bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of microfiltration in decreasing propofol‐induced pain*
Authors: Davies A. F. , Vadodaria B. , Hopwood B. , Dexter T. , Conn D.
Published: March 2003

Summary In a randomised, double‐blinded, two‐centre trial we evaluated the effect of a microbiological filter (Supor®, Pall Life Sciences) on propofol injection pain. We studied 336 unpremedicated adult patients, who graded pain experienced during induction of anaesthesia with propofol on a 4‐point verbal rating scale. Use of the microfilter reduced both the incidence and severity of propofol injection pain (p < 0.001). Incidence of severe pain in the filter group was 2.4% compared with 16.6% in the control group. Overall, 33.7% in the filter group experienced pain compared with 62.1% in the control group. A microbiological filter may provide a non‐pharmacological alternative to a lidocaine/propofol mixture for reducing injection pain. It would also reduce the risk of any glass and bacterial contamination.
Unwanted effects of morphine‐6‐glucuronide and morphine
Authors: Cann C. , Curran J. , Milner T. , Ho B.
Published: March 2003

Summary The active metabolite of morphine, morphine‐6‐glucuronide (M6G), may have fewer unwanted effects than morphine. We randomly allocated 144 women to receive either M6G or morphine as part of general anaesthesia for day case gynaecological laparoscopy. The incidence of nausea, vomiting, pain, sedation and skin rash, and severity of nausea, pain and sedation after surgery were recorded by direct observation in hospital, and by questionnaire until the next morning. Compared with the M6G group, patients who received morphine were more likely to report nausea in the first 2 h after surgery (odds ratio 2.9, CI 1.31–6.21) and to suffer it with greater severity. During the same time period, they were more likely to vomit and feel sleepy, but the intensity of pain and use of rescue analgesics were similar in both groups. The incidences of nausea, vomiting and the feeling of sleepiness continued to be greater in the morphine group during and after the journey home. The next morning, patients in the morphine group remained sleepier, but the incidence of nausea was similar for the two groups. M6G appears to have a better toxicity profile than morphine. More efficacy studies are needed to define accurately the analgesic potency of systemically administered M6G.
Standardized colour coding for syringe drug labels: a National Survey
Authors: Christie I. W. , Hill M. R.
Published: March 2003

Summary A standardised colour code for user‐applied syringe labels for anaesthetic drugs exists in the USA, Australia, New Zealand and Canada. In the UK, there is none. Consequently, an assortment of colour codes for syringe labels is available in the UK. We conducted a postal survey of the 285 College Tutors of the Royal College of Anaesthetists to establish their local syringe drug labelling system and their views on a national, standardised colour code. We found that that 96% of departments currently use coloured syringe drug labels. Of these, 98% use the ‘Medilabel®’ scheme. The College Tutors felt that a standardised colour code for labels is required (94%), that the Association of Anaesthetists or the Royal College of Anaesthetists should be involved in the choice of scheme (76%) and that the scheme chosen should be international (65%). There was a majority feeling that the opinions expressed were representative of other members of the College Tutors' departments. We conclude that a national standard for drug labels is required and that a choice will have to be made between the ‘international’ scheme and the currently dominant Medilabel® scheme.
Routine pre‐operative blood testing: is it necessary?
Authors: Johnson R. K. , Mortimer A. J.
Published: March 2003

Summary In order to determine the value of routine pre‐operative screening investigations, the medical notes of 100 patients undergoing elective surgical procedures under general anaesthesia were subject to prospective audit. Pre‐operative screening investigations (full blood count, urea and electrolytes and random glucose) were analysed in terms of frequency of abnormalities and whether or not the peri‐operative management was changed when the result was abnormal. The frequency of results being present in the note at the time of operation and the costing of the tests was also examined. Atotal of 773 tests was performed of which 70 (9.1%) were abnormal. Peri‐operative management was altered as a result of only two abnormal results (0.2%). Eight complications arose, none of which could have been predicted by the pre‐operative screening tests. In only 57% of cases were the results present in the medical notes at the time of surgery. It is conservatively estimated that a saving of £50 000 per year could be made in our hospital alone by selective ordering of tests.
Learning to apply effective cricoid pressure using a part task trainer
Authors: Owen H. , Follows V. , Reynolds K. J. , Burgess G. , Plummer J.
Published: March 2003

Summary An anatomically‐correct model of a larynx inside a head and neck model was constructed so that the location, direction and amount of force applied to the neck could be measured. Fifty trained staff from three general hospitals were then asked to apply cricoid pressure on the model. None was able to state the force that should be applied (30 N), and only five (10%) actually applied cricoid pressure effectively. After training using the model, 45 (90%) applied cricoid pressure correctly (p < 0.001). This study demonstrates that improved training in cricoid pressure is needed and supports earlier researchers who suggested that this can be achieved using simulators.
The effect of swabs soaked in bupivacaine and epinephrine for pain relief following simple dental extractionsin children
Authors: Andrzejowski J. , Lamb L.
Published: March 2003

We studied 133, ASA I or II children, aged 5–12 yearsundergoing general anaesthesia for simple dental extractions. Induction and maintenance of anaesthesia were achieved using sevoflurane in nitrous oxide and oxygen. At the end of surgery, patients had swabs soaked in a trial solution placed over the exposed teeth sockets. The ‘bupivacaine’ group had swabs soaked in bupivacaine 0.25% with epinephrine 1:200 000, the ‘saline’ group had swabs soaked in saline. Pain scores were recorded on a 4‐point scale as follows: 0 = I don't hurt at all; 1 = I hurt a bit; 2 = I hurt a lot; 3 = I hurt the most. Nurse pain assessments and the patient's own scores were recorded at 15 and 30 min following recovery from anaesthesia. The median pain scores (2 at 15 min and 1 at 30 min postoperatively) were the same in both groups.
Patient‐maintained propofol sedation: a follow‐up safety study using a modified system in volunteers
Authors: Henderson F. , Absalom A. R. , Kenny G. N. C.
Published: March 2003

