bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing Critical Care Unit Performance: a global measure using graphical analysis
Authors: Leary T. , Ridley S. , Burchett K. , Kong A. , Chrispin P. , Wright M.
Published: March 2003

Summary Outcome measurement in critical care is difficult because of the wide variety of patients treated and the diverse therapeutic options and pathways available. Individual outcome measures for critical care are available but are naturally limited to only a single aspect of performance. Most importantly, better performance in one aspect of care may compromise the standard of care in another. A global measure of performance would be helpful. For the year 1999–2000, the five hospitals in the East Anglian Critical Care Network provided data on capacity, workload and performance. The data was transformed and displayed graphically on a radar chart so that the area of the polygon within the radar chart was proportional to each unit's overall performance. The results from the five hospitals suggest that there is little overall difference in the units' global performance but the graphical representation highlighted some individual deficiencies. Graphical analysis of complex processes such as critical care delivery may facilitate performance assessment, providing that the measures chosen, weightings assigned and scales used are standardised with care.
The effects of nitrous oxide on the auditory evoked potential index during sevoflurane anaesthesia
Authors: Barr G. , Anderson R. , Jakobsson J.
Published: March 2003

Summary We have studied the effects of nitrous oxide on the auditory evoked response index (AAI™‐index) derived from the A‐line monitoring device during sevoflurane anaesthesia in 21 patients undergoing minor ambulatory surgery. During sevoflurane anaesthesia with an AAI™‐index < 30, the addition or withdrawal of nitrous oxide in a concentration of 66% end tidal did not show any linear dose dependent change in AAI™‐index. However, comparing nitrous oxide > 40% to nitrous oxide < 10% end tidal concentration the AAI™‐index did decrease, p < 0.05. The AAI™‐index is either non‐linear at deeper anaesthetic levels or is insensitive to the anaesthetic effects of nitrous oxide in terms of MAC‐multiples.
A multi centre telephone survey of compliance with postoperative instructions
Authors: Cheng C. J. C. , Smith I. , Watson B. J.
Published: March 2003

Summary Patients undergoing procedures under general anaesthesia as day cases are routinely given a set of instructions regarding activities to avoid in the first 24 h after discharge. Day surgery units generally specify the need for a responsible carer from time of discharge for a period of 24 h. This study looks at the compliance of 240 patients with postoperative instructions. Of the patients studied, 4.1% drove, 1.7% made important decisions, 3.3% drank alcohol, 0.8% took sedatives and 10% cooked, ironed or looked after children. All patients were discharged into the care of a responsible adult. However, 13.3% failed to have a carer with them for 24 h and 1.3% spent the night alone at home. Of our cohort, 25% were unable to comply with the postoperative instructions in full. The majority of non‐compliance occurred on the day following surgery, suggesting that patients may feel that the advice is excessively cautious.
The in vitro effects of crystalloids and colloids on coagulation
Authors: Ekseth K. , Abildgaard L. , Vegfors M. , Berg‐Johnsen J. , Engdahl O.
Published: March 2003

Summary Classically haemodilution is regarded as causing coagulopathy. However, haemodilution with saline seems to cause a hypercoagulable state both in vivo and in vitro. The aim of the present study was to measure the effect of mild to severe haemodilution using thrombelastography. Blood samples were taken in 12 healthy volunteers and divided into seven aliquots. One aliquot was undiluted and acted as control. The other six were diluted with normal saline, Ringer Acetate, 4% albumin, Dextran 70, 6% and 10% hydroxyethylstarch to 10%, 20%, 40%, 50% and 60% dilution. The dilution was checked by measuring the haemoglobin concentration. Each aliquot was placed in a temperature‐controlled thrombelastography channel. Increased coagulation activity, as measured by thrombelastography changes, was detected at low and medium levels of dilution with all the tested solutions. At more than 40% dilution, coagulation returned to normal while in the case of dextran and hydroxyethylstarch coagulopathy developed. For crystalloids and albumin, dilution had to exceed 50% before coagulation was impaired. If these findings can be reproduced in vivo, they may have implications for transfusion practice and prophylaxis against thrombosis.
Impact of a multimodal anti‐emetic prophylaxis on patient satisfaction in high‐risk patients for postoperative nausea and vomiting
Authors: Eberhart L. H. J. , Mauch M. , Morin A. M. , Wulf H. , Geldner G.
Published: March 2003

Postoperative nausea and vomiting (PONV) are frequent and unpleasant symptoms. This prospective study aimed to assess the efficacy of a multimodal approach to prevent PONV, and patient satisfaction using the willingness‐to‐pay method. Two validated risk scores were applied to forecast the individual risk for PONV in 900 consecutive patients of whom 108 were identified as high‐risk patients (predicted risk: 79–87%). High‐risk patients received multimodal anti‐emetic prophylaxis: total intravenous anaesthesia with propofol, high fractional inspired oxygen (80%), omission of nitrous oxide, dexamethasone 8 mg, haloperidol 10 µg.kg−1, and tropisetron 2 mg. Of the remaining patients with low or moderate risk for PONV, a random sample of 71 females received balanced propofol‐desflurane anaesthesia without prophylactic anti‐emetics. All patients were interviewed 2 and 24 h after surgery for occurrence of nausea and vomiting. Patient satisfaction was measured using the willingness‐to‐pay method. The incidence of PONV (95%‐confidence interval) in the control‐group was 41% (29–51%), slightly lower than predicted by the risk scores (53–57%). The multimodal anti‐emetic approach reduced the predicted risk (79–87%) in the high risk‐group to 7% (3–14%). This was associated with a high willingness‐to‐pay median (25th/75th percentile) of £84 (£33–184) in the multimodal anti‐emetic grouped compared to £14 (£4–30) in the control group. A multimodal anti‐emetic approach can considerably reduce the incidence of PONV in high‐risk patients and is associated with a high patient satisfaction as measured by the willingness‐to‐pay method.
The thienopyridine derivatives (platelet adenosine diphosphate receptor antagonists), pharmacology and clinical developments
Authors: Kam P. C. A. , Nethery C. M.
Published: March 2003

