bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modelling acute tolerance to the EEG effect of two benzodiazepines
Authors: Ihmsen Harald , Albrecht Sven , Hering Werner , Schüttler Jürgen , Schwilden Helmut 
Published: December 2004

Aims  We studied the development of acute tolerance to the EEG effect of midazolam and the new benzodiazepine Ro 48‐6791.Methods  Nine young (24–28 years) and nine elderly (67–81 years) male volunteers received midazolam and Ro 48‐6791 computer‐controlled, targeting linearly increasing plasma concentrations for 30 min (targeted slopes: 40 and 20 ng ml−1 min−1 for midazolam, 3 and 1.5 ng ml−1 min−1 for Ro 48‐6791, for young and elderly, respectively) and a constant concentration for the following 15 min. After recovery, the same infusion scheme was repeated. Plasma concentrations of midazolam, Ro 48‐6791 and its metabolite Ro 48‐6792 were determined from arterial blood samples. The hypnotic effect was assessed using the median frequency of the EEG power spectrum.Results  The concentration–effect relationship in each infusion cycle could be described by a sigmoid Emax model. The half‐maximum concentration EC50 was higher in the second infusion cycle compared with the first one (midazolam, 47% (2.3–91.6%) and 37% (5.3–69.5%); Ro 48‐6791, 22% (−2.8% to 44.6%) and 43% (3.4–82.4%) for young and elderly; mean and 95% confidence interval). The complete time course of the EEG median frequency could be described by an interaction between the parent drug in an effect compartment and a hypothetical competitive drug in an additional tolerance compartment. For Ro 48‐6791, the use of its metabolite Ro 48‐6792 as competitive compound also gave appropriate results.Conclusion  Midzolam and Ro 48‐6791 showed acute tolerance to the EEG effect which might be caused by competitive interaction with the metabolite.
Application of data mining techniques in pharmacovigilance
Authors: Wilson Andrew M. , Thabane Lehana , Holbrook Anne 
Published: December 2004

Aims  To discuss the potential use of data mining and knowledge discovery in databases for detection of adverse drug events (ADE) in pharmacovigilance.Methods  A literature search was conducted to identify articles, which contained details of data mining, signal generation or knowledge discovery in relation to adverse drug reactions or pharmacovigilance in medical databases.Results  ADEs are common and result in significant mortality, and despite existing systems drugs have been withdrawn due to ADEs many years after licensing. Knowledge discovery in databases (KDD) is a technique which may be used to detect potential ADEs more efficiently. KDD involves the selection of data variables and databases, data preprocessing, data mining and data interpretation and utilization. Data mining encompasses a number of statistical techniques including cluster analysis, link analysis, deviation detection and disproportionality assessment which can be utilized to determine the presence of and to assess the strength of ADE signals. Currently the only data mining methods to be used in pharmacovigilance are those of disproportionality, such as the Proportional Reporting Ratio and Information Component, which have been used to analyse the UK Yellow Card Scheme spontaneous reporting database and the WHO Uppsala Monitoring Centre database. The association of pericarditis with practolol but not with other β‐blockers, the association of captopril and other angiotensin‐converting enzymes with cough, and the association of terfenadine with heart rate and rhythm disorders could be identified by mining the WHO database.Conclusion  In view of the importance of ADEs and the development of massive data storage systems and powerful computer systems, the use of data mining techniques in knowledge discovery in medical databases is likely to be of increasing importance in the process of pharmacovigilance as they are likely to be able to detect signals earlier than using current methods.
The influence of diet upon liver function tests and serum lipids in healthy male volunteers resident in a Phase I unit
Authors: Purkins L. , Love E. R. , Eve M. D. , Wooldridge C. L. , Cowan C. , Smart T. S. , Johnson P. J. , Rapeport W. G. 
Published: December 2004