Summary Patient‐maintained sedation is a mode of patient‐controlled sedation during which propofol is administered using a target‐controlled infusion, with patient demand increasing the target concentration. A system tested previously for safety in our institution resulted in oversedation. Aiming to improve safety, we modified the system by increasing the lockout period to 4 min, reducing the starting concentration to 0.5 µg.ml−1 and the increments on demand to 0.1 µg.ml−1. As in the previous study, healthy volunteers attempted to render themselves unconscious by frequently pressing the demand button. To assess effects on memory, volunteers were given keywords to remember every 15 min. The maximum target concentration reached varied between 1.0 and 2.5 µg.ml−1. No volunteers lost consciousness, however, one volunteer had a brief period of apnoea and oxygen desaturation. The Cp50 for loss of memory for words was 1.26 µg.ml−1. Although this version represents an improvement, we conclude that the system is not yet completely suitable for use without anaesthetic supervision.
Multivariate analysis of factors associated with umbilical arterial pH and standard base excess after Caesarean section under spinal anaesthesia*
Authors: Ngan Kee W. D. , Lee A.
Published: March 2003

Summary We have investigated the factors predicting umbilical arterial pH (UA pH) and standard base excess (UA BE) in 337 consecutive elective Caesarean sections performed under spinal anaesthesia. Multiple linear regression analysis was performed with UA pH and UA BE as the dependent factors. We found that the significant factors predicting UA pH were: use of ephedrine, uterine incision‐to‐delivery time, maximum decrease in systolic arterial pressure and the interaction between ephedrine use and duration of hypotension (adjusted R2 = 0.39, F15,321 = 15.4, p < 0.0001). The significant factors predicting UA BE were: use of ephedrine and the interaction between ephedrine use and duration of hypotension (adjusted R2 = 0.52, F15,321 = 25.0, p < 0.0001). We conclude that, in order to minimise the risk of fetal acidosis, ephedrine should not be used before delivery, uterine incision‐to‐delivery time should be as short as possible, and alpha‐agonists such as metaraminol or phenylephrine should be used to minimise both the magnitude and duration of hypotension.
Calibration of three capnographs for use with helium and oxygen gas mixtures*
Authors: Ball J. A. S. , Grounds R. M.
Published: March 2003

Capnography is considered essential in the management of mechanically‐ventilated patients. Helium, as an adjunct to mechanical ventilation, is the subject of renewed interest and used increasingly. However, helium affects the performance of infrared capnometry. We constructed a simple device to generate variable mixtures of helium, oxygen and carbon dioxide within the normal physiological range, and tested the performance of two side‐stream and one in‐line capnographs. We found that addition of helium to the gas mixture caused all three capnographs to underestimate the concentration of carbon dioxide. The underestimation increased as the proportion of helium increased. The maximum underestimation (30%) occurred in a 79:21 helium/oxygen mixture.
Effect of intra‐operative magnesium sulphate on pain relief and patient comfort after major lumbar orthopaedic surgery
Authors: Levaux Ch. , Bonhomme V. , Dewandre P. Y. , Brichant J. F. , Hans P.
Published: March 2003

Summary The effects of intra‐operative magnesium sulphate on pain relief after major lumbar surgery were investigated in 24 patients. Patients were randomly allocated to receive either an infusion of 50 mg.kg−1 magnesium sulphate or an equivalent volume of saline at induction of anaesthesia. Anaesthesia was induced with propofol and remifentanil. Tracheal intubation was facilitated using rocuronium. Maintenance was achieved with remifentanil and sevoflurane in nitrous oxide/ oxygen. Intra‐operative monitoring included standard equipment and neuromuscular transmission. During surgery, neuromuscular block recovery was longer in the magnesium group. Postoperative opioid consumption and pain scores were lower in the magnesium group. The first night's sleep and the global satisfaction scores were better in the magnesium group. The results of the study support magnesium sulphate as a useful adjuvant for postoperative analgesia after major lumbar surgery.
Basin analysis and mineral endowment of the Proterozoic Itajaí Basin, south‐east Brazil
Authors: Rostirolla  , Ahrendt  , Soares  , Carmignani
Published: March 2003

A basin evolution synthesis and an integration of geological and geophysical data, relevant as guides to the exploration of gold and lead–zinc deposits in the Itajaí Basin, are presented in this paper. The Itajaí Basin is interpreted as a collision‐related foreland basin consisting of weakly metamorphosed sediments deposited between the structural front of the Dom Feliciano fold and thrust belt and the proximal flank of the cratonic forebulge. Its sediments represent a second‐order depositional sequence deposited during a foreland transgression–regression cycle related to flexural subsidence. After deposition, the basin underwent a main late‐collisional compressional deformation phase followed by an extensional post‐orogenic relaxation. Known gold and lead–zinc deposits are associated with late‐orogenic faulting of the Itajaí Basin sediments. The gold‐bearing quartz veins are of filonean hydrothermal affiliation, while the lead–zinc deposits were formed by solution‐remobilization in a meteoric–connate–magmatic mineralizing fluid. Major trends of favourability for such deposits are recognized. The most favourable sites for lead–zinc deposits are near known mineralized areas and also along a NE‐orientated fault at the margin adjacent to the Dom Feliciano metamorphic belt. The higher favourability for gold deposits is assigned to an area along the same NE trend, and also around a small known deposit near the cratonic margin.
Crustal structure and riftogenesis of the Valencia Trough (north‐western Mediterranean Sea)
Authors: Maillard  , Mauffret
Published: March 2003

