bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevention of tracheal aspiration using the pressure‐limited tracheal tube cuff
Authors: Young P. J. , Basson C. , Hamilton D. , Ridley S. A.
Published: March 2003

A new design of tracheal tube cuff, the pressure‐limited cuff, used with a constant‐pressure inflation system, was compared with a high‐volume low‐pressure cuffed tracheal tube for leakage of dye placed in the subglottic space into the trachea. Patients requiring ventilation on the intensive care unit were randomly allocated into two groups, one for each type of cuff, and blue food dye was instilled daily via a fine catheter above the cuff into the subglottic space. There were eight patients in the high‐volume low‐pressure group and seven in the pressure‐limited cuff group. Dye leaked into the trachea in seven (87%) of the high‐volume low‐pressure group compared with none (0%) of the pressure‐limited cuff group (p < 0.01). This study demonstrates that the pressure‐limited cuffed tracheal tube, in combination with a constant‐pressure inflation device, prevents leakage of fluid into the lungs that occurs with high‐volume low‐pressure cuffs in the critically ill, intubated patient.
Air emboli with Haemaccel®
Authors: Gray A. J. , Glover P.
Published: March 2003

We report two cases of venous air embolism which occurred in association with infusion of Haemaccel® using a pressure bag. As a result of these incidents, we performed a study that showed that up to 45 ml of air can be infused into a patient from a pressurised Haemaccel® plastic bottle using a standard administration set. We also demonstrated that the volume of air infused was influenced by the type and size of the pressure bag and the warming of the Haemaccel® plastic container.
Blood transfusion for Caesarean section in Malawi A study of requirements, amount given and effect on mortality
Authors: Fenton P. M.
Published: March 2003

A prospective study of mothers needing Caesarean section was undertaken to examine the need for blood transfusion, the actual number of units given and the effectiveness of blood transfusion in preventing maternal mortality. Of 3665 mothers in 22 hospitals in Malawi, 11.1% were assessed as needing a transfusion and 7.2% were transfused. There were significant differences between district and central hospitals in transfusion rates. Of those mothers who were considered to need blood, there was no significant difference in mortality between those who received a transfusion and those who did not.
Prediction of the oculocardiac reflex from pre‐operative linear and nonlinear heart rate dynamics in children
Authors: Kim H. S. , Kim S. D. , Kim C. S. , Yum M. K.
Published: March 2003

This study was aimed to determine whether pre‐operatively measured linear and nonlinear analysis of heart rate variability might predict the occurrence of the oculocardiac reflex (OCR) or other arrhythmia during strabismus surgery in children (n = 185, mean (SD) age = 8.09 (3.31) years). We compared time‐ and frequency‐domain, and nonlinear dynamic indices of pre‐operatively measured RR interval data between the OCR‐positive group (maximum heart rate decrement = 20 beat.min−1 during the traction of extraocular muscle, n = 54), OCR‐negative group (< 20 beat.min−1, n = 78) and arrhythmia‐positive group (all other arrhythmias; n = 53). pNN50, rMSSD, high‐frequency power and nonlinear prediction error were significantly lower in the OCR‐positive and arrhythmia‐positive groups than in the OCR‐negative group. Discriminant analysis using these indices could correctly identify 39/54 (72.2%) OCR‐positive patients. Some pre‐operatively measured indices of linear and nonlinear heart rate variability, especially when used in combination, are valuable for predicting significant bradycardia during strabismus surgery in children.
Ease of tracheal intubation through the intubating laryngeal mask during manual in‐line head and neck stabilisation
Authors: Asai T. , Murao K. , Tsutsumi T. , Shingu K.
Published: March 2003

We studied 40 anaesthetised and paralysed patients, in a randomised manner, to compare the ease of tracheal intubation either using a Macintosh laryngoscope and gum elastic bougie (group C) with the ease of tracheal intubation through the intubating laryngeal mask using a fibreoptic bronchoscope (group L), during manual in‐line stabilisation of the patient's head and neck. In both groups, a maximum of 120 s was allowed for attempts at tracheal intubation. The ease of placement of the intubating laryngeal mask or tracheal intubation was assessed using a 100‐mm visual analogue scale (VAS). In patients in whom tracheal intubation succeeded, time for intubation was measured. The intubating laryngeal mask was placed successfully in 19 of 20 patients, with the median VAS of 18 mm (95% CI: 13–32 mm). The success rate of tracheal intubation in group L (17 patients) was significantly higher than in group C (nine patients) (p < 0.01), tracheal intubation in group L was significantly easier than intubation in group C (p < 0.001; 95% CI for difference in VAS: 18–68 mm) and time taken for tracheal intubation was significantly shorter in group L than in group C (95% CI for difference: 8–50 s).
The effect of sevoflurane on implicit memory: a double‐blind, randomised study
Authors: Renna M. , Lang E. M. , Lockwood G. G.
Published: March 2003

Forty‐eight gynaecological patients were randomly allocated to three groups (target end‐tidal sevoflurane concentration 1.2, 1.5 or 2%), and into subgroups for positive or neutral suggestion. Anaesthesia was induced by inhalation of sevoflurane in oxygen. When the target concentration was achieved, the bispectral index, computed from a bi‐frontal electroencephalogram, was noted. One of two eight‐word lists was then played to prime implicit memory, followed by a positive or neutral suggestion. After surgery, each patient tried to identify 24 words obscured by background noise. Priming increased the likelihood of identifying words in the 1.2% group only, i.e. there was evidence of implicit memory in this group. There was no evidence of a therapeutic effect of positive suggestion (p = 0.3), but the power of this part of the study was low. The bispectral index did not achieve statistical significance as an indicator of susceptibility to priming.
Wound botulism in drug addicts in the United Kingdom
Authors: Mulleague L. , Bonner S. M. , Samuel A. , Nichols P. , Khan M. , Shaw S. , Grüning T.
Published: March 2003

