bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics of morphine are not altered in subjects with Gilbert's syndrome
Authors: Skarke Carsten , Schmidt Helmut , Geisslinger Gerd , Darimont Jutta , Lötsch Jörn
Published: December 2004

Aims  To verify that Gilbert's syndrome, which is caused by decreased glucuronidation capacity of the UDP‐glucuronosyl transferase (UGT)1A1, does not account for impaired morphine clearance.

Methods  Noncompartmental pharmacokinetic parameters for morphine and its glucuronide metabolites were compared between five carriers of Gilbert's syndrome and six noncarriers after a 7.5 mg (19.8 µmol) intravenous injection of morphine sulphate pentahydrate. To estimate the amount of morphine‐6‐glucuronide (M6G) formed from morphine, 1 mg of deuterized M6G was injected intravenously at the same time.

Results  No differences were detected between carriers and noncarriers of Gilbert's syndrome in the clearance of morphine (80.1 ± 12 l h−1vs 87.9 ± 22 l h−1) and in the percentage of morphine that was metabolized to M6G (10.9 ± 1.4 vs 13 ± 2). The areas under the plasma concentration vs time curves of morphine, M6G and morphine‐3‐glucuronide also did not differ between carriers and noncarriers of Gilbert's syndrome.

Conclusions  Gilbert's syndrome is not a factor to be considered when prescribing morphine.
The effect of ethinyloestradiol and levonorgestrel on the CYP2C19‐mediated metabolism of omeprazole in healthy female subjects
Authors: Palovaara Sanna , Tybring Gunnel , Laine Kari
Published: December 2004

Aims  To study the effect of an oral contraceptive (OC) formulation containing ethinyloestradiol and levonorgestrel (LNG) (combination OC) or LNG alone on the CYP2C19‐mediated hydroxylation of omeprazole in healthy females.

Methods  This was an open crossover study with three phases. In phase one, 10 healthy females received a single 40‐mg dose of omeprazole. Thereafter the subjects received in a random order either 40 µg ethinyloestradiol and 75 µg LNG or 60 µg LNG alone once daily for 10 days. On day 10, 1 h after the last OC dose, subjects received a single 40‐mg oral dose of omeprazole. The plasma concentrations of omeprazole, 5′‐hydroxyomeprazole and omeprazole sulphone were determined for up to 8 h.

Results  The use of combination OC increased the area under the curve (AUC) of omeprazole by 38% [95% confidence interval (CI) − 3.8, 80; P = 0.040] and caused a 48% increase (95% CI 28, 68) in the AUC ratio of omeprazole/5‐hydroxyomeprazole. LNG alone did not effect the 5′‐hydroxylation of omeprazole. Neither of the OC preparations seemed to have an inhibitory effect on the formation of omeprazole sulphone by CYP3A4.

Conclusions  Oral contraceptives containing ethinyloestradiol but not those containing only LNG decrease CYP2C19 activity.
Tacrolimus and cerivastatin pharmacokinetics and adverse effects after single and multiple dosing with cerivastatin in renal transplant recipients
Authors: Renders Lutz , Haas Christian S. , Liebelt Jan , Oberbarnscheidt Martin , Schöcklmann Harald O. , Kunzendorf Ulrich
Published: December 2004

Aims  In contrast to cyclosporin, only limited information exists on the interaction potential between the immunosuppressive agent tacrolimus and HMG‐CoA reductase inhibitors, which are metabolized via the cytochrome P450 system. The aim of this study was to investigate the pharmacokinetics, and adverse effects of cerivastatin combined with tacrolimus in renal transplant patients.

Methods  Ten patients with stable kidney graft functions and LDL‐cholesterol serum concentrations > 110 mg dl−1 were included in the study. After an observation period of 3 months, cerivastatin (0.2 mg daily) was administered for an additional 3 months. Tacrolimus steady‐state pharmacokinetics and cerivastatin single‐ and multiple‐dose pharmacokinetics were determined. Lipid concentrations, routine laboratory parameters and adverse events were obtained and analysed throughout the study period of 6 months.

Results  Blood tacrolimus trough concentrations were not affected by cerivastatin (mean ± SD 8.6 ± 2.1 ng ml−1 before, and 8.7 ± 2.4 ng ml−1 at day 90 of cerivastatin dosing, with a 95% confidence interval on the difference = 0.97, 1.08). The mean area under the blood concentration–time curve to 24 h (AUC(0,24 h)) for cerivastatin was 14.5 ± 2.53 µg l−1 h−1 at day 1 after starting treatment and 19.02 ± 3.55 µg l−1 h−1 (3 months later), resulting in a 35% higher (AUC(0,24 h)) compared with the first dose. Total cholesterol, LDL‐cholesterol and triglyceride concentrations were significantly lowered by cerivastatin whereas no significant effect of cerivastatin on serum creatininkinase concentrations was observed and no adverse effects were documented.