Aim  To investigate the effect of diet upon liver function tests and serum lipids within the restricted environment of a Phase I unit.Methods  An open randomized three‐way crossover study was designed with subjects consuming three types of diet. The diets comprised, a balanced normal calorie diet, a high‐carbohydrate high‐calorie diet and a high‐fat high‐calorie diet. Each diet was consumed in a randomized sequence over 8 days with a recovery period of 14 days between periods. The blood concentrations of various laboratory parameters were measured at intervals throughout each dietary period and during the recovery periods.Results  Blood transaminase activity and triglyceride concentrations increased significantly whilst subjects consumed a high‐carbohydrate high‐calorie diet but not when fed either a high‐fat high‐calorie diet or a balanced normal calorie diet.Conclusions  The rises in transaminases and triglycerides were caused by the carbohydrate content of the diet rather than its calorific value. Sucrose rather than starch was the carbohydrate which caused the rise in transaminases and triglycerides. The importance of controlling diet in Phase I studies is stressed.
Large interindividual variability in the in vitro formation of tamoxifen metabolites related to the development of genotoxicity
Authors: Coller Janet K. , Krebsfaenger Niels , Klein Kathrin , Wolbold Renzo , Nüssler Andreas , Neuhaus Peter , Zanger Ulrich M. , Eichelbaum Michel , Mürdter Thomas E. 
Published: December 2004

Aims  To characterize the interindividual variability and the individual CYP involved in the formation of α‐hydroxy‐, N‐desmethyl‐ and N‐didesmethyl‐tamoxifen from tamoxifen.Methods  Microsomes from 50 human livers were used to characterize the interindividual variability in the α‐hydroxylation, N‐desmethylation and N‐didesmethylation of tamoxifen. Selective inhibitors and recombinant enzymes were used to identify the forms of CYP catalysing these reactions.Results  The rates of formation of α‐hydroxy‐, N‐desmethyl‐ and N‐didesmethyl‐tamoxifen were highly variable, and correlated with each other (P < 0.0001). The respective ranges were 0.7–11.4, 25.7–411, and below the limit of quantification – 4.4 pmol mg−1 protein min−1. Formation of all metabolites was observed with expressed recombinant CYP3A4, inhibited by troleandomycin (65, 77 and 35%, respectively, P < 0.05) and associated with CYP3A4 expression (rs = 0.612, rs = 0.585 and rs = 0.430, P < 0.01, respectively).Conclusions  Formation of α‐hydroxy‐, N‐desmethyl‐ and N‐didesmethyl‐tamoxifen in vitro is highly variable and mediated predominantly by CYP3A4.
Effect of rifampicin on pravastatin pharmacokinetics in healthy subjects
Authors: Kyrklund Carl , Backman Janne T. , Neuvonen Mikko , Neuvonen Pertti J. 
Published: December 2004

Aims  Previous work has shown that rifampicin, a potent inducer of several cytochrome P450 (CYP) enzymes and transporters, decreased the plasma concentrations of simvastatin acid by more than 90%. This study was conducted to investigate the effect of rifampicin on the pharmacokinetics of pravastatin.Methods  In a randomised, cross‐over two‐phase study with a washout of 4 weeks, 10 healthy volunteers received a 5‐day pretreatment with rifampicin (600 mg daily) or placebo. On day 6, a single 40 mg dose of pravastatin was administered orally. Plasma concentrations of pravastatin were measured up to 12 h by a sensitive LC‐MS‐MS method.Results  During the rifampicin phase, the mean total area under the plasma concentration‐time curve of pravastatin [AUC(0–∞)] was 69% (range 24–220%) of the corresponding value during the placebo phase (P < 0.05, 95% confidence interval for the difference −51.9 – −0.4 ng ml−1·h). In five of the 10 subjects the AUC(0–∞) of pravastatin during the rifampicin phase was 50% or less of that during the placebo phase. Rifampicin had no significant effect on the peak concentration, elimination half‐life or renal clearance of pravastatin.Conclusions  Rifampicin caused a statistically significant decrease in the plasma concentration of pravastatin given as a single oral dose to healthy subjects. However, the effect of rifampicin varied greatly between subjects. The mean rifampicin‐induced decrease in pravastatin concentration was considerably smaller than that observed previously for simvastatin.
Pharmacokinetic and pharmacodynamic assessment of a five‐probe metabolic cocktail for CYPs 1A2, 3A4, 2C9, 2D6 and 2E1
Authors: Blakey G. E. , Lockton J. A. , Perrett J. , Norwood P. , Russell M. , Aherne Z. , Plume J. 
Published: December 2004