Clostridium novyi has recently been identified as the causative organism responsible for the deaths of 35 heroin addicts who had injected themselves intramuscularly. We present two heroin addicts who developed C. botulinum infection following intramuscular or subcutaneous injection of heroin. Like C. novyi, this grows under anaerobic conditions and clinical presentation may be similar; however, descending motor or autonomic signs are invariably present in botulism. The prognosis is good if the diagnosis is made early and appropriate treatment commenced.
Evaluation of a new percutaneous dilatational tracheostomy set
Authors: Bewsher M. S. , Adams A. M. , Clarke C. W. M. , McConachie I. , Kelly D. R.
Published: March 2003

Percutaneous tracheostomy is a well established technique used primarily to assist weaning from mechanical ventilation on many intensive care units. We report our experiences of a total of 36 procedures performed with the new Blue Rhino™ Percutaneous Tracheostomy Introducer Set developed by Ciaglia. The technique was successful in all cases and was simpler and quicker to perform than with the earlier Ciaglia percutaneous tracheostomy set. Difficulties were encountered when using Shiley™ tracheostomy tubes. Significant complications included one posterior wall tear and one tracheal cartilage ring fracture.
Fasting regimens for regional ophthalmic anaesthesia
Authors: Steeds C. , Mather S. J.
Published: March 2003

Members of the British Ophthalmic Anaesthesia Society were surveyed using a postal questionnaire. The response rate was 72.3%. Respondents were asked about starvation before regional anaesthesia for cataract surgery, the use of sedation in these patients, monitoring and if oxygen supplementation was given. The results show that most patients are not starved before this type of regional anaesthesia, and that the majority of patients receive no supplementary sedation or intravenous analgesia. Over 70% of patients received oxygen supplementation.
The effect of 10° head‐up tilt in the right lateral position on the systemic blood pressure after subarachnoid block for Caesarean section
Authors: Loke G. P. Y. , Chan E. H. Y. , Sia A. T. H.
Published: March 2003

Forty women presenting for elective Caesarean section under spinal anaesthesia were randomly assigned to have anaesthesia induced in the right lateral position either in the horizontal position or with 10° head‐up tilt. Hyperbaric bupivacaine 2 ml 0.5% with 0.1 mg of morphine was injected intrathecally before the parturients were placed in the supine position with 15° left lateral tilt. Blood pressure and heart rate were monitored every minute and the sensory level (loss of sharp sensation to pinprick) was monitored every 3 min until clamping of the umbilical cord. Ephedrine 6 mg was given every minute that the systolic blood pressure decreased below 90 mmHg. The mean systolic blood pressure during the first 5 min after induction of spinal anaesthesia was lower in the control group compared to the tilted group (99 mmHg vs. 109 mmHg; p = 0.043). The upper limit of block was higher in the control group compared to the tilted group (p = 0.002). The use of 10° head‐up tilt resulted in a reduced incidence of hypotension initially and less extensive sensory block.
Glycopyrronium and hypotension following combined spinal–epidural anaesthesia for elective Caesarean section in women with relative bradycardia*
Authors: Rucklidge M. W. M. , Durbridge J. , Barnes P. K. , Yentis S. M.
Published: March 2003

The ability of glycopyrronium to reduce the severity of hypotension following subarachnoid block in parturients with a relative bradycardia was evaluated in a double‐blind randomised controlled study. Women with a resting heart rate of ≤ 80 beat.min−1 presenting for elective Caesarean section were randomly allocated to receive either glycopyrronium 2 µg.kg−1 or normal saline intravenously once positioned for combined spinal‐epidural anaesthesia. Following spinal injection of 2.6 ml hyperbaric bupivacaine 0.5% and fentanyl 15 µg, women randomly allocated to the saline group were given 6 mg ephedrine so that all parturients received some prophylaxis against hypotension other than the fluid preload. Further ephedrine and fluid boluses were administered if mean arterial pressure fell 20% or more from resting values. Using a sequential analysis technique, analysis after the first 20 subjects indicated the study should be stopped, with no difference in ephedrine requirements or hypotension between the groups. We conclude that pretreatment with glycopyrronium 2 µg.kg−1 is no more effective than 6 mg ephedrine in preventing hypotension following subarachnoid block in parturients with relatively low resting heart rates.
Efficacy of catheter needles with safeguard mechanisms
Authors: Asai T. , Hidaka I. , Kawashima A. , Miki T. , Inada K. , Kawachi S.
Published: March 2003