Conclusions  Tacrolimus increased the AUC(0, 24 h) of cerivastatin by a mean of 35% in renal transplant patients. Cerivastatin had no detectable effect on the pharmacokinetics of tacrolimus.
Population pharmacokinetics of platinum after nedaplatin administration and model validation in adult patients
Authors: Ishibashi Toru , Yano Yoshitaka , Oguma Takayoshi
Published: December 2004

Aims  The pharmacokinetics of unbound platinum after administration of an anticancer drug nedaplatin, cis‐diammineglycolateplatinum were examined using population analysis. The relevant covariates and the extent of inter‐ and intra‐individual variability were evaluated.

Methods  In order to clarify the pharmacokinetic profile of nedaplatin, unbound platinum concentrations (789 points) in plasma after intravenous infusion of nedaplatin were obtained from 183 courses for 141 patients. Plasma concentration data were analysed by nonlinear mixed effect modelling using NONMEM to evaluate the population mean parameters and variances for inter‐ and intra‐individual random effects. The final population model was validated by parameter sensitivity analysis using objective function mapping, the bootstrap resampling and a data‐splitting technique, i.e. the Jackknife method, and the predictive performance of the final model was evaluated.

Results  A two‐compartment pharmacokinetic model with zero‐order input and first order elimination described the current data well. The significant covariates were creatinine clearance (CLcr) for clearance of platinum (CL) {population mean [95% confidence interval (CI)] CL (l h−1) = 4.47 (3.27, 5.67) + 0.0738 (0.0581, 0.0896) × CLcr (CLcr: ml min−1)} and body weight (BW: kg) for volume of distribution of platinum (Vc) [Vc (l) = 12.0 (7.5, 16.5) + 0.163 (0.081, 0.246) × BW]. Inter‐individual variations (CV%, 95% CI) for CL and Vc were 25.5% (20.7, 29.6) and 21.4% (17.0, 24.1), respectively, and intra‐individual variation (CV%, 95% CI) was 12.6% (10.5, 14.4). The effects of pretreatment with nedaplatin or other platinum agents on clearance and volume of distribution were also tested, but no significant effect was found. The relationship between the observed and predicted unbound platinum concentration by empirical Bayesian prediction showed good correlation with no bias, suggesting that the final model explains well the observed data in the patients. The mean prediction error and root mean square prediction error (95% CI) were − 0.0164 µg ml−1 (− 0.4379, 0.4051) and 0.2155 µg ml−1 (not calculable, 0.6523), respectively. The values of mean, standard error and 95% CI for objective function mapping, the bootstrap resampling, the Jackknife estimates and the final model coincided well.

Conclusions  A population pharmacokinetic model was developed for unbound platinum after intravenous infusion of nedaplatin. Only creatinine clearance was found to be a significant covariate of clearance, and BW was found to be a significant covariate of volume of distribution. These population pharmacokinetic estimates are useful for setting initial dosing of nedaplatin using its population mean and can also be used for setting appropriate dosage regimens using empirical Bayesian forecasting.
Adverse drug reactions in elderly patients
Authors: Routledge P. A. , O'Mahony M. S. , Woodhouse K. W.
Published: December 2004

Many studies from around the world show a correlation between increasing age and adverse drug reaction (ADR) rate, at least for some medical conditions. More than 80% of ADRs causing admission or occurring in hospital are type A (dose‐related) in nature, and thus predictable from the known pharmacology of the drug and therefore potentially avoidable. Frail elderly patients appear to be particularly at risk of ADRs and this group is also likely to be receiving several medicines. The toxicity of some drug combinations may sometimes be synergistic and be greater than the sum of the risks of toxicity of either agent used alone. In order to recognize and to prevent ADRs (including drug interactions), good communication is crucial, and prescribers should develop an effective therapeutic partnership with the patient and with fellow health professionals. Undergraduate and postgraduate education in evidence‐based therapeutics is also vitally important. The use of computer‐based decision support systems (CDSS) and electronic prescribing should be encouraged, and when problems do occur, health professionals need to be aware of their professional responsibility to report suspected adverse drug events (ADEs) and ADRs. ‘Rational’ or ‘obligatory’ polypharmacy is becoming a legitimate practice as increasing numbers of individuals live longer and the range of available therapeutic options for many medical conditions increases. The clear risk of ADRs in this situation should be considered in the context that dose‐related failure of existing therapy to manage the condition adequately may be one of the most important reasons for admission of the elderly to hospital. Thus, age itself should not be used as a reason for withholding adequate doses of effective therapies.
Stroke, dementia, and drug delivery
Authors: Ford G. A. , Bryant C. A. , Mangoni A. A. , Jackson S. H. D.
Published: December 2004