Summary The thienopyridines, ticlopidine and clopidogrel, are antiplatelet drugs. They are prodrugs and are metabolised in the liver to active metabolites that are non‐competitive antagonists of the platelet adenosine diphosphate receptor, P2Y12. Inhibition of platelet aggregation by these drugs is delayed until 24–48 h after administration, with maximal inhibition achieved after 3–5 days. Recovery of platelet function after drug withdrawal is slow (7–14 days). Ticlopidine and clopidogrel are effective in preventing atherothrombotic events in cardiovascular, cerebrovascular and peripheral vascular disease. Gastrointestinal side effects and skin rashes are common. However, neutropenia and thrombotic thrombocytopenic purpura are significant and sometimes fatal adverse effects of ticlopidine. Clopidogrel appears to offer several advantages over ticlopidine: a more rapid onset of action and a lower incidence of neutropenia and thrombotic thrombocytopenic purpura.A combination of clopidogrel and aspirin has become standard for antithrombotic therapy in cardiovascular disease. The anaesthetic considerations of patients taking the thienopyridine compounds are discussed.
Mainstream vs. sidestream capnometry for prediction of arterial carbon dioxide tension during supine craniotomy
Authors: Chan K. L. , Chan M. T. V. , Gin T.
Published: March 2003

Summary We compared the performance of mainstream capnometry as a measure of arterial carbon dioxide tension (Paco2) with sidestream recordings in adult neurosurgical patients undergoing supine craniotomy. Two hundred and forty patients were randomly assigned so that the end‐tidal carbon dioxide tension (PÉco2) was measured using either a mainstream or sidestream infrared capnometer. All patients received propofol anaesthesia and ventilation was adjusted according to clinical requirement. Arterial blood gas analyses were performed after induction, prior to dural incision, during surgery and before wound closure. Simultaneous haemodynamic and ventilatory parameters were also recorded. For 1007 paired measurements of PÉco2 and Paco2 (mainstream, n = 503; sidestream, n = 504), the mean (SD) mainstream arterial to end‐tidal carbon dioxide tension difference, 0.64 (0.16) kPa, was smaller than the corresponding sidestream values, 0.99 (0.40) kPa (p < 0.001). The limits of agreement for the mainstream analyser, 0.32–0.96 kPa, were also narrower than the sidestream recordings, 0.19–1.79 kPa (p < 0.001). In both capnometers, the arterial to end‐tidal difference in carbon dioxide tension did not change with time. However, there was greater within‐patient variation in the sidestream group. Our study showed that mainstream PÉco2 provided a more accurate estimation of Paco2 than sidestream measurement.
The incidence of flushing on induction of anaesthesia in patients who blush easily
Authors: Olday J. , Currie E. , Drummond G. B.
Published: March 2003

Summary Flushing (reddening and blotching of the skin) is seen frequently at induction of anaesthesia, is associated with anaesthetic agents such as thiopental and muscle relaxants, and is attributed to histamine release. The changes are generally confined to the neck and upper chest (the blush area). In conscious subjects, the mechanisms responsible for blushing in the same skin distribution are well defined and neurally mediated. We investigated the relationship between a history of blushing easily and flushing after intravenous induction of anaesthesia. We interviewed 898 patients about to undergo general anaesthesia and asked them if they blushed easily. Anaesthesia was induced with thiopental followed by suxamethonium and/or alcuronium. We noted skin colour and the presence of a flush every 5 min for 20 min. Women reported blushing more than men (47% of women, compared with 33% of men, p < 0.001), and blushing was more common in young people (p < 0.001). In those women with a history of blushing, 32% flushed on induction of anaesthesia, compared with 6% of those who did not blush. In men, a flush was seen in 22% of those who blushed, and in 0.2% of those who did not. These differences in the frequency of flushing were significant (p < 0.001). In conclusion, flushing after induction of anaesthesia appears to be related to individual predisposition and may be neurally mediated.
Tectonic and sedimentological evolution of the Pliocene–Quaternary basins of Zakynthos island, Greece: case study of the transition from compressional to extensional tectonics
Authors: Zelilidis  , Kontopoulos  , Avramidis  , Piper
Published: March 2003