Aims  The primary objectives of the present study were to establish whether there was a pharmacokinetic or pharmacodynamic interaction between the probe drugs caffeine (CYP1A2), tolbutamide (CYP2C9), debrisoquine (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4), when administered in combination as a cocktail. Furthermore, the tolerability of these probe drugs, both alone and in combination as a cocktail was assessed.Methods  Twelve healthy volunteer subjects (age range 22–48 years) were entered into an open, fixed sequence, 6‐limb, single centre study. The randomization was such that all drugs were given individually followed by the full ‘cocktail’ as the last treatment limb. The phenotypic index used to assess the intrinsic activity of the CYP isoforms included metabolite/parent ratios in plasma and urine (CYPs 1A2, 2E1 & 2C9), parent/metabolite ratios in urine (CYP2D6) and plasma AUClast (CYP3A4). Blood pressure and blood glucose measurements were used to assess pharmacodynamic interactions. Tolerability was assessed through reporting of adverse eventsResults  Overall, there was little evidence that the probe drugs interacted metabolically when co‐administered as the cocktail. The ratio of the geometric mean (and 90% confidence interval) of the phenotypic index, obtained after administration of the probe as part of the cocktail and when given alone were: caffeine, 0.86 (0.67–1.10), midazolam, 0.96 (0.74–1.24), tolbutamide, 0.86 (0.72–1.03), debrisoquine 1.04 (0.97–1.12) and chlorzoxazone, 0.95 (0.86–1.05). There was no difference in blood pressure and blood glucose concentrations following the cocktail and dosing of the individual probes. There was no effect on ECG recordings at any time‐point. The adverse events reported for individual drug administrations were mild, transient and expected. Overall no more adverse events were reported on the cocktail study days than on the days when the drugs were administered alone.Conclusions  The five probe drugs when coadministered, in this dosing regimen, demonstrated no evidence of either a metabolic or pharmacodynamic interaction that might confound the conclusions drawn during a cocktail study. The present cocktail methodology has the potential to become a useful tool to aid the detection of clinically important drug–drug interactions during drug development.
Acute systemic effects of inhaled salbutamol in asthmatic subjects expressing common homozygous β2‐adrenoceptor haplotypes at positions 16 and 27
Authors: Lee Daniel K. C. , Bates Caroline E. , Lipworth Brian J. 
Published: December 2004

Aims   The relationship between β2‐adrenoceptor polymorphisms at positions 16 and 27, and the acute systemic β2‐adrenoceptor effects of inhaled salbutamol is unclear. We therefore elected to evaluate the influence of common homozygous β2‐adrenoceptor haplotypes on the acute systemic β2‐adrenoceptor effects following inhaled salbutamol in asthmatic subjects.Methods   An initial database search of 531 asthmatic subjects identified the two commonest homozygous haplotypes at positions 16 and 27 to be Arg16‐Gln27 (12%) and Gly16‐Glu27 (19%). After a 1‐week washout period where all β2‐adrenoceptor agonists were withdrawn, 16 Caucasian subjects (Arg16‐Gln27: n = 8 and Gly16‐Glu27: n = 8) were given a single dose of inhaled salbutamol (1200 µg), followed by serial blood sampling for serum potassium, along with measurements of diastolic blood pressure and heart rate, at 5‐min intervals for 20 min.Results   The two groups were well matched for age, sex, FEV1, and inhaled corticosteroid dose. Baseline values for serum potassium, diastolic blood pressure and heart rate were not significantly different comparing Arg16‐Gln27 vs Gly16‐Glu27. The mean ± SEM maximum serum potassium change from baseline over 20 min was significantly greater (P = 0.04) for Arg16‐Gln27: −0.37 ± 0.05 mmol l−1vs Gly16‐Glu27: −0.23 ± 0.04 mmol l−1; 95% CI for difference: −0.01 to −0.28 mmol l−1. The maximum diastolic blood pressure change from baseline over 20 min was significantly greater (P = 0.0008) for Arg16‐Gln27: −13 ± 1 mmHg vs Gly16‐Glu27: −4 ± 2 mmHg; 95% CI for difference: −5, 14 mmHg. There was no significant difference comparing the maximum heart rate change from baseline for Arg16‐Gln27: 10 ± 3 beats min−1vs Gly16‐Glu27: 10 ± 3 beats min−1.Conclusions   Caucasian asthmatic subjects with the Arg16‐Gln27 haplotype exhibited a greater systemic response to inhaled salbutamol, compared with those with the Gly16‐Glu27 haplotype. The attenuated β2‐adrenoceptor response in the Gly16‐Glu27 haplotype would be in keeping with increased susceptibility to prior down‐regulation by endogenous catecholamines.
Cardiovascular prophylaxis with aspirin: costs of supply and management of upper gastrointestinal and renal toxicity
Authors: Morant S. V. , McMahon A. D. , Cleland J. G. F. , Davey P. G. , MacDonald T. M. 
Published: December 2004