Stroke and dementia represent a major health burden for elderly subjects as they are associated with significant morbidity and mortality. The rates of stroke and dementia are progressively increasing due to the ageing population in most westernized countries. Therefore, both these conditions represent a major therapeutic target. However, the therapeutic options available for the management of stroke and dementia remain largely unsatisfactory, the main reason being the difficulty in transferring the results obtained in animal and in vitro studies to the clinical setting. This review focuses on the recent advances in pathophysiology and treatment of these conditions and future directions for research. Moreover, the technique of functional magnetic resonance imaging is discussed in detail as a tool to assess the effects of therapeutic agents on the central nervous system and monitor the progression of diseases. Finally, an overview of the issue of drug delivery into the central nervous system is presented.
Clinical Pharmacology
Authors: Shenfield Gillian
Published: December 2004

P. N. Bennett & M. J. Brown  Published by Churchill Livingstone, Edinburgh  ISBN 0‐443‐06480‐6. Price: £39.99.
Vasopeptidase inhibitors: will they have a role in clinical practice?
Authors: Worthley Matthew I. , Corti Roberto , Worthley Stephen G.
Published: December 2004

The human cardiovascular system is regulated by haemodynamic, neurohumoral and structural mechanisms. The endothelium and the neurohumoral system play a key role in modulating both vascular tone and structure by producing vasoactive substances, and in the modulation of blood cell adhesion. Although the neurohormonal systems are essential in vascular homeostasis, they become maladaptive in conditions such as hypertension, coronary disease and heart failure.

 The clinical success of blocking the renin‐angiotensin system by angiotensin converting enzyme (ACE)‐inhibitors and the sympathetic nerve system by β‐blockers demonstrates the importance of neurohumoral blockade. The inadequate effect of angiotensin converting enzyme (ACE) or neutral endopeptidase (NEP) inhibitor monotherapy seen in some patients treated for hypertension or congestive heart failure, and the promising effect seen after their combination, led to the development of drugs that simultaneously inhibit both enzyme systems.

 Neutral endopeptidase, like ACE, is an endothelial cell surface zinc metallopeptidase with similar structure and catalytic site to ACE. NEP is the major enzymatic pathway for degradation of natriuretic peptides. The natriuretic peptide system can be viewed as the endogenous inhibitor of the renin angiotensin system. The dual metalloprotease inhibitors of ACE and NEP, called vasopeptidase inhibitors therefore represent a new and attractive therapeutic strategy for the treatment of cardiovascular disease. The ability to add incremental benefit over already proven therapy, with an acceptable side‐effect profile however, is questionable in this new class of agents.
Differences between clinical trials and postmarketing use
Authors: Martin Karin , Bégaud Bernard , Latry Philippe , Miremont‐Salamé Ghada , Fourrier Annie , Moore Nicholas
Published: December 2004

Aims   Clinical trials constitute the gold standard to assess the efficacy and safety of new medicines. However, because they are conducted in standardized conditions far from the real world of prescription and use, discrepancies in patient selection or treatment conditions may alter both the effectiveness and risks. On the basis of three examples, our objectives were to study the differences between the characteristics of treated populations and treatment patterns in clinical trials and in postmarketing settings and to discuss the potential consequences on actual efficacy and safety.

Methods   Treated populations were compared with patients included in premarketing clinical trials. Comparisons were made on the basis of demographic characteristics and treatment patterns.

Results   Whatever the indicator and the drug studied, differences were observed: from 0.04% to 63% for tacrine, from 0% to 37% for celecoxib and from 6% to 52% for simvastatin, with possible consequences on the effectiveness and safety of the drug concerned. Our results confirm the under‐representation of women and elderly patients in premarketing clinical trials, e.g. an M : F ratio of 4.6 in clinical trails of simvastatin vs 1.0 in the joint population. Moreover, the concomitant use of medicines was made extremely restrictive by the protocols of these trials while this was not the case in the postmarketing phase. This has possible consequences on the effectiveness and safety of the drug concerned.

Conclusions   These results plead for systematic ad hoc observational postmarketing studies for any novel and/or expensive medicine to assess the relevance of premarketing data.
Quality of drug information on the World Wide Web and strategies to improve pages with poor information quality.  An intervention study on pages about sildenafil
Authors: Martin‐Facklam Meret , Kostrzewa Michael , Martin Peter , Haefeli Walter E.
Published: December 2004

Aims  The generally poor quality of health information on the world wide web ( WWW) has caused preventable adverse outcomes. Quality management of information on the internet is therefore critical given its widespread use. In order to develop strategies for the safe use of drugs, we scored general and content quality of pages about sildenafil and performed an intervention to improve their quality.