Pliocene–Quaternary basins of the Ionian islands evolved in a complex tectonic setting that evolved from a mid to late Cenozoic compressional zone of the northern external Hellenides to the rapidly extending Pliocene–Quaternary basins of the Peloponnese. The northern limit of the Hellenic Trench marks the junction of these two tectonic regimes. A foreland‐propagating fold and thrust system in the northern external Hellenides segmented the former Miocene continental margin basin in Zakynthos and permitted diapiric intrusion of Triassic gypsum along thrust ramps. Further inboard, coeval extensional basins developed, with increasing rates of subsidence from the Pliocene to Quaternary, resulting in four principal types of sedimentation: (1) condensed shelf‐sedimentation on the flanks of rising anticlines; (2) coarse‐grained sedimentation in restricted basins adjacent to evaporitic diapirs rising along thrust ramps; (3) larger basins between fold zones were filled by extrabasinal, prodeltaic mud and sand from the proto‐Acheloos river; (4) margins of subsiding Quaternary basins were supplied at sea‐level highstands by distal deltaic muds and at lowstands by locally derived coarse clastic sediment.
Architecture and evolution of syn‐rift clastic depositional systems towards the tip of a major fault segment, Suez Rift, Egypt
Authors: Young M. J. , Gawthorpe R. L. , Sharp I. R.
Published: March 2003

ABSTRACT This paper investigates syn‐rift stratigraphic architecture and facies relationships along a 7 km long strike section towards the tip of a major, basin‐bounding normal fault segment (Thal Fault) in the Suez Rift, Egypt. In this location, the fault is composed of two precursor fault strands, Gushea and Abu Ideimat, linked by a jog or transfer fault. We document a Miocene syn‐rift succession, deposited more than c. 5.5 Myr after rift initiation, that is composed of a range of carbonate‐clastic facies associated with coarse‐grained deltaic, shoreface and offshore depositional systems. Key regionally correlatable stratal surfaces within this succession define time equivalent stratal units that exhibit variability in thickness and architecture, related to the interplay of both regional and local controls, in particular, the evolution of two, small‐scale (<6 km long) precursor fault strands (Gushea and Abu Ideimat). Integration of structural and stratigraphic data indicates that the boundary (relay ramp) between these two fault strands was a relative high during much of the rift event, with hard‐linkage and considerable displacement accumulation not occurring until at least c. 7.5 Myr after rift initiation. This is because: (i) the preserved stratigraphy is thinner in the hanging wall of the strand boundary; (ii) a eustatic sea‐level fall with an amplitude of 100 m generated more than 25 m of incision at the strand boundary, a region that has a final fault displacement of c. 600 m; and (iii) the fault strand boundary persisted as a footwall low and transport pathway for coarse‐grained deltas entering the basin. This study indicates that variability in stratal thickness and stratigraphic architecture towards the tip of the Thal Fault was related to the linkage history of two small‐scale (c. 6 km long) precursor fault segments. We suggest that similar, small‐scale stratal variability may occur repeatedly along the entire length of major basin‐bounding fault segments due to the process of fault growth by the linkage of smaller scale precursor strands.
Cooling of the Sverdrup Basin during Tertiary basin inversion: implications for hydrocarbon exploration
Authors: Arne D.C. , Grist A.M. , Zentilli M. , Collins M. , Embry A. , Gentzis T.
Published: March 2003

ABSTRACT The regional thermal history of the north‐eastern Sverdrup Basin, Canadian Arctic Archipelago, has been assessed using apatite fission‐track thermochronology and vitrinite reflectance data. Fission‐track data for 27 samples from six wells through the Mesozoic section on Axel Heiberg and Ellesmere Islands reveal significant Palaeocene cooling associated with basin inversion during the Eurekan Orogeny. Fission‐track data for 29 outcrop samples, ranging in stratigraphic age from Cambrian to Tertiary, also reveal significant Palaeocene cooling. Vitrinite reflectance data from carbonaceous shales and coal seams in well and outcrop samples are consistent with these conclusions. The degree of Palaeocene cooling observed is greatest for well and outcrop samples in the cores of anticlines or the hanging walls of thrust faults, such as the Fosheim anticline, and faults, such as the Lake Hazen fault system, and the East Cape and Vesle Fiord thrust faults. Palaeocene cooling is largely attributed to the denudation of structures during the Eurekan Orogeny.

At one locality on north‐western Ellesmere Island, which is on the northern flank of the Sverdrup Basin, the underlying Franklinian basement rocks yield Early Cretaceous fission track ages with relatively long mean track lengths. This indicates that this part of the basin was uplifted at this time and that subsequent sedimentation and subsidence in the Cretaceous and early Tertiary were modest. This locality thus appears to be on the rift shoulder, which developed along the flank of the Amerasia Basin in the Lower Cretaceous.

At a locality on western Axel Heiberg Island, which is downflank from the rift shoulder, the Upper Jurassic Awingak sandstone has a Late Cretaceous fission track age. This is best explained by heating above the total annealing temperature for fission‐tracks in apatite by extensive Lower Cretaceous intrusions and subsequent heat dissipation and cooling in the Late Cretaceous followed by further substantial cooling due to Tertiary denudation.

These results indicate that maximum burial temperatures occurred in the presently exposed Mesozoic section prior to basin inversion during the Eurekan Orogeny. It can therefore be inferred that peak hydrocarbon generation and primary migration predated the formation of structural traps during the Tertiary at shallow depths within the northern Sverdrup Basin.
Forebulge migration in the Cretaceous Western Interior basin of the central United States
Authors: White T. , Furlong K. , Arthur M.
Published: March 2003

ABSTRACT This study combines stratigraphic evidence with geodynamic modelling to demonstrate that a forebulge played an identifiable role in Cenomanian–Turonian erosion and sediment accumulation in the North American Western Interior basin. The early to middle Turonian forebulge migrated progressively eastwards, and by the upper middle Turonian acted as a ‘backstop’ against which barrier islands formed in the axial basin.