The Valencia Trough is a rift formed during the late Oligocene – early Miocene opening of the western Mediterranean Sea. In this paper, we focus on the crustal structure and on the deep structure of the basin which is hard to delineate because of the widespread volcanism that conceals part of the basement. This work is the result of the study of a dense network of seismic profiling surveys and exploratory wells made in the region. The structure of the deep basement reveals the importance of transfer fracture zones which represent steps in the deepening of the basin. The thinning of the crust follows the basement deepening and we find the same partitioning of structural blocks at the crustal level. Transfer faults also represent limits in the thinning of the crust and each compartment thus delineated has a different thinning and different extensional ratios. Such a discrepancy between the thinning of the upper crust and the thinning of the lower crust may be common in many other rift zones, but is seldom as well imaged as in this study of the Valencia Trough. The transfer zones are related to extensional processes but a simple shear opening is envisaged to explain the discrepancies between thinning and extension and the asymmetry of the margins. The more efficient thinning in the lower crust can be explained by a thermal anomaly in accordance with the recent evolution of the trough. The steady thinning of the margins is discussed in terms of a marginal basin in a compressional context.
Evolution of the intracratonic Officer Basin, central Australia: implications from subsidence analysis and gravity modelling
Authors: Haddad D , Watts A. B. , Lindsay J.
Published: March 2003

ABSTRACT The intracratonic basins of central Australia are distinguished by their large negative Bouguer gravity anomalies, despite the absence of any significant topography. Over the Neoproterozoic to Palaeozoic Officer Basin, the anomalies attain a peak negative amplitude in excess of 150 mGal, amongst the largest of continental anomalies observed on Earth. Using well data from the Officer and Amadeus basins and a data grid of sedimentary thicknesses from the eastern Officer Basin, we have assessed the evolution of these intracratonic basins. One‐dimensional backstripping analysis reveals that Officer and Amadeus basin tectonic subsidence was not entirely synchronous. This implies that the basins evolved as discrete geological features once the Centralian Superbasin was dismembered into its constituent basins. Two‐ and three‐dimensional backstripping and gravity modelling suggest that the eastern Officer Basin evolved from a broad continental sag into a region of intracratonic flexural subsidence from the latest Neoproterozoic, when flexure of the lithosphere deepened the northern basin. The results from gravity modelling improve when the crust is thickened beneath the northern margin of the basin and thinned at the southern margin, as has been suggested by recent deep seismic data. The crustal thickening beneath the basin's northern margin abuts the region of greatest topographic relief and is consistent with the observed structure at the edges of many orogenic belts. If the Officer Basin evolved as a foreland‐type basin from the late Proterozoic and has retained those features to the present, then one implication is that in the absence of any significant topography, cratonic lithosphere must be able to support stresses over very long periods of geological time.
Modelling the drainage evolution of a river–shelf system forced by Quaternary glacio‐eustasy
Authors: Meijer X. D.
Published: March 2003

The Quaternary glaciations had a profound impact on the geomorphology and stratigraphy of passive continental margins. The challenge is to resolve the contributions of the main forcing controls relative sea‐level change and sediment flux. The key to answer this question is to understand the interaction between the marine and terrestrial environments, where river dynamics play an essential role. A comprehensible three‐dimensional numerical model is presented in order to investigate quantitatively the behaviour of river–shelf sedimentary systems under glacio‐eustatic conditions. Distinctive features observed in the model results include river avulsion, delta‐lobe switching, incision and knickpoint migration. An important event in the development of the modelled river–shelf system is the establishment of a direct and inextricable link between the drainage basin and the depocentre on the shelf edge, thereby bypassing the exposed shelf. This is termed as ‘drainage connection’. In the model, the timing of drainage connection occurs over a broad interval when the model run is repeated many times with small differences in the initial topography, reflecting the sensitivity of the system to its initial state. It demonstrates the inherent variability in the evolution of a sedimentary system as a consequence of non‐linear behaviour. A statistical approach to modelling is suggested in order to deal with this problem.
Inter‐ethnic comparisons of the pharmacokinetics of the HMG‐CoA reductase inhibitor cerivastatin
Authors: Mück W. , Unger S. , Kawano K. , Ahr G.
Published: March 2003

Aims
 During the world‐wide clinical development of the HMG‐CoA reductase inhibitor cerivastatin, pharmacokinetic data have been collected from studies performed in Europe, North America and Japan, covering different ethnic groups, mainly Caucasians and Japanese subjects, but also Black and Hispanics. The aim of the present investigation was to search for any inter‐ethnic differences in cerivastatin pharmacokinetics.

Methods
 All concentration data were assessed by fully validated specific h.p.l.c. assays employing post‐column photochemical derivatization with ultra‐violet light and subsequent fluorescence detection. The comparability of analytical results was guaranteed by cross‐validations between all analytical laboratories. The inter‐ethnic comparison was based on retrospective analysis of the overall pharmacokinetic data pool (n=340 complete profiles) in the key parameters AUC, Cmax, tmax and t1/2, assessed via non‐compartmental methods.