Summary There has been considerable interest in using safeguarded needles to reduce needlestick injury. In a randomised design, we studied the efficacy and safety of two such needles (the Insyte AutoGuard and the Protective Acuvance), by comparing them with a conventional catheter needle (Insyte), for intravenous cannulation (18 G) in 150 patients and for intra‐arterial cannulation in another 150 patients (20 G). For intravenous cannulation, the success rates were similar in the three groups but insertion of the AutoGuard or Acuvance catheter was significantly more difficult than the conventional catheter. For the Acuvance, the back‐flow of blood into the chamber was sometimes too slow. For intra‐arterial cannulation, insertion of the AutoGuard was significantly more difficult than the other two devices, mainly because the backflow chamber of the AutoGuard was too short so that the chamber often filled with blood before cannulation. Insertion of the Acuvance was significantly more difficult than the conventional catheter. For both intravenous and intra‐arterial insertion, handling of the withdrawn needle was judged significantly safer in the AutoGuard group than the other two groups, whereas there was no significant difference in the safety between the Acuvance and conventional groups. In five subjects from the AutoGuard group, blood splashed on retraction of the needle. Blood contamination during needle withdrawal occurred frequently in the control and Acuvance groups, but rarely occurred in the AutoGuard group. Therefore, the AutoGuard needle is more suitable for intravenous cannulation, and the Acuvance is more suitable for intra‐arterial cannulation.
Closed loop control of sedation for colonoscopy using the Bispectral Index*
Authors: Leslie K. , Absalom A. , Kenny G. N. C.
Published: March 2003

Summary Sixteen patients undergoing colonoscopy were sedated with propofol using a closed‐loop control system guided by the Bispectral Index (BIS). Propofol administration, via a target‐controlled infusion, was controlled by a proportional‐integral‐differential control algorithm. The median (range) propofol target concentration during closed‐loop control was 2.3 (1.7–3.6) µg.ml−1. The performance characteristics of the system were excellent, with a median absolute performance error of 7 (1–15)%. Patients were drowsy yet rousable, with a median (range) BIS set‐point of 80 (75–85). No patient became apnoeic, required airway support or became haemodynamically unstable whilst sedated. Eight patients moaned or moved during colonoscopy and four had recall. Median (range) time to full consciousness was 4 (2–20) min after the end of closed‐loop control. Patient and surgeon satisfaction were high. We conclude that BIS may be a suitable control variable for closed‐loop control of sedation with propofol.
Combined use of esmolol and nicardipine to blunt the haemodynamic changes following laryngoscopy and tracheal intubation*
Authors: Tan P.‐H. , Yang L. C. , Shih H. C. , Lin C. R. , Lan K. C. , Chen C. S.
Published: March 2003

Summary We examined the effect of different combinations of esmolol and nicardipine upon the circulatory response to tracheal intubation. One hundred patients were randomly allocated into five groups of twenty to receive pretreatments of saline or different combinations of esmolol (0.5 or 1.0 mg.kg−1) and nicardipine (15 or 30 µg.kg−1). Significant tachycardia persisted over a 5‐min period after intubation in all five groups compared with baseline levels (p < 0.05). Patients receiving esmolol 1.0 mg.kg−1 and nicardipine 30 μg.kg−1 showed no significant change in systolic blood pressure after tracheal intubation compared with baseline and significant lower peak systolic blood pressure than those receiving saline (p = 0.023).
The effect of low dose sevoflurane on saccadic eye movement latency
Authors: Carpenter R. H. S. , Descamps M. J. L. , Morley C. H. , Leary T. S. , Jones J. G.
Published: March 2003

Summary We investigated the effects of a low concentration of sevoflurane on a saccadic eye movement task that reflects the performance of higher neural decision and control mechanisms. The experiments were performed double‐blind in five subjects, using either 0.15% end‐tidal sevoflurane in oxygen, or pure oxygen as a placebo. Saccades were recorded and analysed using a computer‐based recording system that also controlled the presentation of visual targets. Administration of oxygen produced no significant change in median latency compared with breathing air; but in four of the five subjects, administration of sevoflurane in oxygen caused a significant increase in latency. These results suggest that measurement of median saccadic latency may be a useful functional measurement of impairment of performance during recovery from anaesthesia.
Association between intra‐operative incidents and postoperative outcome and resource utilisation
Authors: Niskanen M. M. , Ruokonen E. T.
Published: March 2003

Summary We assessed the predictive value of intra‐operative quality indicators (incidents) with respect to outcome (hospital mortality) and resource utilisation (length of stay in the postanaesthesia care unit and in hospital). Institutional data obtained from reports of a quality system that complies with the ISO 9002 standard were evaluated retrospectively. Incidents occurred in 2009 of 25 091 anaesthetics. Mortality was higher after incidents than after uneventful anaesthetics, but in multivariate analysis the incidents did not contribute to mortality. Length of stay in the postanaesthesia care unit and hospital were longer after incidents (p < 0.001 for both). In multivariate analysis, incidents independently contributed to length of stay in the postanaesthesia care unit among ASA I−III patients (p < 0.05, 0.001 and 0.001, respectively) and to length of hospital stay among ASA II−III patients undergoing scheduled operations (p < 0.05 and < 0.01, respectively). Intra‐operative incidents are associated with increased resource utilisation following surgery.
Deliberate release of biological agents
Authors: Sardesai A. M. , Brown N. M. , Menon D. K.
Published: March 2003

Summary Deliberate release of biological agents is a growing threat, but clinical recognition of the resulting diseases is hampered by their rarity and similar presentation to more common illnesses. Despite substantial publicity, access to information may be difficult. Further, the available data are fragmented and not always relevant to critical care settings. We describe the clinical presentations of some important infections, highlighting the features that are relevant to critically ill patients. We provide an integrated set of guidelines for diagnosis, patient care and infection control and have attempted to list important print‐ and web‐based resources for further information.
Convulsions following axillary brachial plexus blockade with levobupivacaine
Authors: Pirotta D. , Sprigge J.
Published: March 2003