This paper focuses on the progressive migration of an unconformity on the forebulge. The lengthwise orogen‐parallel orientation and time‐transgressive orogen‐normal migration of the forebulge unconformity are characteristics that differentiate it from unconformities developed on reactivated basement structures. We present a conceptual model in which the unconformity formed as the seafloor was uplifted by forebulge‐related flexure to a water depth at which submarine bypass and erosion occurred. A numerical model that describes forebulge migration in response to load dispersal by erosion of the orogenic front and sedimentation into the foredeep indicates that the distance from the thrust front to the forebulge is within reasonable bounds established using a flexural rigidity of 3×1024 Nm.

We identify architecturally similar, coeval unconformities from Montana to New Mexico, and interpret the similar distance from the thrust front to a point where each unconformity dissipates as indicative of a uniform lithospheric flexural response along the orogenic front. Here we ascribe cratonward (west‐to‐east) forebulge migration to erosional load redistribution, whereas orogen‐parallel (north–south) stratigraphic climb of the forebulge unconformities developed in response to depocentre migration. Inherited lithospheric inhomogeneities may have allowed the forebulge in central Colorado to crest farther from the orogen than to the north and south.
Folding and faulting in coulomb materials
Authors: Waltham D.
Published: March 2003

Sand in laboratory scale analogue models of folding and faulting is usually assumed to behave as a simple Coulomb material in which failure occurs along planes inclined at an angle completely determined by the internal angle of friction. This simple model has inspired use of the inclined simple shear model to explain analogue model behaviour. Unfortunately the inclined simple shear model is incapable of describing the full richness of behaviour in sand‐based analogue models since it cannot cope with rotations and it cannot satisfy general boundary conditions. A rotational simple shear description is developed in this paper which overcomes these obstacles. It is shown that this description explains high‐angle back thrusts in contractional models, that it quantitatively predicts fault throws in listric‐fault extensional models and that it provides a complete kinematic description for domino‐fault block models including the transition from uniform stretch at the model base to rigid rotation in the model upper half.
The dose–response effects of terbutaline on the variability, approximate entropy and fractal dimension of heart rate and blood pressure
Authors: Jartti Tuomas T. , Kuusela Tom A. , Kaila Timo J. , Tahvanainen Kari U. O. , Välimäki Ilkka A. T.
Published: March 2003

Aims
 To study the dose‐response effects of intravenous terbutaline on the cardiovascular and respiratory autonomic nervous regulation.

Methods
 The study followed a randomized, placebo‐controlled crossover design in six healthy adult volunteers. The terbutaline dose ranged from 10 to 30 μg min−1. We continuously measured electrocardiogram, finger systolic arterial pressure (SAP) and flow‐volume spirometry in supine and upright positions at baseline and during 3 h drug infusion. The periodic variability components of R‐R intervals (time between successive heart beats) and SAP in relation to respiration were assessed using spectral analysis techniques. The regularity of the time series was assessed by approximate entropy (ApEn) and the convolutedness by fractal dimension (FD).

Results
 Terbutaline dose‐dependently decreased total variability of R‐R intervals, low frequency (LF) variability of R‐R intervals (10 s waves), high frequency (HF) variability of R‐R intervals (respiratory variability), total variability of SAP, HF variability of SAP, baroreflex sensitivity, plasma potassium concentration, approximate entropy of R‐R interval and of SAP as well as fractal dimension of R‐R interval. Terbutaline dose‐dependently increased heart rate, LF/HF ratios of R‐R intervals and of SAP, LF variability of SAP, minute ventilation and plasma terbutaline concentration.

Conclusions
 Terbutaline infusion decreases parasympathetic cardiovascular reactivity, baroreflex sensitivity, dimensionality of heart rate and plasma potassium concentration; it increases sympathetic dominance in cardiovascular autonomic balance, minute ventilation, and the regularity of heart rate and blood pressure time series.
Tamoxifen and risk of idiopathic venous thromboembolism
Authors: Meier Christoph R. , Jick Hershel
Published: March 2003

Aims
 To evaluate a possible positive association between tamoxifen treatment and the risk of developing idiopathic venous thromboembolism (VTE) in women with breast cancer in the absence of clinical risk factors for venous thromboembolism other than breast cancer itself.

Methods
 Using information from the large UK‐based General Practice Research Database, we identified, within a cohort of more than 10 000 women with breast cancer, all women who developed a first‐time diagnosis of deep vein thrombosis or pulmonary embolism of uncertain cause between January 1, 1991 and December 31, 1996. In a case‐control analysis, we compared their tamoxifen exposure experience prior to the thromboembolic event with that of a randomly selected group of control women with breast cancer who were matched to cases on age, year of the breast cancer diagnosis and calendar time.

Results
 We identified 25 cases of idiopathic VTE and 172 controls, all of whom had breast cancer, but were otherwise free from other risk factors for VTE. Past tamoxifen exposure was not materially associated with an elevated risk of developing VTE, and we therefore combined never and past users as reference group. The relative risk estimate of VTE for current tamoxifen exposure, as compared with never and past use combined, was 7.1 (95% CI 1.5–33), adjusted for body mass index, smoking status and hysterectomy status. High body mass index was an independent predictor of VTE itself.