Results
 Based on the comparison of selected individual single‐ and multiple‐dose escalation studies in healthy young males, performed when starting the clinical development, exposure and disposition of the parent compound and its cytochrome P450‐mediated biotransformation products M‐1 and M‐23, and amounts of metabolites M‐1, M‐23 and M‐24 excreted in urine were comparable for US Americans, mainly Caucasians, and Japanese. Retrospective analysis of the complete pharmacokinetic data pool revealed that there are no statistically significant differences in dose‐normalized AUC‐ and Cmax‐values. The respective ratios of weight‐adjusted geometric least‐squares (LS) means (95% confidence intervals) between Japanese and Caucasians were: for AUCdose‐norm 0.96 (0.86–1.08) for single dose, and 1.04 (0.86–1.24) for multiple dose; for Cmax,dose‐norm 0.93 (0.83–1.05) for single dose, and 1.01 (0.82–1.25) for multiple dose. Half‐life was slightly, but statistically significantly shorter in Japanese than in Caucasian subjects following single dose: ratios (95% CI) were 0.68 (0.61–0.77) for single dose, and 1.00 (0.79–1.26) for multiple dose. Times to peak tended to be slightly greater in Japanese: differences of weight‐adjusted LS means (95% CI) were 0.60 h (0.28 h—0.92 h) for single dose, and 1.15 h (0.48 h—1.81 h) for multiple dose. Black and Hispanics did not differ in their pharmacokinetic characteristics from Caucasians.

Conclusions
 Based on inter‐study comparisons and a retrospective analysis of the complete PK data pool there is no evidence for any clinically relevant inter‐ethnic differences in cerivastatin pharmacokinetics in Caucasians, Black and Japanese subjects after oral therapeutic doses.
Clinically relevant drug–drug interactions in oncology
Authors: McLeod Howard L.
Published: March 2003

Although anticancer agents are one of the most toxic classes of medication prescribed today, there is relatively little information available about clinically relevant drug–drug interactions. Pharmacokinetic drug interactions have been described, including alterations in absorption, catabolism, and excretion. For example, an increased bioavailability of 6‐mercaptopurine has been observed when combined with either allopurinol or methotrexate, leading to increased toxicity in some patients. Induction of etoposide or teniposide clearance by anticonvulsants has also been described, resulting in a lower systemic exposure and risk for lower anticancer activity. Alterations in elimination of methotrexate has been observed with probenecid, presumably through competition for renal secretion. There are also several examples of pharmacodynamic interactions. The combination of 5‐fluorouracil plus folinic acid results in more efficient inhibition of thymidylate synthase, a finding which is now utilized routinely in the treatment of colorectal cancer. Improvements in thein vitroand early clinical testing now allow a relatively high degree of prediction of potential clinical drug interactions, prior to observations of untoward drug effects. In conclusion, drug interactions among commonly used anticancer agents have been identified. Their clinical significance can have more impact than many other classes of medications due to the narrow therapeutic index of antineoplastic agents and the potential for lethal side‐effects. It is only through prospective, preclinical and early clinical evaluation that the presence of clinically significant drug interactions can be identified and the information used to provide better therapy for this significant health problem.
Predicting the time course of haemoglobin in children treated with erythropoietin for renal anaemia
Authors: Port  , Ding  , Fies  , Schärer
Published: March 2003

Aims To establish a pharmacodynamic model that allows one to predict the haemoglobin (Hb) response to EPO in children as a function of dose and time, and to derive recommendations for initial dosing and subsequent dose adjustment.

Methods Haemoglobin was monitored in eight children aged 8–15 years with anaemia due to renal failure during treatment with EPO. All patients were free of conditions known to impair the response to EPO. Pretreatment Hb was 4.9–9.0 g dl−1. The drug was administered once weekly by subcutaneous injection; doses ranged from 1700 to 6800 U week−1. Hb was monitored for 4–38 months. The Hb‐time data were analysed by applying a population pharmacodynamic model proposed for EPO in adult haemodialysis patients [1]. Internal model validation was carried out by using a bootstrap procedure.

Results The increase of Hb during treatment with EPO was linear until steady state was reached after 103±33 days (mean±interindividual s.d.). The weekly gain in Hb from the onset of therapy to steady state was 0.0805±0.026 gdl−1 (mean±interindividual s.d.) for every 1000 U EPO week−1; it did not exhibit a dependence on body weight. Estimated mean prediction errors are ±1.53 g dl−1 for predictions that are based on the mean population parameters and±0.83 g dl−1 for predictions that take into account the complete individual Hb‐time data up to and including steady state.

Conclusions The model describes the time course of the Hb response to EPO in children with renal anaemia. The required weekly EPO dose should initially be calculated from the individual pretreatment Hb and the desired Hb at steady state by using the mean population estimates of the weekly gain in Hb per dose unit before steady state (β) and the time needed to reach steady state (τ). A reduction of the initial dose according to body weight is not justified by the available evidence. β should be re‐estimated individually after 6 weeks of treatment and dose should be adjusted accordingly. A final dose adjustment should be made when steady state has been reached based on individual estimates of β and τ.
Comparison of the vasoconstrictor effects of rizatriptan and sumatriptan in human isolated cranial arteries: immunohistological demonstration of the involvement of 5‐HT1B‐receptors
Authors: Longmore  , Razzaque  , Shaw  , Davenport  , Maguire  , Pickard  , Schofield  , Hill
Published: March 2003

Aims We compared the vasoconstrictor effects of 5‐HT with those of the selective 5‐HT1B/1D‐receptor agonists sumatriptan and rizatriptan in human isolated cranial (middle meningeal) arteries. In addition selective 5‐HT1B‐ or 5‐HT1D‐receptor antibodies were used in combination with semiquantitative immunohistochemical techniques to compare the levels of expression of these receptors in human middle meningeal and coronary arteries.