Neurotoxicity manifesting as convulsions is a recognised complication of the administration of local anaesthetic drugs as part of a regional anaesthetic technique. We describe a case of self‐limiting convulsions following the institution of an axillary brachial plexus block with levobupivacaine. Although the occurrence of convulsions following the administration of racemic bupivacaine is a well‐recognised complication, there have been no clinical case reports published describing convulsions following the use of levobupivacaine in regional anaesthesia.
Bispectral index‐guided management of anaesthesia in permanent vegetative state
Authors: Pandit J. J. , Schmelzle‐Lubiecki B. , Goodwin M. , Saeed N.
Published: March 2003

A patient in a permanent vegetative state required general anaesthesia for dental surgery. Because of the uncertainties involved in the appropriate monitoring and assessment of the conscious level of patients in a permanent vegetative state, it was decided to use the bispectral index to help guide the anaesthetic depth during surgery. We found that the bispectral index profile during anaesthesia and surgery was similar to that of a normal subject. The findings raise the possibility that patients in permanent vegetative states might sense noxious stimuli at a cortical level.
An evaluation of ultrasound imaging for identificationof lumbar intervertebral level
Authors: Furness G. , Reilly M. P. , Kuchi S.
Published: March 2003

The accuracy of ultrasound imaging to identify lumbar intervertebral level was assessed in 50 patients undergoing X‐ray of the lumbar spine. Using an ultraviolet marker, an anaesthetist attempted to mark the L2/3, L3/4 and L4/5 intervertebral spaces. A radiologist unaware of these marks attempted to mark the same spaces with the aid of ultrasound imaging. X‐ray‐visible pellets were taped to the back at the various marks prior to lateral lumbar X‐ray. Ultrasound imaging identified the correct level in up to 71% of cases, but palpation was successful in only 30% (p < 0.001). Up to 27% of marks using the palpation method were more than one spinal level above or below the assumed level using palpation, but none were more than one level high or low using ultrasound guidance.
The efficacy of lidocaine administered via the LITATM tracheal tube in attenuating the extubation response in beta‐blocked patients following craniotomy*
Authors: Andrzejowski J. , Francis G.
Published: March 2003

Summary The Laryngotracheal Instillation of Topical Anaesthetic (LITA™) tracheal tube has an additional pilot tube through which local anaesthetic can be instilled into the larynx via 10 small holes above and below the cuff. We studied 40 patients undergoing supratentorial craniotomy. They were premedicated with two oral doses of propranolol 1 mg.kg−1. The anaesthetic consisted of infusions of remifentanil, propofol and vecuronium. On insertion of the first skin clip at the end of surgery, 5 ml of either saline or 2% lidocaine was injected into the appropriate lumen of the tracheal tube. There was no difference between the groups in the degree of coughing or the haemodynamic response to tracheal extubation.
Crustal thickening and crustal extension as controls on the evolution of the drainage network of the central Swiss Alps between 30 Ma and the present: constraints from the stratigraphy of the North Alpine Foreland Basin and the structural evolution of the Alps
Authors: Schlunegger Fritz , Slingerl Rudy , Matter Albert
Published: March 2003

The combined information about sedimentary petrography from the North Alpine Foreland Basin and structural geology from the Alps allows a qualitative reconstruction of the drainage network of the central Swiss Alps between 30 Ma and the present. This study suggests that crustal thickening and crustal thinning significantly controlled the location of the drainage divide. It also reveals the possible controls of crustal thickening/thinning on the change of the orientation of the drainage network from across‐strike between 30 and 14 Ma to along‐strike thereafter.

Initial crustal thickening in the rear of the wedge is considered to have formed the drainage divide between north and south at 30 Ma. Because the location of crustal thickening shifted from east to west between ≈30–20 Ma, the catchment areas of the eastern dispersal systems reached further south than those of the western Alpine palaeorivers for the same time slice. Similarly, the same crustal dynamics appear to have controlled two phases of denudation that are reflected in the Molasse Basin by petrographic trends. Uplift in the rear of the wedge caused the Alpine palaeorivers to expand further southward. This is reflected in the foreland basin by increasing admixture of detritus from structurally higher units. However, tectonic quiescence in the rear of the wedge allowed the Alpine palaeorivers to cut down into the Alpine edifice, resulting in an increase of detritus from structurally lower units. Whereas uplift in the rear of the wedge was responsible for initiation of the Alpine drainage systems, underplating of the external massifs some 50 km further north is thought to have caused along‐strike deviation of the major Alpine palaeorivers.

Besides crustal thickening, extension in the rear of the wedge appears to have significantly controlled the evolution of the drainage network of the western Swiss Alps. Slip along the Simplon detachment fault exposed the core of the Lepontine dome, and caused a 50‐km‐northward shift of the drainage divide.
The dynamics of foreland basin carbonate platforms: tectonic and eustatic controls
Authors: Galewsky Joseph
Published: March 2003

A numerical model linking a coral growth algorithm and an algorithm for flexural subsidence reproduces many of the characteristics of drowned foreland basin carbonate platforms. This model successfully matches the observed distribution and drowning age of drowned carbonate platforms in the Huon Gulf, Papua New Guinea, a modern submarine foreland basin. Analysis of equations describing flexural subsidence and eustatic sea‐level variations suggest that there are minimum convergence rates and periodicities of sea‐level variation required to drown foreland basin carbonate platforms. For convergence rates on the order of a few millimetres per year, sea‐level must vary on time‐scales of about 105 years in order to induce a rate of relative sea‐level rise great enough to drown an otherwise healthy foreland basin carbonate platform.
Neoproterozoic tectonic and climatic evolution recorded in the Gariep Belt, Namibia and South Africa
Authors: Frimmel H. E. , Fölling P. G. , Eriksson P. G.
Published: March 2003

