bluuebunny/crossref_metadata_2025_split huggingface dataset:
Azathioprine without oral ciclosporin in the long‐term maintenance of remission induced by intravenous ciclosporin in severe, steroid‐refractory ulcerative colitis
Authors: Domènech E. , Garcia‐Planella E. , Bernal I. , Rosinach M. , Cabré E. , Fluvià L. , Boix J. , Gassull M. A. 
Published: March 2003

SummaryBackground : Intravenous ciclosporin is considered to be the only alternative to avoid surgery in severe, steroid‐refractory ulcerative colitis. In responders, some authors recommend a switch to oral ciclosporin to act as a ‘bridge’ until the therapeutic action of azathioprine is achieved for maintenance treatment.Aim : To report the short‐ and long‐term outcome of intravenous ciclosporin‐responsive ulcerative colitis patients treated with oral azathioprine without oral ciclosporin.Methods : The records of all patients treated with intravenous ciclosporin for severe, steroid‐refractory ulcerative colitis were reviewed. Responders following treatment with azathioprine but without oral ciclosporin as maintenance therapy were included. Patients with colonic cytomegalovirus infection and/or follow‐up of less than 1 year were excluded.Results : Twenty‐seven patients were included. Steroids were discontinued in 24 (89%). The median follow‐up was 36 months. Eighteen (75%) patients presented mild or moderate relapses, which were easily managed with salicylates or steroids. Cumulative probabilities of relapse were 42%, 72% and 77% at 1, 3 and 5 years, respectively. Eleven (40.7%) patients underwent elective colectomy. Cumulative probabilities of colectomy were 29%, 35% and 42% at 1, 3 and 5 years, respectively. No opportunistic infections were observed.Conclusions : Oral azathioprine seems to be enough to maintain long‐term remission induced by intravenous ciclosporin in patients with steroid‐refractory ulcerative colitis. The ‘bridging step’ with oral ciclosporin may not be necessary in this subset of patients, although a randomized controlled trial is warranted to confirm this hypothesis.
NSAIDs, gastroprotection and cyclo‐oxygenase‐II‐selective inhibitors*
Authors: Micklewright R. , Lane S. , Linley W. , McQuade C. , Thompson F. , Maskrey N. 
Published: March 2003

SummaryIn patients at high risk of NSAID‐associated serious upper gastrointestinal complications, gastroprotection with misoprostol or a proton pump inhibitor should be considered. Only misoprostol, 800 µg/day, has been shown to reduce serious upper gastrointestinal complications in a large clinical outcome trial. The benefit of Helicobacter pylori eradication in reducing NSAID‐associated gastrointestinal toxicity is controversial, and routine testing for and eradication of H. pylori in NSAID users are not currently advised.The gastrointestinal safety of rofecoxib and celecoxib has been assessed in large clinical outcome trials which, on first analysis, show benefits over non‐selective NSAIDs in the incidence of serious upper gastrointestinal complications. However, longer term gastrointestinal data from the celecoxib study (CLASS) and cardiovascular adverse event data from the rofecoxib study (VIGOR) have questioned the risk–benefit profile of these new drugs and, until they are better understood, it seems sensible not to use them routinely in large numbers of individuals. The gastrointestinal safety of meloxicam and etodolac has not been adequately assessed in such trials. Therefore, evidence for their use instead of non‐selective NSAIDs, or instead of celecoxib or rofecoxib, is not robust.
Convulsions following axillary brachial plexus blockade with levobupivacaine
Authors: Pirotta D. , Sprigge J. 
Published: March 2003

SummaryNeurotoxicity 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

SummaryA 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

SummaryThe 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.
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.
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.
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.
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.
Comparison of the vasoconstrictor effects of the selective 5‐HT1D‐receptor agonist L‐775,606 with the mixed 5‐HT1B/1D‐receptor agonist sumatriptan and 5‐HT in human isolated coronary artery
Authors: Longmore J. , Maguire J. J. , MacLeod A. , Street L. , Schofield W. N. , Hill R. G. 
Published: March 2003

