period of 1 week by constant rate application via subcutaneously implanted osmotic minipumps. Also, the concentrations of VPA metabolites observed in mouse plasma were similar to those seen in human plasma. The drug application could be prolonged by replacing exhausted pumps with freshly‐filled devices. Removal of the implanted pumps and measurement of the decay of the drug levels revealed that the half‐life of the main plasma metabolite 2‐en(2‐propyl‐2‐pentenoic acid) exceeded that of VPA. This result was confirmed by constant‐rate application of this metabolite; the plasma clearance of 2‐en (as calculated from the steady‐state levels observed) was found to be lower than that of VPA. Brain levels of VPA and 2‐en during steady‐state were 3–10 per cent of corresponding plasma levels. The blood‐brain kinetics of 2‐en following administration of VPA were similar to those observed following application of 2‐en itself. VPA was cleared faster from the brain than from the plasma, while 2‐en was more persistent in the brain than in the plasma. Our results indicate that controlled, constant‐rate application of drugs such as VPA, via implantable osmotic minipumps, may be a valuable procedure for a number of pharmacological and toxicological studies, particularly where persistent drug levels must be maintained for extended time periods.
Pharmacokinetic evaluation of the blood‐to‐lymph transfer of cyclosporin a in rats
Authors: Ueda Clarence T. , Lemaire Michel , Misslin Pierrette
Published: October 2006

The blood‐to‐lymph transfer kinetics of cyclosporin A (CyA) were investigated in thoracic duct cannulated rats after a 3mg kg−1 i.v. bolus injection of tritium‐labelled drug. Blood CyA concentrations declined bi‐exponentially with a terminal half‐life of 13·1 ± 1·8 h. The appearance rate of CyA in the lymph was also bi‐phasic, initially rising and then declining in parallel with the concentrations of CyA in the blood. A pharmacokinetic model describing the blood‐to‐lymph transfer kinetics of CyA is presented. From the slopes of graphs relating the appearance rate of CyA in the lymph to the corresponding midpoint blood drug concentration, the estimated blood‐to‐lymph clearance rate of CyA (ClL)b was 0·262·0·132 mlh−1 (ClL)b was positively correlated with the average lymph flow rate (Q̄L) but was significantly less than Q̄L. On the other hand, the plasma‐to‐lymph clearance rate of CyA (ClL)P of 0·393 ± 0·198 mlh−1 was positively correlated and similar to Q̄L. Lymph concentrations of CyA were approximately 40–60 per cent of the corresponding blood concentrations. The results of this investigation showed the existence of an intervening compartment between the blood and lymph fluids which would be consistent with the presence of lymph nodes. It was shown that the blood‐to‐lymph transfer of CyA was dependent on the flow rate of the lymph and that CyA appeared to be cleared from the plasma (or serum) fraction of the blood.
Pharmacokinetic studies with atenolol in the dog
Authors: McAinsh James , Holmes Brian F.
Published: October 2006

The pharmacokinetics of the cardioselective β‐adrenoreceptor blocking agent atenolol have been determined following intravenous and oral dosing to the dog. After intravenous administration at 200 mg the blood levels of parent drug were found to decay tri‐exponentially with a final elimination phase half‐life of about 4–5 h. The volume of distribution for the central compartment was 40 per cent body weight and the whole body volume of distribution was 160 per cent body weight. The percentage urinary recovery of parent drug was 83 per cent.

Following oral dosing at 400 mg (as a solution and as a clinical trial tablet) the percentage urinary recovery was 65 per cent and the half‐life extended slightly to between 5 and 6h. The peak blood levels were however very similar for the two formulations (17 and 15μg/ml for the solution and tablet respectively) and occurred at the same time (l–2h after dosing). The total areas under the blood concentration time curves were similar and the values (100 and 104ugml−1h respectively) agreed well with that anticipated on the basis of the intravenous data. It was concluded that the two formulations were bioequivalent and that following oral dosing atenolol was almost completely absorbed with little metabolism or biliary excretion.

Following chronic oral dosing at 50, 100, and 200mg/kg/day the systemic blood levels were found to increase with dose at all time points throughout the study. There was no sex or dose dependency of the half‐life and its value on chronic dosing was very similar to that on acute dosing. The dose dependency of the area under the blood concentration time curves was reflected in the plateau blood levels and there was very good agreement between the experimental values and the theoretical relationship based on the acute pharmacokinetic data. In accordance with the half‐life there was no accumulation at any of the dose levels studied. Thus it can be concluded that atenolol obeys linear pharmacokinetics over the dose range studied.
Bioavailability of medroxalol in man
Authors: Keeley Frederick J. , Weiner Daniel L. , Okerholm Richard A.
Published: October 2006

Ten healthy male volunteers received single oral doses of 100 mg of medroxalol administered as a solution, a preliminary tablet formulation and a single dose of 100 mg administered intravenously in a randomized three‐way crossover study. Mean terminal half‐lives of 12·4, 134, and 11·3 h were observed for the intravenous, solution and tablet formulation, respectively.