Aims  To determine the cost to the NHS of prescribed low‐dose aspirin.Methods  This was a population based observational cohort study. Patients from Tayside Scotland (17 244 new users of dispensed aspirin each with 10 matched comparators) were included. A pragmatic analysis totalled costs from the start to end of the study and compared these with a matched cohort of aspirin nonusers to estimate excess costs. Fastidious analyses were done of subjects with no prior history of upper gastrointestinal (UGI) or renal disease where the cost that occurred during aspirin exposure, the 30 days following aspirin exposure and subsequent nonexposure was calculated adjusting for risk factors in each period.Results  Subjects took aspirin for only 1.18 of the 2.53 years follow‐up (47% compliance). Aspirin use cost an additional £49.86 per year (pragmatic analysis) made up of £1.96 for aspirin tablets (4%), £5.49 for dispensing costs (11%), £24.60 for UGI complications (49%) and £17.81 for renal complications (36%). The costs for managing complications were substantially lower in the fastidious analysis (£2.66 for UGI complications and £2.92 for renal complications). Assuming that the antiplatelet trial meta‐analysis is an accurate assessment of the benefits of aspirin, the costs of preventing one vascular event lay between £62 500 (primary prevention, pragmatic analysis) and £867 (secondary prevention, fastidious analysis). These costs may be underestimates due to the low compliance observed.Conclusions  Compliance with aspirin was poor. Serious adverse events were uncommon but despite this aspirin cost the NHS between 6 and 25 times the cost of aspirin tablets due to dispensing costs and the cost of managing adverse effects.
Population pharmacokinetics of artemether and dihydroartemisinin following single intramuscular dosing of artemether in African children with severe falciparum malaria
Authors: Mithwani Sadik , Aarons Leon , Kokwaro Gilbert O. , Majid Oneeb , Muchohi Simon , Edwards Geoffrey , Mohamed Sumia , Marsh Kevin , Watkins William 
Published: December 2004

Aims  To determine the population pharmacokinetics of artemether and dihydroartemisinin in African children with severe malaria and acidosis associated with respiratory distress following an intramuscular injection of artemether.Methods  Following a single intramuscular (i.m.) injection of 3.2 mg kg−1 artemether, blood samples were withdrawn at various times over 24 h after the dose. Plasma was assayed for artemether and dihydroartemisinin by gas chromatography‐mass spectrometry. The software program NONMEM was used to fit the concentration–time data and investigate the influence of a range of clinical characteristics (respiratory distress and metabolic acidosis, demographic features and disease) on the pharmacokinetics of artemether and dihydroartemisinin.Results  A total of 100 children with a median age of 36.4 (range 5–108) months were recruited into the study and data from 90 of these children (30 with respiratory distress and 60 with no respiratory distress) were used in the population pharmacokinetic analysis. The best model to describe the disposition of artemether was a one‐compartment model with first‐order absorption and elimination. The population estimate of clearance (clearance/bioavailability, CL/F) was 14.3 l h−1 with 53% intersubject variability and that of the terminal half‐life was 18.5 h. If it was assumed that artemisin displays ‘flip‐flop’ kinetics, the elimination half‐life was estimated to be 21 min and the corresponding volume of distribution was 8.44 l, with an intersubject variability of 104%. None of the covariates could be identified as having any influence on the disposition of artemether. The disposition of dihydroartemisinin was fitted separately using a one‐compartment linear model in which the volume of distribution was fixed to the same value as that of artemether. Assuming that artemether is completely converted to dihydroartemisinin, the estimated value of CL/F for dihydroartemisinin was 93.5 l h−1, with an intersubject variability of 90.2%. The clearance of dihydroartemisinin was formation rate limited.Conclusions  Administration of a single 3.2 mg kg−1 i.m. dose of artemether to African children with severe malaria and acidosis is characterized by variable absorption kinetics, probably related to drug formulation characteristics rather than to pathophysiological factors. Use of i.m. artemether in such children needs to be reconsidered.
CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes
Authors: Hutchinson Mark R. , Menelaou Andrew , Foster David J. R. , Coller Janet K. , Somogyi Andrew A. 
Published: December 2004