Conclusions
 Our study provides evidence that current use of tamoxifen increases the risk of idiopathic venous thromboembolism.
Population pharmacokinetics of ondansetron: a covariate analysis
Authors: De Alwis D. P. , Aarons L. , Palmer J. L.
Published: March 2003

Aims
 To construct a population model to account for the variability in ondansetron pharmacokinetics and to evaluate methods for the efficient development of population models.

Methods
 Population models were developed using 99 subjects consisting of paediatric patients, young, elderly and aged volunteers. A two compartment pharmacokinetic model with a zero order input was used to describe the pharmacokinetics of ondansetron. Three stepwise methods were proposed and used alongside a three step approach to develop population models with both rich and sparse data sets. The stepwise methods were based on obtaining empirical Bayes posterior estimates of pharmacokinetic parameters within a nonlinear mixed effect modelling (NONMEM) program. The parameters were then regressed against covariates in a stepwise procedure. Variance parameters were obtained by fitting the proposed population model to the data in one further NONMEM run. The population model was validated against a test data set of 54 subjects, including children, young and elderly patients and volunteers.

Results
 The population model adequately described the differences in ondansetron pharmacokinetics between paediatric patients, young, elderly and aged volunteers. Different covariates were identified by the various methods. Weight was found to have a strong positive linear relationship with all four pharmacokinetic parameters. Clearance showed a weak negative relationship with age. Males were found to have a greater clearance than females after weight adjustment.

Conclusions
 The stepwise search procedures potentially are capable of considerably reducing the time required to develop population pharmacokinetic models. The model developed for ondansetron gave accurate predictions of both the concentration‐time profile and variability in an independent data set.
Possible association between ocular chloramphenicol and aplastic anaemia—the absolute risk is very low
Authors: Laporte Joan‐Ramon , Vidal Xavier , Ballarín Elena , Ibáñez Luisa
Published: March 2003

Aims
 To determine whether topical ocular chloramphenicol increases the risk of aplastic anaemia and to estimate the magnitude of this risk, if any.

Methods
 Population‐based prospective case‐control surveillance of aplastic anaemia in a community of 4.2 million inhabitants from 1980 to 1995 (67.2 million person‐years) plus case‐population estimate of the risk, based on sales figures of ocular chloramphenicol in the study area during the study period.

Results
 One hundred and forty‐five patients with aplastic anaemia and 1,226 controls were included in the analysis. Three cases (2.1%) and 5 controls (0.4%) had been exposed to ocular chloramphenicol during the relevant etiological period. The adjusted odds ratio was 3.77 (95% confidence interval, 0.84–16.90). Two cases had also been exposed to other known causes of aplastic anaemia. The incidence of aplastic anaemia among users of ocular chloramphenicol was 0.36 cases per million weeks of treatment. The incidence among non users was 0.04 cases per million weeks.

Conclusions
 An association between ocular chloramphenicol and aplastic anaemia cannot be excluded. However, the risk is less than one per million treatment courses.
Direct assessment of peripheral pharmacokinetics in humans: comparison between cantharides blister fluid sampling, in vivo microdialysis and saliva sampling
Authors: Brunner Martin , Schmiedberger Arno , Schmid Rainer , Jäger Dorothea , Piegler Eveline , Eichler Hans Georg , Müller Markus
Published: March 2003

Aims Skin blister fluid sampling, in vivo microdialysis and saliva sampling are commonly employed as surrogates for the measurement of drug concentrations in peripheral compartments. Although expected to exhibit comparable results, data derived from these techniques have never been directly compared. Thus, the aim of the present study was to evaluate the comparability of these techniques.

Methods Paracetamol, a model drug with low protein binding, was administered to seven healthy volunteers at an oral dose of 2000 mg. Subsequently, tissue kinetics were measured simultaneously in cantharides induced skin blisters, microdialysates of subcutaneous‐ and skeletal muscle‐tissue and saliva and compared to serum concentrations.

Results Mean ratio (AUCblister/AUCserum ) was 0.88 (95% CI, 0.50–1.26), mean ratio (AUCmuscle/AUCserum ) was 1.08 (0.67–1.49), mean ratio (AUCsubcutaneous/AUCserum ) was 0.96 (0.41–1.51) and mean ratio (AUCsaliva/AUCserum ) was 1.83 (1.39–2.27). In this study the concentration profiles after single oral administration differed among the three methods. The time course of the concentrationperipheral compartment/concentrationserum‐ratios showed that cantharides blister and microdialysate concentrations closely paralleled serum levels. An equilibration period of less than 2 h had to be taken into account for blister measurements. In contrast, saliva concentrations were significantly higher than corresponding serum concentrations.

Conclusions Skin blister sampling and microdialysis closely mirrored corresponding serum concentrations and, thus, proved to be suitable techniques for the assessment of peripheral compartment pharmacokinetics. In contrast, saliva data overestimated the corresponding serum concentrations.
Pharmacokinetic and pharmacodynamic profile of donepezil HCl following evening administration
Authors: Tiseo  , Rogers  , Friedhoff
Published: March 2003

Aims The primary objective of this study was to characterize the pharmacokinetics and pharmacodynamics of single daily doses of donepezil (5 and 10 mg) each evening for 28 consecutive days. A secondary objective was to measure the plasma protein binding of donepezil at steady state.