Aims Vasoconstriction in human coronary artery can be mediated via activation of both 5‐HT2 and 5‐HT1B‐receptors. Coronary vasoconstriction is a rare, but potential adverse effect of the antimigraine drug sumatriptan. In order to investigate the receptor population involved we compared the vasoconstrictor effects of sumatriptan (a mixed 5‐HT1B/1D‐receptor agonist) with those of L‐775,606 (a selective 5‐HT1D‐receptor agonist) and 5‐HT (the endogenous ligand) in human isolated coronary arteries. Methods Coronary arteries were obtained from human hearts removed prior to transplant surgery. Several endothelium denuded ring segments (4 mm in length) were obtained from each artery and mounted for isometric tension recording. Each segment was first exposed to 45 mm KCl and then to 5‐HT (1 nm‐100 μm ). Concentration‐effect curves to L‐775,606 (1‐(3‐(5‐(1,2,4‐triazol‐4‐yl)‐1H‐indol‐3‐yl)propyl)‐4‐(2‐(3‐fluorophenyl)ethyl)piperazine) and sumatriptan were then performed in a consecutive and random manner. The response to repeated application of 5‐HT was obtained in separate segments. Results Twenty‐five segments from seven different coronary arteries were studied. Concentration‐effect curves were fitted to the data using nonlinear regression analysis. The maximum contraction for L‐775,606 was significantly less than that for sumatriptan with Emax values (% relative to 45 mm KCl=100%) of 30.1±4.22 and 41.5±2.7, respectively. L‐775,606 was significantly (30‐fold) less potent than sumatriptan in causing contraction compared with sumatriptan (EC50 values were 6.0 μm and 0.2 μm, respectively). For comparison the Emax value for 5‐HT was 77.2% and the EC50 value was 0.2 μm. Conclusions The selective 5‐HT1D‐receptor agonist L‐775,606 has less propensity towards vasoconstriction in human isolated coronary artery (endothelium‐denuded) than was mixed 5‐HT1B/1D‐receptor agonist sumatriptan. The contractions produced were at concentrations where L‐775,606 would be expected to occupy 5‐HT1B‐receptors.
Effects of the 5‐HT3 antagonist cilansetron vs placebo on phasic sigmoid colonic motility in healthy man: a double‐blind crossover trial
Authors: Stacher Georg , Weber Ute , Stacher‐janotta Giselheid , Bauer Peter , Huber Kurt , Holzäpfel Antje , Krause Günter , Steinborn Claus 
Published: March 2003

Aims  5‐hydroxytryptamine3 receptor antagonists act antiemetically and slow colonic transit. This study evaluated effects of the high‐affinity 5‐HT3 antagonist, cilansetron, on fasting, meal‐and anticholinesterase‐stimulated phasic contractile activity of the human sigmoid colon as well as on bowel habits and stool consistency.Methods  Five female and seven male healthy volunteers received, during three 7 day periods separated by 7 day wash‐out periods, 4 mg cilansetron, 8 mg cilansetron or placebo three times daily orally under random, double‐blind, crossover conditions. On day 8 of each treatment period, motility 20–40 cm from the anal verge was recorded using five pressure sensors spaced at 5 cm intervals. After a basal 30 min, subjects swallowed a further dose of the scheduled treatment; 60 min later, blood was taken for the determination of plasma cilansetron levels. Thereafter, subjects ingested a 4200 kJ meal and 250 ml sweetened mallow tea (166 kJ); 90 min after meal onset, 1 mg neostigmine was administered intramuscularly and motility recording was continued for 60 minResults  Phasic contractile activity and intraluminal base‐line pressure increased postprandially and more so after neostigmine. With cilansetron, the area under the pressure curve as the primary outcome variable and the number of contractions were significantly greater than with placebo (P = 0.005), amplitude and duration of contractions and base‐line pressure were not affected. The effects of the two cilansetron dosages did not differ. With cilansetron, stool tended to become firmer. No adverse effects were observed. Plasma levels were highest with 8 mg cilansetron.Conclusions  Cilansetron slightly augments meal‐stimulated and markedly neostigmine‐stimulated phasic motility of the sigmoid colon. When administered over 7 days, it tends to increase stool consistency and is well tolerated.