ABSTRACT The Pan‐African Gariep Belt in south‐western Namibia and westernmost South Africa provides an excellent window into the interplay between tectonic and climatic changes during the Neoproterozoic era. Recently acquired chemostratigraphic data from cap carbonate sequences above glaciogenic diamictite horizons, together with U–Pb zircon and Pb–Pb carbonate ages, indicate sedimentation in the Gariep Basin from continental break‐up around 770 Ma to basin closure and continent collision around 545 Ma. The basin is subdivided into an eastern failed rift graben and a western half graben that evolved into an oceanic basin between the Kalahari and the Rio de la Plata cratons. Three megasequences are distinguished in the external, para‐autochthonous part of the belt (Port Nolloth Zone): an early continental, predominantly siliciclastic, sag rift megasequence (M1), a passive continental margin, carbonate‐rich megasequence (M2), and a syn‐orogenic carbonate and flysch megasequence (M3). Two glaciogenic diamictite horizons at the end of M1 and M2 are recognized and they are correlated with the global ∼750 Ma Sturtian and ∼580 Ma Marinoan glaciations, respectively. While the former is restricted to proximal continental rift shoulders, the latter extends into the oceanic realm which marks the internal part of the belt (Marmora Terrane). Only the younger diamictite is associated with iron formation. The sequence of regressive and transgressive stages recorded by the sediment fill does not reflect simply the tectonic evolution from rifting to drifting and eventual basin closure, but is strongly controlled by severe climatically induced sea‐level changes that were either competing with or reinforcing tectonically induced sea‐level changes.
Single dose pharmacokinetics of lamivudine in subjects with impaired renal function and the effect of haemodialysis
Authors: Johnson M. A. , Verpooten G. A. , Daniel M. J. , Plumb R. , Moss J. , Van Caesbroeck D. , De Broe M. E.
Published: March 2003

Aims
 The purpose of this study was to investigate the pharmacokinetics of a single oral dose of lamivudine administered to subjects with renal impairment and to determine whether lamivudine was dialysable in subjects with severe renal impairment undergoing haemodialysis.

Methods
 Twenty‐nine subjects were enrolled, nine with normal renal function (creatinine clearance (CLCR ) 82–117 ml min−1 ), eight with moderately impaired renal function (CLCR 25–49 ml min−1 ), six with severe impairment (CLCR 13–19 ml min−1 ) and six with severe impairment who were also receiving haemodialysis. After an overnight fast, nondialysis subjects received a single oral dose of lamivudine. Subjects on haemodialysis were given two doses on separate occasions (intra and interdialysis). Blood was obtained before lamivudine administration and at regular intervals to 48 h post dose. Timed urine collections were performed for subjects able to produce urine. Pharmacokinetic parameters were calculated by using standard non compartmental techniques.

Results
 Decreasing renal function was associated with reduced lamivudine clearance in a proportional and apparently linear relationship. Lamivudine was well dialysed with an extraction ratio in the order of 50%. However, because lamivudine has a large volume of distribution (≈100 l), a haemodialysis session of 4 h did not affect overall exposure to a clinically significant degree in most subjects.

Conclusions
 Impaired renal function does require lamivudine dose modification according to the degree of impairment, but no further modification of dose is required for subjects undergoing regular haemodialysis.
Improvement in the gastrointestinal absorption of troglitazone when taken with, or shortly after, food
Authors: Young M. A. , Lettis S. , Eastmond R.
Published: March 2003

Aims
 Troglitazone, an insulin action enhancing agent, is currently in clinical development for the treatment of non insulin dependent diabetes mellitus. The objective of this study was to establish the effect of food on the systemic absorption and metabolism of troglitazone.

Methods
 After an overnight fast, 12 healthy male volunteers each received, in random order, troglitazone (400 mg orally) alone, concomitantly with (at the start of), and 30 min after, a standardized diabetic breakfast as part of a three‐period crossover study.

Results
 When troglitazone was administered with or after food, geometric mean values of area under the plasma concentration‐time curves (AUClast ) relative to fasting state were increased significantly by 59% in both cases (95% CI 1–150%, P=0.046 and 2–148%, P=0.040) with values of 11.4, 11.5 and 7.2 μg ml−1 h respectively. Maximum observed plasma concentration (Cmax ) increased by 96% and 72% (95% CI 29–197%, P=0.003 and 15–158%, P=0.011) with values of 2.2, 2.0 and 1.1 μg ml−1 respectively. Changes in tlag were not clinically significant. Increases in AUC(0,∞) for the main circulating sulphate metabolite relative to fasting were also significant (41%, 95% CI 5–89%, P=0.025 and 34%, 95% CI 1–79%, P=0.044 respectively) with values of 82.6, 78.6 and 58.5 μg h ml−1. Cmax increased by 68% (95%, CI 10–156%, P=0.019) and 65% (95% CI 9–149%, P=0.020) with values of 3.2, 3.1 and 1.9 μg ml1 respectively. Reductions in t1/2 (16 and 21%, 95% CI 0–30, 6–33) although statistically significant (P=0.050 and P=0.009) were not clinically significant with values of 22.3, 20.4 and 24.5 h for with food, after food and fasting respectively. Troglitazone was well tolerated in all cases throughout the study with a trend for improved tolerability of gastrointestinal symptoms when taken 30 min after a meal.