Methods Middle meningeal and coronary arteries were obtained (with consent) from either neurosurgical patients or donor hearts, respectively. Segments of middle meningeal artery were mounted in organ baths for isometric recording and cumulative concentration‐effect curves to 5‐HT, rizatriptan and sumatriptan were obtained. Frozen fresh sections of middle meningeal and coronary arteries were subjected to standard immunohistochemical techniques using specific 5‐HT1B‐ or 5‐HT1D‐receptor primary antibodies and a radiolabelled secondary antibody. Data were subjected to analysis of variance (anova ) and nonlinear regression analysis.

Results 5‐HT, rizatriptan and sumatriptan were potent vasoconstrictors in human isolated middle meningeal artery (EC50 values=32, 90 and 71 nm, respectively). A significantly higher level of 5‐HT1B‐receptor immunoreactivity was detected in middle meningeal artery compared with coronary artery (anova, F=7.95, DF=1,4, P<0.05).

Conclusions Rizatriptan and sumatriptan act selectively to cause vasoconstriction in human isolated middle meningeal artery and are 10‐fold more potent than in human coronary artery. The higher level of expression of 5‐HT1B‐receptors in middle meningeal compared with coronary artery provides a pharmacological basis for the craniovascular selectively of both rizatriptan and sumatriptan.
Failure to respond to treatment with typical antipsychotics is not associated with CYP2D6 ultrarapid hydroxylation
Authors: Aitchison Katherine J. , Munro Janet , Wright Padraig , Smith Shulabade , Makoff Andrew J. , Sachse Christoph , Sham Pak C. , Murray Robin M. , Collier David A. , Kerwin Robert W.
Published: March 2003

Aims To investigate whether or not there is a correlation between failure to respond to typical antipsychotics and CYP2D6 ultrarapid metaboliser status.

Methods CYP2D6 phenotype (metaboliser status) was assigned following genotyping for gene duplication, as well as for the CYP2D6*3, CYP2D6*4, and CYP2D6*5 null alleles in 235 treatment‐refractory patients and 73 nonrefractory patients.

Results Four (1.7%) of the 235 treatment‐refractory subjects were positive on the duplication assay, but, of these, two were found to represent duplications of a null allele (CYP2D6*4 ), therefore leaving only two (0.85%) positive for duplication of a wild type allele (ultrarapid metabolisers). Three (4.1%) of the nonrefractory subjects had a genotype consistent with ultrarapid metaboliser status. Fisher’s exact test gave a two‐tailed P value of 0.091, i.e. a trend towards an excess of ultrarapid metabolisers in the nonrefractory group, which was in the opposite direction to that predicted by our hypothesis.

Conclusions Although the results show a trend towards an excess of ultrarapid metabolisers in the nonrefractory group, the percentages in the two groups of patients are both within the range for ultrarapid metabolisers in Caucasian populations. Our data are not consistent with ultrarapid metaboliser status being a major cause of failure to respond to typical antipsychotics.
The influence of frusemide formulation on diuretic effect and efficiency
Authors: Wakelkamp Monique , Blechert Åsa , Eriksson Maria , Gjellan Kirsti , Graffner Christina
Published: March 2003

Aims Changes in drug delivery rate may result in clinically important changes in drug effects. For the loop diuretic frusemide, it would be desirable to develop controlled release preparations, that could maintain an effective urinary excretion rate over a prolonged period of time. The aim of this study was to investigate the influence of frusemide formulation on frusemide recovery, diuretic effect and efficiency.

Methods Twelve subjects were given 60 mg of four different frusemide controlled release formulations in a single‐dose, double‐blind, randomized 4‐way cross‐over design. The formulations were three study drugs with different extended dissolution rates (ER1Tab, ER2Tab and ER3Caps ) and one reference drug (LR). Urinary volume and contents of frusemide in urine were measured in samples collected over 24 h.

Results Substantial differences in frusemide recovery and diuretic efficiency were observed between LR and all other formulations. At 24 h, mean total frusemide recoveries of ER1Tab, ER2Tab and ER3Caps were 52%, 36% and 57% lower, respectively, compared with LR (P<0.01). Also at 24 h, mean total diuretic efficiency for ER1Tab, ER2Tab and ER3Caps was 83%, 31% and 135% higher, respectively, compared to LR. The rapid dissolution and absorption of LR resulted in a high diuretic response from 0 to 3 h after dosing. However, from 0 to 24 h, there were no differences in diuretic response between the formulations.

Conclusions Controlled release formulations of frusemide with a low and extended rate of dissolution lead to a more prolonged absorption and subsequent diuresis, but still maintain a similar cumulative response, due to their higher diuretic efficiency.
Fluoxetine inhibits the metabolism of tolterodine—pharmacokinetic implications and proposed clinical relevance
Authors: Brynne  , Svanström  , Åberg‐Wistedt  , Hallén  , Bertilsson
Published: March 2003

Aims To investigate the change in disposition of tolterodine during coadministration of the potent cytochrome P450 2D6 (CYP2D6) inhibitor fluoxetine.