Mean urinary recovery of parent drug at 48 h was 8·9 per cent, 3·9 per cent, and 3·2 per cent. Absolute bioavailability estimated from plasma AUC was 54 per cent for the solution and 38 per cent for the tablet, and the relative bioavailability from the tablet was 71 per cent.
Measurement of plasma concentrations of vasodilators and metabolites by the tea analyzer
Authors: Yu W. C. , Goff E. U.
Published: October 2006

The determination of therapeutic levels of glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), pentaerythritol tetranitrate (PETN), and their metabolites in human plasma was conducted using the TEA Analyzer interfaced to a high‐performance liquid chromatograph (HPLC‐TEA). Chromatographic separation of these compounds was accomplished under isocratic HPLC conditions.

The sensitivity of the instrument was established to be 0·1 ng for each of the three nitrate esters.

At the Sngml−1 plasma fortification level, the precision of the method gives mean relative standard deviations (RSD) of ± 10·2 per cent, ± 6·5 per cent, and ± 5·9 per cent for GTN, ISDN, and PETN, respectively.

The recoveries for the nitrate esters and their metabolites from human plasma over the range 1·50ng ml−1 are presented.

The specific and sensitive HPLC‐TEA method developed in this study provides a reliable and rapid assay for the routine analysis for metabolism or bioavailability studies of nitrate esters and their metabolites in plasma of blood, with a detection limit as low as 1 ng ml−1.
Preliminary observations on dissolution and bioavailability of triamterene–hydrochlorothiazide combination products
Authors: Shah Vinod P. , Walker Mark A. , Prasad Vadlamani K. , Lin Julianne , Knapp Gene , Cabana Bernard E.
Published: October 2006

The dissolution profiles of two brands of triamterene–hydrocholorthiazide (TRM–HCT) combination tablets and two brands of TRM–HCT combination capsules were studied using the USP paddle method at 100 rev min−1 in acid medium (0·1 N). The tablets represent two products marketed in Germany, whereas the capsules represent the approved innovator's product and an unapproved generic product. The tablets dissolved almost 100 per cent in 15 min whereas the capsules dissolved less than 25 per cent in 60 min. A pilot bioavailability study was carried out in four normal healthy male volunteers. Urine samples were collected over a 48 h period and analysed for TRM, its major metabolite TRM‐sulfate, and HCT using HPLC methods. The dissolution characteristics of TRM can be associated with the total drug excretion (absorption) of the product. On the other hand, the excretion (absorption) of HCT was independent of dissolution characteristics of the products. However, in TRM–HCT combination product, there appears to be a 50 per cent reduction in HCT excretion (absorption) when compared to the reported excretion (absorption) from a marketed single‐entity product.
Pharmacokinetics and bioavailability of theophylline following enema and suppository admininstration in man
Authors: Cole Mohammed L. , Kunka Robert L.
Published: October 2006

The pharmacokinetics and bioavailability of theophylline from a commercial oral elixir of theophylline, a rectal suppository of aminophylline, and a rectal enema of theophylline monoethanolamine was compared in six normal subjects. Using a complete crossovver design, the fasted subjects received a single dose of each dosage form. Blood and saliva samples were collected at frequent time intervals for 24 h, and the plasma assayed for theophylline by a specific thin‐layer chromatography densitometric method. No statistically significant differences existed among the three dosage forms with respect to Cmax and AUC corrected for the elimination rate constant and the dose (mg kg−1). However, tmax was significantly larger for the suppository. While the rate of absorption was significantly slower for the suppository, no differences in the extent of absorption existed among the three dosage forms. A one‐compartment open model with apparent first‐order absorption adequately described the plasma concentration–time data for the elixir and enema, whereas the suppository data were best fitted by a one‐compartment open model with apparent zero‐order absorption and a lag time. A rate‐limiting, concentration‐independent release of drug from the base most likely accounts for the slow absorption of theophylline from the suppository. While the saliva: plasma ratio remained fairly constant for most of the study period, the large variability found during the absorption phase following drug administration limits the usefulness of this parameter as a monitor of theophylline plasma concentrations.