Conclusions
 The absorption of troglitazone is enhanced significantly by food with little effect on the main metabolic pathway. Increased absorption of troglitazone in the presence of food is likely to be a consequence of enhanced solubility in bile combined with an increase in dissolution time. On the basis of these findings, troglitazone should be taken either with, or up to 30 min after, food.
Mesalazine release from a pH dependent formulation: effects of omeprazole and lactulose co‐administration
Authors: Hussain F. N. , Ajjan R. A. , Moustafa M. , Weir N. W. , Riley S. A.
Published: March 2003

Aims
 Delayed‐release formulations of mesalazine often rely on the gastrointestinal luminal pH profile to deliver 5‐aminosalicylic acid (5ASA) to the colon. The aim of this study was to examine the influence of luminal pH on mesalazine release.

Methods
 We studied the effect of co‐administration of omeprazole and lactulose on the steady‐state pharmacokinetics of Eudragit S‐coated mesalazine in healthy volunteers.

Results
 No significant changes in urinary or faecal levels of 5ASA or its main metabolite, N‐acetyl 5ASA, were apparent.

Conclusions
 This study suggests that co‐administration of omeprazole and lactulose does not impair the release of delayed‐release mesalazine.
The effect of aspirin on thrombin stimulated platelet adhesion receptor expression and the role of neutrophils
Authors: Taylor* Marcia L. , Ilton Marcus K. , Misso Neil L. A. , Watkins D. Neil , Hung Joseph , Thompson Philip J.
Published: March 2003

Aims
 Aspirin has proven clinical efficacy in limiting the thrombotic complications of atherosclerotic vascular disease but its mechanism of action remains unclear. Recent evidence suggests the anti‐platelet action of aspirin may be partly mediated by neutrophil derived nitric oxide (NO). The aim of the study was to determine the effects of aspirin on thrombin‐induced platelet expression of the α‐granule membrane protein, P‐selectin, and the platelet surface glycoprotein required for aggregation, GPIIb‐IIIa, and to assess whether this was enhanced by the presence of neutrophils.

Methods
 Platelet P‐selectin and GPIIb‐IIIa receptor expression were assessed by flow cytometric analysis of washed platelets stimulated with thrombin (0.025 iu ml−1, sub aggregatory concentration) alone or after pre‐incubation with aspirin (0.05, 0.1, 0.5, 1.0 mg ml−1 ) either in the presence or absence of neutrophils (100 platelets per neutrophil). NO release was determined by assay of nitrite in the supernatants from parallel samples.

Results
 In preliminary aggregation studies, aspirin at all concentrations inhibited arachidonic acid but not thrombin‐induced platelet aggregation. Similarly, aspirin at all concentrations failed to inhibit thrombin‐induced platelet P‐selectin or GPIIb‐IIIa expression and this was not influenced by the presence of neutrophils. A reduction in P‐selectin and GPIIb‐IIIa receptor density on non‐activated platelets co‐incubated with unstimulated neutrophils was associated with NO release from neutrophils, but this was not enhanced by the addition of aspirin.

Conclusions
 These results confirm that thrombin‐induced platelet α‐granule release, with consequent P‐selectin expression, and platelet GPIIb‐IIIa expression, are not affected by aspirin inhibition of cyclo‐oxygenase and suggest that the anti‐thrombotic efficacy of aspirin in vivo may partly depend on other mechanisms. This study did not demonstrate an effect of neutrophils or neutrophil derived NO on aspirin inhibition of platelet adhesion receptor expression.
Pharmacokinetics of chlorofluorocarbon and hydrofluoroalkane metered‐dose inhaler formulations of beclomethasone dipropionate
Authors: Lipworth  , Jackson
Published: March 2003

Aims To compare the pharmacokinetic profile of BeclazoneTM (beclomethasone dipropionate) in its chlorofluorocarbon (CFC)‐based and CFC‐free formulations.

Methods Ten healthy adults received a single 1000 μg nominal dose (ex‐valve) of beclomethasone dipropionate from a CFC inhaler (BEC‐CFC) or from a CFC‐free inhaler containing hydrofluoroalkane (HFA)‐134a (BEC‐HFA) in an open‐label, randomized, two‐way, crossover study. Blood samples were collected predose and over 12 h after inhalation. Comparisons were made of maximum plasma concentration of beclomethasone 17‐monopropionate (17‐BMP) (Cmax ), and area under the plasma concentration vs time curve (AUC).

Results The tmax was significantly (P<0.05) earlier with BEC‐HFA and plasma levels were significantly higher following administration of BEC‐HFA than BEC‐CFC. Geometric mean values for AUC were 1.5 fold greater (90% CI 1.3–1.9) and for Cmax were 1.9 fold greater (90% CI 1.6–2.6) following BEC‐HFA than BEC‐CFC.

Conclusions Our data in healthy volunteers would not be consistent with the manufacturers’ recommendation for a microgram equivalent (1:1) nominal dose switch between these HFA and CFC formulations. Further well designed trials are required in asthmatic patients to properly define their respective dose–response relationships for antiasthmatic and systemic adverse effects.
Reliability of the omeprazole hydroxylation index for CYP2C19 phenotyping: possible effect of age, liver disease and length of therapy
Authors: Kimura Miyuki , Ieiri Ichiro , Wada Yukiko , Mamiya Kohsuke , Urae Akinori , Iimori Emiko , Sakai Terufumi , Otsubo Kenji , Higuchi Shun
Published: March 2003

Aims To evaluate the reliability of the omeprazole hydroxylation index as a marker for polymorphic CYP2C19 activity in a Japanese population of healthy young subjects (n=78) and patients with peptic ulcer (n=72).