Methods This was a double‐blind, randomized, multiple‐dose study in healthy male (n=13) and female (n=3) volunteers. Subjects were randomized to receive, once daily, either oral doses of 5 mg donepezil for 28 days or doses of 5 mg donepezil for 7 days followed by 10 mg donepezil for 21 days. All doses were administered in the evening. Donepezil concentrations and protein binding in plasma were determined by HPLC with UV detection and equilibrium dialysis, respectively. Inhibition of acetylcholinesterase (AChE) activity in red blood cell (rbc) membranes was assessed using a specific radioenzyme assay.

Results The pharmacokinetics of donepezil were linear, dose proportional and stationary over the course of the study. Mean Cmax, tmax , AUC(0–24), t½ and Vλz /F at steady state were 34.1 ng ml−1, 3.0 h, 634.8 ng h ml−1, 72.7 h, and 11.8 l kg−1, respectively, for the 5 mg group and 60.5 ng ml−1, 3.9 h, 1127.8 ng h ml−1, 73.5 h and 11.6 l kg−1, respectively, for the 10 mg group. Accumulation of the drug was observed for 14–21 days, until steady state was achieved. A direct consistent relationship was observed between donepezil plasma concentration and percentage rbc‐AChE inhibition during each 24 h evaluation period, indicating no hysteresis in donepezil pharmacodynamics. The pharmacodynamic parameters, Emin, Emax and Ess, were 62.2%, 71.8% and 65.3%, respectively, for the 5 mg donepezil dose, and 74.7%, 83.6% and 77.8%, respectively, for the 10 mg donepezil dose. Donepezil was 95.6% bound to plasma protein at steady state. The binding was high capacity and low affinity, and neither concentration nor time dependent. Both dosage regimens were well tolerated; no clinically significant changes in laboratory or vital sign parameters were observed in any subject.

Conclusions The measured pharmacokinetic and pharmacodynamic parameters for both 5 and 10 mg day−1 donepezil administered in the evening are in good agreement with previous results obtained with morning administration, indicating no time of dosing effect.
Metabolism and elimination of 14C‐donepezil in healthy volunteers: a single‐dose study
Authors: Tiseo  , Perdomo  , Friedhoff
Published: March 2003

Aim The aim of this study was to investigate the metabolism and elimination of donepezil HCl in humans, following the administration of a single 5 mg (liquid) oral dose containing a mixture of unlabelled and 14C‐labelled donepezil.

Methods This was an open‐label, non‐randomized study in healthy male volunteers (n=8). Characterization of donepezil metabolism and elimination was performed by analysing blood, urine and faecal samples collected over a 10‐day period following drug administration. Each collected sample was assayed for total radioactivity, and aliquots from specified time‐points and/or pooled samples were assayed for the presence of donepezil metabolites by thin‐layer chromatography (TLC). Donepezil concentrations in plasma were determined by HPLC.

Results Recovery of radioactivity in subject samples averaged 72% of the administered dose. Recovery of the administered dose in urine (57%) was significantly greater than that recovered in faeces (15%). Unchanged donepezil accounted for the largest component of the recovered dose in each matrix. Three metabolic pathways were identified: (i) O‐dealkylation and hydroxylation to metabolites M1 and M2, with subsequent glucuronidation to metabolites M11 and M12; (ii) hydrolysis to metabolite M4; and (iii) N‐oxidation to metabolite M6.

In plasma, the parent compound accounted for about 25% of the dose recovered during each sampling period, as well as of the cumulative dose recovered. The recovered residue showed higher levels of the hydroxylated metabolites M1 and M2 than of their glucuronide conjugates M11 and M12, respectively. In urine, the parent compound accounted for 17%, on average, of the dose recovered from each pooled sample, as well as of the total recovered dose. The major metabolite was the hydrolysis product M4, followed by the glucuronidated conjugates M11 and M12. In faeces, the parent compound also predominated, although it accounted for only 1% of the recovered dose. A large percentage of the radioactivity in faeces consisted of unidentified very polar metabolites, which were retained at the TLC origin. Of the extracted metabolites, the hydroxylation products M1 and M2 were the most abundant, followed by the hydrolysis product M4 and the N‐oxidation product M6.

Conclusions Donepezil is hepatically metabolized and the predominant route for the elimination of both parent drug and its metabolites is renal, as 79% of the recovered dose was found in the urine with the remaining 21% found in the faeces. Moreover, the parent compound, donepezil, is the predominant elimination product in urine. The major metabolites of donepezil include M1 and M2 (via O‐dealkylation and hydroxylation), M11 and M12 (via glucuronidation of M1 and M2, respectively), M4 (via hydrolysis) and M6 (via N‐oxidation).
Phenotypes and genotypes for CYP2D6 and CYP2C19 in a black Tanzanian population
Authors: Bathum Lise , Skjelbo Erik , Mutabingwa Theonest K. , Madsen Hanne , Hørder Mogens , Brøsen Kim
Published: March 2003

Aims CYP2D6 and CYP2C19 are polymorphically expressed enzymes that show marked interindividual and interethnic variation. The aim of this study was to determine the frequency of the defective alleles in CYP2D6 and CYP2C19 in Africans and to test whether the genotype for CYP2C19 is better correlated with the proguanil/cylcoguanil ratio than the mephenytoin S/R ratio.