Methods Thirteen patients received tolterodine l‐tartrate 2 mg twice daily for 2.5 days, followed by fluoxetine 20 mg once daily for 3 weeks and then concomitant administration for an additional 2.5 days. They were characterized as extensive metabolizers (EM1 with one functional CYP2D6 gene, EM2 with two functional genes) or poor metabolizers (PM).

Results Nine patients, three EM2 and four EM1 and two PM, completed the trial. Following tolterodine administration, the area under the serum concentration–time curve (AUC) of tolterodine was 4.4‐times and 30‐times higher among EM1 and PM, respectively, compared with EM2. The AUC of the 5‐hydroxymethyl metabolite (5‐HM) was not quantifiable in PM. Fluoxetine significantly decreased (P<0.002) the oral clearance of tolterodine by 93% in EM2 and by 80% in EM1. The AUC of 5‐HM increased in EM2 and decreased in EM1. However, the exposure to the active moiety (unbound tolterodine +5‐HM) was not significantly increased in the two phenotypes. The subdivision of the EM group showed a 2.1‐fold increase in active moiety in EM2 but the exposure was still similar to EM1 compared with before the interaction.

Conclusions The study suggests a difference in the pharmacokinetics of tolterodine and its 5‐hydroxymethyl metabolite depending on the number of functional CYP2D6 genes. Fluoxetine significantly inhibited the hydroxylation of tolterodine. Despite the effect on the pharmacokinetics of tolterodine in extensive metabolizers, the clinical effect is expected to be within normal variation.
Pharmacokinetics of efavirenz (EFV) alone and in combination therapy with nelfinavir (NFV) in HIV‐1 infected patients
Authors: Villani  , Regazzi  , Castelli  , Viale  , Torti  , Seminari  , Maserati
Published: March 2003

Aims To define the pharmacokinetic profile of efavirenz (EFV) in HIV‐1 infected patients, when administered alone or with nelfinavir (NFV).

Methods Eleven HIV‐positive patients, in steady‐state treatment with EFV and 11 patients in steady‐state treatment with EFV+NFV, were evaluated. Blood samples for pharmacokinetic analysis were obtained during a dosage interval. Plasma concentrations of EFV were determined by h.p.l.c.

Results No significant difference was found between the principal pharmacokinetic parameters of EFV when administered alone or in combination with NFV (mean AUC: 57.1–7727.3 vs 60.9±12.3 μg ml−1 h; mean CL/F: 0.18±0.072 vs 0.16±0.04 l h−1 kg−1; mean Cmax: 4.0±1.7 vs 4.3±1.2 μg ml−1, and mean tmax: 4.1±1.7 vs 3.5±0.5 h) Mean trough plasma concentrations (C0) of EFV were 1.64±0.93 μg ml−1, with and without NFV. A good correlation was found between C0 and AUC(0,24h) (r=0.96; P<0.01).

Conclusions Despite the common metabolic pathway, there was no significant influence of NFV on the pharmacokinetics of EFV. EFV exhibits a relatively low interindividual variability and a dosing regimen of 600 mg day−1 assures plasma concentrations that are adequate for inhibition of viral replication.
CYP3A4 drug interactions: correlation of 10 in vitro probe substrates
Authors: Kenworthy  , Bloomer  , Clarke  , Houston
Published: March 2003

Aims Many substrates of cytochrome P450 (CYP) 3A4 are used for in vitro investigations of drug metabolism and potential drug–drug interactions. The aim of the present study was to determine the relationship between 10 commonly used CYP3A4 probes using modifiers with a range of inhibitory potency.

Methods The effects of 34 compounds on CYP3A4‐mediated metabolism were investigated in a recombinant CYP3A4 expression system. Inhibition of erythromycin, dextromethorphan and diazepam N‐demethylation, testosterone 6β‐hydroxylation, midazolam 1‐hydroxylation, triazolam 4‐hydroxylation, nifedipine oxidation, cyclosporin oxidation, terfenadine C‐hydroxylation and N‐dealkylation and benzyloxyresorufin O‐dealkylation was evaluated at the apparent Km or S50 (for substrates showing sigmoidicity) value for each substrate and at an inhibitor concentration of 30 μm.

Results While all CYP3A4 probe substrates demonstrate some degree of similarity, examination of the coefficients of determination, together with difference and cluster analysis highlighted that seven substrates can be categorized into two distinct substrate groups. Erythromycin, cyclosporin and testosterone form the most closely related group and dextromethorphan, diazepam, midazolam and triazolam form a second group. Terfenadine can be equally well placed in either group, while nifedipine shows a distinctly different relationship. Benzyloxyresorufin shows the weakest correlation with all the other CYP3A4 probes. Modifiers that caused negligible inhibition or potent inhibition are generally comparable in all assays, however, the greatest variability is apparent with compounds causing, on average, intermediate inhibition. Modifiers of this type may cause substantial inhibition, no effect or even activation depending on the substrate employed.

Conclusions It is recommended that multiple CYP3A4 probes, representing each substrate group, are used for the in vitro assessment of CYP3A4‐mediated drug interactions.
Impact of gastric emptying on the pharmacokinetics of ethanol as influenced by cisapride
Authors: Kechagias  , Jönsson  , Jones
Published: March 2003

Aims To examine the influence of cisapride on the pharmacokinetics of ethanol and the impact of gastric emptying monitored by the paracetamol absorption test.