Methods Healthy subjects were administered a single dose of omeprazole (20 mg), whereas patients received 20 mg daily for at least 1 week. The ratio of the serum concentration of omeprazole to hydroxyomeprazole at 3 h postdose was determined and used as a measure of CYP2C19 activity. The CYP2C19 wild type (wt) gene and four mutant alleles associated with the poor metaboliser phenotype of (S)‐mephenytoin, CYP2C19*2 in exon 5, CYP2C19*3 in exon 4, CYP2C19m4 in exon 9, and CYP2C19m3 in the initial codon were analysed.

Results In the healthy volunteer study there was complete concordance between genotype and phenotype. However, eight of the patients who had the EM genotype had a high value for their hydroxylation index, and were classified as phenotypic PMs. No CYP2C19m4 and CYP2C19m3 mutations were detected in the eight mismatched patients. They were all genotypic heterozygous EMs, elderly (≥65 years) and/or had hepatic disease. Therefore, impaired CYP2C19 activity combined with partial saturation of omeprazole metabolism during multiple dosing may have contributed to the discrepancy between CYP2C19 genotyping and phenotyping.

Conclusion Although omeprazole has been used instead of mephenytoin as a probe for polymorphic CYP2C19, it does not appear to be reliable enough for clinical application in Japanese patients.
The pharmacokinetics and safety profile of oral ganciclovir in combination with trimethoprim in HIV‐ and CMV‐seropositive patients
Authors: Jung Donald , AbdelHameed Magdy H. , Hunter John , Teitelbaum Philip , Dorr Albert , Griffy Kay
Published: March 2003

Aims We investigated the pharmacokinetics and safety profile of oral ganciclovir coadministered with trimethoprim in HIV‐and CMV‐seropositive patients.

Methods In an open‐label, randomized, 3‐way crossover study, 12 adult males received oral ganciclovir 1000 mg every 8h, oral trimethoprim 200 mg once daily, or both drugs concomitantly in a sequence of three 7‐day treatment periods. Pharmacokinetic parameters were determined and adverse events recorded for each treatment.

Results The presence of trimethoprim significantly decreased CLr (12.9%, P=0.0068) and increased t1/2 (18.1%, P=0.0378) of ganciclovir. However, these changes are unlikely to be clinically meaningful. There were no statistically significant changes in trimethoprim pharmacokinetic parameters in the presence of ganciclovir, with the exception of a 12.7% increase in Cmin. Ganciclovir was well tolerated when administered alone or in combination with trimethoprim.

Conclusions There was no clinically significant pharmacokinetic interaction between oral ganciclovir and trimethoprim when coadministered.
Low use of long‐term hormone replacement therapy in Denmark
Authors: Olesen Charlotte , Steffensen Flemming Hald , Sørensen Henrik Toft , Nielsen Gunnar Lauge , Olsen Jørn , Bergman Ulf
Published: March 2003

Aims To examine individual use of hormone replacement therapy (HRT) in a defined population of Danish women during a 5‐year period. HRT may reduce osteoporosis and cardiovascular disease in postmenopausal women, but may also have side‐effects. Little is known about the use of HRT in most populations.

Methods A Pharmacoepidemiological Prescription Database was used to identify all reimbursed prescriptions for HRT in the county during the period 1991 to 1995. The Danish retail pharmacies’ drug subsidy system made it possible to identify prescriptions by individual use.

Results We examined 255 797 HRT prescriptions issued during the period in the County of North Jutland. Total sales reached 16.5 million defined daily doses (DDDs), purchased by 31 653 women, which corresponds to 26.9% of the female population above the age of 39 years. The annual prevalence proportion of current users rose from 10.4% to 14.8% during the study period, and the therapeutic intensity (DDD/1000 women/day) increased from 20.6 to 32.0. The mean DDD sum of systemic HRT per user was 73.4 in 1991; it and the proportion of users who received less than 90 DDD per year (83.4% in 1991) remained almost constant during the study period. The amount of oestrogen unopposed by progestin was high, 28.1% of all prescriptions.

Conclusions Less than one‐fifth of the study population used HRT for more than 3 months per year, and only 32.8% of the women who were new users of HRT in 1992 continued this therapy throughout the study period.
Interpretation of middle ear fluid concentrations of antibiotics: comparison between ceftibuten, cefixime and azithromycin
Authors: Scaglione  , Demartini  , Dugnani  , Arcidiacono  , Pintucci  , Fraschini
Published: March 2003

Aims The aim of this study was to determine the potential influence of variables such as the cell content in the fluid, and serum levels, on the concentrations of ceftibuten, cefixime and azithromycin in the middle ear fluid of patients suffering from acute otitis media.

Methods This randomized, open study compared the penetration of ceftibuten (9 mg kg−1, 18 patients), cefixime (8 mg kg−1, 16 patients) and azithromycin (10 mg kg−1, 16 patients) into the intracellular and extracellular compartments of middle ear fluid of 50 paediatric patients (aged 8–14 years) with acute otitis media. Middle ear fluid was extracted by tympanocentesis 4, 12 and 24 h after dosing and divided into two fractions: with cells (as collected) (C+) and cell‐free (C−). Antibiotics were assayed in C+ and C− samples by h.p.l.c.