Methods Two hundred and sixteen black Tanzanians were phenotyped for CYP2D6 with the use of sparteine, and for CYP2C19 with the use of mephenytoin and proguanil. Of these 196 subjects were also genotyped for CYP2D6 (including the CYP2D6*1, CYP2D6*3 and CYP2D6*4 alleles) and 195 were genotyped for CYP2C19 (including the CYP2C19*1, CYP2C19*2 and the CYP2C19*3 alleles). Furthermore 100 subjects were examined for the allele duplication in CYP2D6, leading to ultrarapid metabolism, with long PCR.

Results The sparteine metabolic ratio (MR) was statistically significantly higher in the Tanzanian group of homozygous, extensive metabolizers compared to a historical control group of white Danish extensive metabolizers. Only one poor metabolizer for CYP2D6 (MR=124 and genotype CYP2D6*1/CYP2D6*4 ) was found. The gene frequencies were 0.96 for the CYP2D6*1 allele and 0.04 for the CYP2D6*4 allele. No CYP2D6*3 alleles were found. Nine subjects had an allele duplication in CYP2D6 (9%). For CYP2C19 there were seven subjects (3.6%) who were phenotyped as poor metabolizers, but only three subjects (1.5%) had a genotype (CYP2C19*2/CYP2C19*2 ) indicative of poor metabolism. The gene frequencies were 0.90 for the CYP2C19*1 allele and 0.10 for the CYP2C19*2 allele. No CYP2C19*3 alleles were found. The mephenytoin S/R ratios were not bimodally distributed.

Conclusions Both the genotyping and phenotyping results show that there is a substantial difference between an African black population and a Caucasian population in the capacity to metabolize drugs via CYP2D6 and CYP2C19.
A comparison of the residual effects of zaleplon and zolpidem following administration 5 to 2 h before awakening
Authors: Danjou  , Paty  , Fruncillo  , Worthington  , Unruh  , Cevallos  , Martin
Published: March 2003

Aims To compare the duration of the residual hypnotic and sedative effects of zaleplon with those of zolpidem and placebo following nocturnal administration at various times before morning awakening.

Methods Zaleplon 10 mg, zolpidem 10 mg, or placebo was administered double‐blind to 36 healthy subjects under standardized conditions in a six‐period, incomplete‐block, crossover study. Subjects were gently awakened and given medication at predetermined times 5, 4, 3, or 2 h before morning awakening, which occurred 8 h after bedtime. When the subjects awoke in the morning, a battery of subjective and objective assessments of residual effects of hypnotics was administered.

Results No residual effects were demonstrated after zaleplon 10 mg, when administered as little as 2 h before waking, on either subjective or objective assessments, whereas zolpidem 10 mg showed significant residual effects on DSST and memory (immediate and delayed free recall) after administration up to 5 h before waking and choice reaction time, critical flicker fusion threshold and Sternberg memory scanning after administration up to 4 h before waking. Residual effects of zolpidem were apparent in all objective and subjective measurements when the drug was administered later in the night.

Conclusions The present results demonstrate that zaleplon at the dose of 10 mg is free of residual hypnotic or sedative effects when administered nocturnally as little as 2 h before waking in normal subjects. In contrast, residual effects of zolpidem are still apparent on objective assessments up to 5 h after nocturnal administration, longer than has been reported from studies involving daytime administration.
The effect of dosing regimen on the pharmacokinetics of risedronate
Authors: Mitchell  , Heise  , Pallone  , Clay  , Nesbitt  , Russell  , Melson
Published: March 2003

Aims To examine the effect of timing of a risedronate dose relative to food intake on the rate and extent of risedronate absorption following single‐dose, oral administration to healthy male and female volunteers.

Methods A single‐dose, randomized, parallel study design was conducted with volunteers assigned to four treatment groups (31 or 32 subjects per group, 127 subjects total). Each subject was orally administered 30 mg risedronate. Group 1 was fasted for 10 h prior to and 4 h after dosing (fasted group); Groups 2 and 3 were fasted for 10 h and were dosed 1 and 0.5 h, respectively, before a high‐fat breakfast; and Group 4 was dosed 2 h after a standard dinner. Blood and urine samples were collected for 168 h after dosing. Pharmacokinetic parameters were estimated by simultaneous analysis of risedronate serum concentration and urinary excretion rate‐time data.

Results Extent of risedronate absorption (AUC and Ae ) was comparable (P=0.4) in subjects dosed 2 h after dinner and 0.5 h before breakfast; however, a significantly greater extent of absorption occurred when risedronate was given 1 or 4 h prior to a meal (1.4‐ to 2.3‐fold greater). Administration 0.5, 1, or 4 h prior to a meal resulted in a significantly greater rate of absorption (Cmax 2.8‐, 3.5‐, and 4.1‐fold greater, respectively) when compared with 2 h after dinner.

Conclusions The comparable extent of risedronate absorption when administered either 0.5–1 h before breakfast or 2 h after an evening meal support previous clinical studies where risedronate was found to have similar effectiveness using these dosing regimens. This flexibility in the timing of risedronate administration may provide patients an alternative means to achieve the desired efficacy while maintaining their normal daily routine.
Metabolism and excretion of tolcapone, a novel inhibitor of catechol‐O‐methyltransferase
Authors: Jorga Karin , Fotteler Bärbel , Heizmann Peter , Gasser Rodolfo
Published: March 2003

Aims To investigate the rate of excretion and routes of metabolism of tolcapone, a novel inhibitor of catechol‐O‐methyltransferase (COMT).