Aim To determine the Michaelis‐Menten kinetics of hydrocodone metabolism to its O‐ and N‐demethylated products, hydromorphone and norhydrocodone, to determine the individual cytochrome P450 enzymes involved, and to predict thein vivohepatic intrinsic clearance of hydrocodone via these pathways.Methods Liver microsomes from sixCYP2D6extensive metabolizers (EM) and oneCYP2D6poor metabolizer (PM) were used to determine the kinetics of hydromorphone and norhydrocodone formation. Chemical and antibody inhibitors were used to identify the cytochrome P450 isoforms catalyzing these pathways. Expressed recombinant cytochrome P450 enzymes were used to characterize further the metabolism of hydrocodone.Results Hydromorphone formation in liver microsomes fromCYP2D6EMs was dependent on a high affinity enzyme (Km = 26 µm) contributing 95%, and to a lesser degree a low affinity enzyme (Km = 3.4 mm). In contrast, only a low affinity enzyme (Km = 8.5 mm) formed this metabolite in the liver from theCYP2D6PM, with significantly decreased hydromorphone formation compared with the livers from the EMs. Norhydrocodone was formed by a single low affinity enzyme (Km = 5.1 mm) in livers from bothCYP2D6EM and PM. Recombinant CYP2D6 and CYP3A4 formed only hydromorphone and only norhydrocodone, respectively. Hydromorphone formation was inhibited by quinidine (a selective inhibitor of CYP2D6 activity), and monoclonal antibodies specific to CYP2D6. Troleandomycin, ketoconazole (both CYP3A4 inhibitors) and monoclonal antibodies specific for CYP3A4 inhibited norhydrocodone formation. Extrapolation ofin vitrotoin vivodata resulted in a predicted total hepatic clearance of 227 ml h−1 kg−1and 124 ml h−1 kg−1forCYP2D6EM and PM, respectively.Conclusions The O‐demethylation of hydrocodone is predominantly catalyzed by CYP2D6 and to a lesser extent by an unknown low affinity cytochrome P450 enzyme. Norhydrocodone formation was attributed to CYP3A4. Comparison of recalculated published clearance data for hydrocodone, with those predicted in the present work, indicate that about 40% of the clearance of hydrocodone is via non‐CYP pathways. Our data also suggest that the genetic polymorphisms ofCYP2D6may influence hydrocodone metabolism and its therapeutic efficacy.
Factors affecting variability in distribution of tacrolimus in liver transplant recipients
Authors: Zahir H. , McCaughan G. , Gleeson M. , Nand R. A. , McLachlan A. J. 
Published: December 2004

Aims  Therapeutic drug monitoring (TDM) of tacrolimus is complicated by conflicting data on the correlation between tacrolimus trough blood concentrations and the incidence of rejection. The aim of this cross‐sectional study was to investigate the blood distribution and protein binding of tacrolimus in liver transplant recipients to explore better predictors of clinical outcome.Methods  Blood and plasma distribution of 3H‐dihydro‐tacrolimus was investigated in 40 liver transplant recipients using Ficoll Paque and density gradient ultracentrifugation, respectively, and equilibrium dialysis to investigate plasma protein binding.Results  In blood tacrolimus was mainly associated with the erythrocyte fraction (83.2%, range 74.6–94.9%), followed by diluted plasma (16.1%, range 4.5–24.9%), and lymphocyte fraction (0.61%, range: 0.11–1.53%). In plasma, lipoprotein deficient serum fraction (54.2%, range 38.5–68.2%) was the main reservoir of tacrolimus. The unbound fraction of tacrolimus was found to be 0.47 ± 0.18% (range 0.07–0.89%). The percentage of tacrolimus associated with the lymphocytes (0.8 ± 0.4 vs 0.3 ± 0.1%, P = 0.012) and estimated unbound concentration (0.42 ± 0.21 ng l−1vs 0.24 ± 0.08 ng l−1, P < 0.001) of tacrolimus were significantly different in stable transplant recipients and those experiencing rejection. Haematocrit and red blood cell count significantly influenced the percentage of tacrolimus associated with erythrocytes. The fraction unbound of tacrolimus was correlated with α1‐acid glycoprotein and high density lipoprotein cholesterol concentrations.Conclusions  Tacrolimus unbound concentration was observed to be lower in liver transplant recipients experiencing rejection and further study is required to evaluate its utility in the TDM of tacrolimus.