Results Ceftibuten achieved greater penetration into middle ear fluid than cefixime and azithromycin. Higher concentrations of ceftibuten (CTB) and cefixime (CFX) were found in the C− fraction (CTB: 4 h 13.3±1.86; 12 h 4.7±1.18; 24 h 0.5±0.2. CFX: 4 h 3.2±1.4; 12 h 1.5±0.5; 24 h>0.1 mg l−1 ) than in the C+ fraction (CTB:4 h 8.4±4.3; 12 h 2.88±1.19; 24 h 0.3±0.27. CFX: 4 h 1.2±0.6; 12 h 0.8±0.2; 24 h>0.1 mg l−1 ) at the each time point, while the opposite was true for azithromycin (C−: 4 h 0.11±0.04; 12 h 0.12±0.08; 24 h 0.23±0.12. C+: 4 h 0.38±0.24; 12 h 0.9±0.03; 24 h 1.05±0.3 mg l−1 ).

Conclusions This study demonstrates that the penetration of antibiotics into the middle ear fluid is influenced by its serum concentrations as well as by the cell content in the fluid. Ceftibuten achieved higher middle ear fluid concentrations than cefixime in C+ and C− fractions at all time points. Both ceftibuten and cefixime concentrations are negatively influenced by the cell content in the fluid. In contrast the concentration of azithromycin to the middle ear fluid is positively influenced by the cell content in the fluid.
Cellular uptake of fluvastatin, an inhibitor of HMG‐CoA reductase, by rat cultured hepatocytes and human aortic endothelial cells
Authors: Ohtawa Masakatsu , Masuda Naoki , Akasaka Izumi , Nakashima Akinori , Ochiai Keiko , Moriyasu Matsuko
Published: March 2003

Aims To clarify the mechanism for cellular uptake of fluvastatin (FV) into rat primary cultured hepatocytes and human aortic endothelial cells (HAEC).

Methods Rat primary cultured hepatocytes and Endocell‐AO as normal human aortic endothelial cells were used. Effects of incubation time, concentration‐ and temperature‐dependency on cellular FV uptake were investigated after incubation with [14C]‐FV and its enantiomers, (+)‐FV and (−)‐FV. Rat primary cultured hepatocytes were washed with either Na+‐containing buffer or Na+‐free buffer and incubated with metabolic inhibitors or bile acids. Intracellular radioactivity was measured by liquid scintillation counting. The determination of intracellular unchanged FV and its enantiomers was carried out by stereospecific h.p.l.c.

Results In rat cultured hepatocytes, concentration‐ and temperature‐dependent saturable uptake of [14C]‐FV was observed (Km=37.6 μm, V max=869 pmol (mg protein)−1 min−1 ), suggesting a specific uptake mechanism. The uptake of each enantiomer also showed a specific uptake mechanism as observed for the racemate with no difference between enantiomers; (+)‐FV, Km=38.5 μm, V max=611 pmol (mg protein)−1 min−1, (−)‐FV, Km=41.5 μm, V max=646 pmol (mg protein)−1 min−1. In the presence of cholate and taurocholate, the uptake of FV was inhibited by 39–46%. Pravastatin inhibited FV uptake by 29%. In the absence of Na+, the uptake of FV was markedly inhibited 91–96% by bile acid. The uptake of FV into HAEC at 37° C and 4° C increased with the concentration of FV, but no saturable uptake was observed.

Conclusions FV transport system may be, at least in part, Na+‐ and ATP‐dependent, and may have some features in common with the bile acid transport system and the organic anion transport system. Since saturable uptake was not observed in HAEC, FV appears to be taken up into these cells mainly via nonspecific simple diffusion.
Study of cardiac repolarization in healthy volunteers performed with mizolastine, a new H1‐receptor antagonist
Authors: Chaufour  , Caplain  , Lilienthal  , L’Héritier  , Deschamps  , Dubruc  , Rosenzweig
Published: March 2003

Aims The occurence of serious dysrhythmias, such as torsades de pointes, with terfenadine and astemizole had led to a reexamination of the potential effect of H1 antihistamines on cardiac repolarization. Mizolastine is a potent, selective, nonsedating peripherally acting H1‐receptor antagonist which is registered for rhinitis and urticaria at a recommended dose of 10 mg once daily. The present study was carried out to investigate the effects of therapeutic and supratherapeutic doses of mizolastine, on ventricular repolarization in healthy volunteers.

Methods Twenty‐four healthy young volunteers participated in a double‐blind, placebo‐controlled, randomised study with three parallel groups. Each group consisted of 2 way cross‐over 7 day treatment periods where mizolastine (10, 20 or 40 mg) and placebo were randomly administered. On day 1 and day 7, 12‐lead ECG recordings were performed prior and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, and 20 h after dosing and from day 2 to day 6, before dosing and 1, 2, 3, and 4 h after.

Results Whatever the analysis used (raw data, changes from baseline, incidence of individual out‐of‐range values) no significant differences were observed at any dose level vs placebo, on any of ECG parameters (HR, PR, QRS, QT, and QTc). In particular, no effect of mizolastine vs placebo was shown on QT and QTc although 95% CIs were wide. The only subject who exhibited a QTc≥450 ms received placebo for 7 days.

Conclusions This study found no evidence of an effect of mizolastine up to 40 mg (four times the therapeutic dose) on ventricular repolarization in healthy volunteers.