Methods Six healthy male volunteers were given 200 mg [14C]‐tolcapone (approximately 50 μCi) orally. To assess excretion balance and to identify metabolites, urine and faeces were collected before administration and until radioactivity fell below 75 d min−1 ml−1 (urine) and 100 d min−1 mg−1 (faeces). Blood samples were collected frequently before and after administration to determine plasma radioactivity, to identify tolcapone metabolites and to measure plasma tolcapone and its methylated derivative 3‐O‐methyltolcapone (3‐OMT).

Results The mean proportion of the dose excreted in urine was 57.3% and in faeces 40.5%. Excretion was almost complete (more than 95%) in all participants after 9 days. The major early metabolite present in plasma was the 3‐O‐β,d‐glucuronide conjugate, which was detectable within 2 h after dosing. The major late metabolite in plasma was 3‐OMT. The 3‐O‐β,d‐glucuronide was also the most abundant metabolite in urine and faeces, accounting for 27% and 33%, respectively, of the total radioactivity excreted by these routes and for 26% of the original dose. Reduction of the nitro moiety yields an amine derivative, detected in both urine and faeces, with subsequent modifications, such as acetylation of the amine group and conjugation with glucuronic acid or sulphate, or both. Oxidative reactions due to cytochrome P450 enzymes are of small significance, as is 3‐O‐methylation by COMT.

Conclusions Tolcapone is almost completely metabolized and excreted in urine and faeces (only 0.5% of tolcapone was excreted unchanged); glucuronidation is the most important route of metabolism. The relatively long duration of excretion is caused by the long half‐life of 3‐OMT.
A mechanism‐based pharmacokinetic‐enzyme model for cyclophosphamide autoinduction in breast cancer patients
Authors: Hassan  , Svensson  , Ljungman  , Björkstrand  , Olsson  , Bielenstein  , Abdel‐Rehim  , Nilsson  , Johansson  , Karlsson
Published: March 2003

Aims This study investigated the pharmacokinetics of cyclophosphamide (CP) and its main metabolite 4‐hydroxycyclophosphamide (4‐OH‐CP) in patients with breast cancer undergoing high dose chemotherapy prior to autologous stem cell transplantation. An enzyme turn‐over model was also developed to study the time course of cyclophosphamide induction.

Methods Fourteen patients received a combination of CP (6 g m−2 ), thiotepum (500 mg m−2 ) and carboplatin (800 mg m−2 ) as a 96 h infusion. Plasma concentrations of CP and 4‐OH‐CP were determined with h.p.l.c. and a pharmacokinetic and enzyme turn‐over model applied to data using NONMEM.

Results CP plasma concentrations were described by a two‐compartment model with a noninducible and an inducible pathway, the latter forming 4‐OH‐CP. In the final enzyme model, CP affects the amount of enzymes by increasing the enzyme production rate. CP concentrations decreased during the infusion with no subsequent change in 4‐OH‐CP concentrations. CP inducible and noninducible clearance were estimated to 1.76 l h−1 (90% C.I. 0.92–2.58) and 1.14 l h−1 (0.31–1.85), respectively. The induction resulted in an approximately doubled CP clearance through the inducible pathway at the end of treatment. The model predicted the enzyme turn‐over half‐life to be 24 h.

Conclusions The presented mechanism‐based enzyme induction model where the pharmacokinetics of the inducer and the enzyme pool counterbalance each other successfully described CP autoinduction. It is reasonable to believe that CP affects its own elimination by increasing the enzyme production rate and thereby increasing the amount of enzyme by which CP is eliminated.
Combination of calcium channel blockers and β‐adrenoceptor blockers for patients with exercise‐induced angina pectoris: a double‐blind parallel‐group comparison of different classes of calcium channel blockers
Authors: Van Der Vring  , Daniëls  , Holwerda  , Withagen  , Schelling  , Cleophas  , Hendriks
Published: March 2003

Aims The combination of calcium channel blockers and β‐adrenoceptor blockers is more effective for the treatment of exercise‐induced angina pectoris than β‐adrenoceptor blocker monotherapy. As ischaemia in exercise‐induced angina is preceded by increase in heart rate, calcium channel blockers with negative chronotropic properties may perform better for this purpose than nonchronotropic compounds.

Methods A 335 patient double‐blind parallel‐group study comparing 14 day treatment with amlodipine 5 and 10 mg, with diltiazem 200 and 300 mg, and mibefradil 50 and 100 mg added to baseline β‐adrenoceptor blocker treatment was performed. Exercise testing (ETT) was performed by bicycle ergometry.

Results Although none of the calcium channel blockers improved duration of exercise or amount of workload, all significantly delayed onset of 1 mm ST‐segment depression on ETT (P<0.001 for any treatment vs baseline). In addition, mibefradil, both low and high dose treatment, produced the longest delays (low dose: different from diltiazem and amlodipine by 24.1 and 29.8 s, respectively, P<0.003 and <0.001; high dose: different from diltiazem and amlodipine by 33.7 and 37.0 s, respectively, P<0.001 and <0.001). These effects were linearly correlated with the reduction in rate pressure product (RPP). Serious symptoms of dizziness occurred significantly more frequently on mibefradil (P<0.05), and 19 patients on mibefradil withdrew from trial.

Conclusions Calcium channel blockers with negative chronotropic properties provide greater delay of ischaemia in patients with exercise‐induced angina, but the concomitant risk of intolerable dizziness attenuates this benefit.