Methods Ten healthy male volunteers took part in a cross‐over design experiment. They drank a moderate dose of ethanol 0.30 g kg−1 body weight exactly 1 h after eating breakfast either without any prior drug treatment or after taking cisapride (10 mg three times daily) for 4 consecutive days. In a separate study, the same dose of ethanol was ingested on an empty stomach (overnight fast). Paracetamol (1.5 g) was administered before consumption of ethanol to monitor gastric emptying. Venous blood was obtained at 5–10 min intervals for determination of ethanol by headspace gas chromatography and paracetamol was analysed in serum by high performance liquid chromatography (h.p.l.c.).

Results The maximum blood‐ethanol concentration (Cmax ) increased from 3.8±1.7 to 5.6±2.3 mmol l−1 (±s.d.) after treatment with cisapride (95% confidence interval CI on mean difference 0.28–3.28 mmol l−1 ). The area under the blood‐ethanol curve (AUC) increased from 6.3±3.5 to 7.9±2.6 mmol l−1 h after cisapride (95% CI −0.74–3.9 mmol l−1 h). The mean blood ethanol curves in the cisapride and no‐drug sessions converged at ≈2 h after the start of drinking. Both Cmax and AUC were highest when the ethanol was ingested on an empty stomach (Cmax 9.5±1.7 mmol l−1 and AUC 14.6±1.9 mmol l−1 h), compared with drinking 1 h after a meal and regardless of pretreatment with cisapride.

Conclusions A small but statistically significant increase in Cmax occurred after treatment with cisapride owing to faster gastric emptying rate as shown by the paracetamol absorption test. However, the rate of absorption of ethanol, as reflected in Cmax and AUC, was greatest after drinking the alcohol on an empty stomach. The cisapride–ethanol interaction probably lacks any clinical or forensic significance.
Therapeutic drug monitoring in a developing country: an overview
Authors: Gogtay  , Kshirsagar  , Dalvi
Published: March 2003

Therapeutic Drug Monitoring (TDM) was introduced in India in the mid and late 1980s and the last 10 years have seen it grow, together with the growth of separate Clinical Pharmacology departments. The TDM service in the country is broadly of two types: in large teaching hospitals where the service is available through departments of Clinical Pharmacology, and in the private sector, where drug estimations are done by clinical biochemistry departments with minimal interpretation. This article is based on literature review and our own experiences over a 10 year period in a department of Clinical Pharmacology. It focuses on the evolution of TDM, its problems such as lack of funding, special aspects such as the impact of ethnic differences, nutritional deficiencies, quality of medicines and availability of generic products; its utility as a research tool and its future.
Angioedema due to ACE inhibitors: increased risk in patients of African origin
Authors: Gibbs  , Lip  , Beevers
Published: March 2003

Aims To determine patterns in presentation, risk factors, management and outcome of patients with ACE inhibitor associated angioedema in one British teaching hospital.

Methods Cases of ACE inhibitor associated angioedema in patients presenting to the City Hospital, Birmingham between 1993 and 1999 were collected and entered prospectively onto a computerised register.

Results A total of 20 cases (mean age 60 years, range 42–82 years) of ACE inhibitor associated angioedema were reported (11 female and 9 male) with 65% (n=13) of patients being black/Afro‐Caribbean. In 70% of cases (n=14), angioedema occurred within 4 weeks of starting therapy, although three patients presented following long‐term treatment (24–48 months). ACE inhibitors were continued in 50% (n=10) patients, despite at least one documented episode of angioedema. Admission to hospital was necessary in 40% (n=8) patients, with three of these admitted to the intensive care unit, and one of these died as a result of severe laryngeal obstruction.

Conclusions ACE inhibitor related angioedema is a serious and potentially fatal complication which is relatively rare in the general population, but is more common amongst black/Afro‐Caribbean patients. ACE inhibitors are frequently continued following an episode of angioedema and it is important that these episodes are minimised by prompt cessation of the drug, careful patient counselling and heightened awareness in all clinicians who prescribe this common group of drugs.
Placebo effect in the treatment of duodenal ulcer
Authors: De Craen Anton J. M. , Moerman Daniel E. , Heisterkamp Simon H. , Tytgat Guido N. J. , Tijssen Jan G. P. , Kleijnen Jos
Published: March 2003

Aims To assess whether frequency of placebo administration is associated with duodenal ulcer healing.

Methods A systematic literature review of randomized clinical trials was undertaken. 79 of 80 trials that met the inclusion criteria. The pooled 4 week placebo healing rate of all duodenal ulcer trials that employed a four times a day regimen was compared with the rate obtained from trials with a twice a day regimen.

Results The pooled 4 week healing rate of the 51 trials with a four times a day regimen was 44.2% (805 of 1821 patients) compared with 36.2% (545 of 1504 patients) in the 28 trials with a twice a day regimen (difference, 8.0% [equal effects model]; 95% confidence interval, 4.6% to 11.3%). Depending on the statistical analysis, the rate difference ranged from 6.0% (multivariable random effects model) to 8.0% (equal effects model). A number of sensitivity analyses showed comparable differences between the two regimens. Most of these sensitivity analyses were not significant, probably because a number of trials were excluded resulting in a loss of power.

Conclusions We found a relation between frequency of placebo administration and healing of duodenal ulcer. We realize that the comparison was based on nonrandomized data. However, we speculate that the difference between regimens was induced by the difference in frequency of placebo administration. A better knowledge of various placebo effects is required in order to make clinically relevant assessments of treatment effects derived from placebo‐controlled trials.
CYP2D6 polymorphism in a Gabonese population: contribution of the CYP2D6*2 and CYP2D6*17 alleles to the high prevalence of the intermediate metabolic phenotype
Authors: Panserat  , Sica  , Gérard  , Mathieu  , Jacqz‐Aigrain  , Krishnamoorthy
Published: March 2003

Aims To determine the molecular basis of the intermediate extensive metaboliser (EM) CYP2D6 phenotype in healthy Gabonese subjects.

Methods The CYP2D6 phenotype of 154 healthy Gabonese subjects was assessed by giving the subject a single dose of 30 mg dextromethorphan, and collecting their urine for the next 8 h. The CYP2D6 genotype was determined for 50 individuals of the EM phenotypic group by Southern blotting and various PCR‐based procedures aimed at identifying different CYP2D6 alleles.

Results We found that in the studied Gabonese population, as compared with a French population, there is significantly higher frequency of intermediate EM phenotype having lower frequency of CYP2D6 PM alleles. To clarify this discrepancy phenotype‐genotype relationship was studied. We found that the CYP2D6*17 and CYP2D6*2 alleles, prevalent in this black population, are characterised by their low capacity for dextromethorphan demethylation. Our data also show that the CYP2D6*1 allele is associated with the highest in vivo activity followed by the CYP2D6*2 allele and then the CYP2D6*17 allele.

Conclusions The higher frequencies of the CYP2D6*2 and CYP2D6*17 alleles than the CYP2D6*1 allele account for the high frequency of the intermediate EM phenotype in this black population. The polymorphism of the CYP2D6 enzyme activity in African populations could have important implications for use of drugs that are substrates for CYP2D6 and have a narrow therapeutic window.
Fosinopril reduces left ventricular mass in untreated hypertensive patients: a controlled trial
Authors: Cheung Bernard M. Y. , Lau Chu‐Pak
Published: March 2003

Aims Left ventricular hypertrophy is a powerful predictor of cardiovascular morbidity and mortality. We tested the hypothesis that fosinopril, an angiotensin‐converting enzyme inhibitor, reduces left ventricular mass in hypertensive patients.

Methods Thirty‐three patients with untreated mild essential hypertension were randomised to treatment with oral fosinopril (10 mg–20 mg daily) or placebo for 12 weeks. The primary outcome measure was the change in left ventricular mass index determined by echocardiography.

Results Diastolic blood pressure changed from 95.5±2.1 mmHg at baseline to 96.6±2.8 mmHg at the final visit in control patients and changed from 96.6±2.3 mmHg to 91.5±3.0 mmHg in patients treated with fosinopril (P= 0.04). Systolic blood pressure changed from 147.4±3.2 mmHg at baseline to 152.7±4.4 mmHg at the final visit in control patients and changed from 157.6±5.1 mmHg to 149.1±6.1 mmHg in patients treated with fosinopril (P=0.02). Fosinopril reduced diastolic pressure by 6.3 (95%CI 0.3–12.4) mmHg and systolic pressure by 13.3 (95%CI 2.7–23.8) mmHg compared with placebo. The left ventricular mass index changed from 110.0±8.3 g m−2 to 113.1±8.7 g m−2 in the control patients and changed from 120.8±5.8 g m−2 to 109.0±7.5 g m−2 in patients treated with fosinopril (P=0.02). Fosinopril reduced left ventricular mass index by 14.9 (95%CI 2.2–27.6) g m−2 compared with placebo. There was no significant change in the left ventricular systolic or diastolic function, nor were there any significant changes in plasma electrolytes and renal function.

Conclusions Treatment with fosinopril for 12 weeks reduced left ventricular mass significantly in hypertensive patients.
A placebo‐controlled study of interaction between nabumetone and acenocoumarol
Authors: Pardo  , García‐Losa  , Fernández‐Pavón  , Del Castillo  , Pascual‐García  , García‐Méndez  , Dal‐Ré
Published: March 2003

Aims The use of nonsteroidal anti‐inflammatory drugs (NSAIDs) in patients treated with oral anticoagulants is generally discouraged due to the risk of interactions that could increase the risk of bleeding complications. Available data suggest the NSAID, nabumetone, does not produce such an interaction. We investigated whether nabumetone would interact with acenocoumarol, an oral anticoagulant widely used in some European countries.

Methods A double‐blind, randomized, placebo‐controlled study was conducted evaluating nabumetone (1–2 g daily for up to 4 weeks) in osteoarthritis patients with thromboembolic risk previously stabilized on acenocoumarol. The primary efficacy end point was the proportion of patients whose International Normalized Ratio (INR) remained within established margins and whose acenocoumarol dose was not changed. Fifty‐six patients were randomized to receive nabumetone (n=27) or placebo (n=29).

Results Eighteen patients in each group (67% for nabumetone and 62% for placebo) completed the study without showing INR or acenocoumarol dose changes, and were considered as study successes. Nine patients (33%) with nabumetone and 11 (38%) with placebo were considered study failures in the intention‐to‐treat analysis (one patient on nabumetone and four on placebo did not complete the study due to reasons not related to INR and acenocoumarol dose changes). No significant differences were found between groups with regard to study successes. There were two minor bleeding complications, one in each group. Six patients per group presented with eight adverse experiences in each group.

Conclusions Treatment with nabumetone did not alter INR levels compared with placebo in patients stabilized on oral acenocoumarol who require NSAID therapy. These results suggest that nabumetone does not produce a clinically relevant interaction with acenocoumarol. In orally anticoagulated patients without other associated risk factors, treatment with nabumetone for up to 4 weeks does not require increased monitoring of INR levels.