Methods  The internet was searched with Yahoo and AltaVista for pages about sildenafil and 303 pages were included. For assessment of content quality a score based on accuracy and completeness of essential drug information was assigned. For assessment of general quality, four criteria were evaluated and their association with high content quality was determined by multivariate logistic regression analysis. The pages were randomly allocated to either control or intervention group. Evaluation took place before, as well as 7 and 22 weeks after an intervention which consisted of two letters with individualized feedback information on the respective page which were sent electronically to the address mentioned on the page.

Results  Providing references to scientific publications or prescribing information was significantly associated with high content quality (odds ratio: 8.2, 95% CI 3.2, 20.5). The intervention had no influence on general or content quality.

Conclusions  To prevent adverse outcomes caused by misinformation on the WWW individualized feedback to the address mentioned on the page was ineffective. It is currently probably the most straight‐forward approach to inform lay persons about indicators of high information quality, i.e. the provision of references.
The arginine‐16 β2‐adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol
Authors: Lee Daniel K. C. , Currie Graeme P. , Hall Ian P. , Lima John J. , Lipworth Brian J.
Published: December 2004

Aims   The relationship between β2‐adrenoceptor polymorphisms and bronchoprotective response with long‐acting β2‐adrenoceptor agonists is unknown.

Methods   We retrospectively analysed data from six placebo‐controlled randomized studies in corticosteroid treated asthmatics where formoterol or salmeterol were administered over a 1–2‐week period, with prior 1–2 week washout, assessing the primary end point of methacholine PD20 and adenosine monophosphate PC20, following first and last dose, expressed as doubling dose difference from placebo.

Results   There was no significant heterogeneity between the different studies. Patients who had homozygous or heterozygous genotypes containing the arginine‐16 polymorphism (Arg16‐Arg16 or Arg16‐Gly16) had greater bronchoprotective subsensitivity compared with the homozygous glycine‐16 genotype (Gly16‐Gly16), amounting to a mean doubling dose difference of 1.49 (95% CI 0.50, 2.48), after the last dose. Subsensitivity of response was greater with formoterol than salmeterol after the last dose in all genotypes, especially with the arginine‐16 polymorphism, amounting to a doubling dose difference of 3.00 (95% CI 1.01, 4.99) between formoterol and salmeterol.

Conclusions   Our retrospective analysis showed that the arginine‐16 polymorphism was associated with subsensitivity of response for bronchoprotection, which was greater for formoterol than salmeterol. A prospective study will be required in order to further evaluate these findings, particularly to assess whether these differences are mirrored by exacerbations.
Population pharmacokinetics of weekly docetaxel in patients with advanced cancer
Authors: Slaviero Kellie A. , Clarke Stephen J. , McLachlan Andrew J. , Blair Elaine Y. L. , Rivory Laurent P.
Published: December 2004

Aims   Previous pharmacokinetic studies of the 3‐weekly regimen (100 mg m−2 every 3 weeks) of docetaxel have shown that docetaxel clearance is affected by liver function, body surface area, age, serum α1‐acid glycoprotein and cytochrome P450 3A4 (CYP3A4) activity. However, the pharmacokinetics of a weekly docetaxel (40 mg m−2 week−1) schedule are not well characterized. The aims of this study were (a) to investigate the pharmacokinetics of docetaxel (40 mg m−2 week−1) using sparse concentration‐time data collected from patients with advanced cancer and (b) to utilize a population pharmacokinetic approach to identify patient covariates that significantly influence the clearance of docetaxel when administered according to this regimen.

Methods   A two‐compartment pharmacokinetic model was used to describe the docetaxel concentration–time data from 54 patients with advanced cancer. The mean population and individual posterior Bayesian estimates of docetaxel clearance were estimated using P‐PHARM. The relationships between docetaxel clearance and 21 covariates were investigated. This included estimates of CYP3A4 function in each patient using the erythromycin breath test (1/tmax). Significant covariates were included into the final population pharmacokinetic model. Pharmacokinetic models were validated using a data splitting approach with a dataset consisting of 16 patients.

Results   Significant relationships were found between docetaxel clearance and 1/tmax (erythromycin breath test parameter) and several of the liver function enzymes and CL was best described by the equation; CL = 21.51 + 217 (1/tmax) − 0.13 (ALT). This final population pharmacokinetic model provided both precise and unbiased predictions of docetaxel concentrations in a validation group of patients and an estimate of the population mean (95% confidence interval) clearance of docetaxel was 30.13 l h−1 (12.54, 46.04 l h−1) with an intersubject variability 30%.

Conclusions   A population pharmacokinetic model has been developed and validated for weekly docetaxel (40 mg m−2) in patients with advanced cancer. These results indicate that CYP3A4 activity and hepatic function have an impact on the pharmacokinetics of docetaxel when administered weekly.
Clinical pharmacology studies in UK Phase 1 units: an AHPPI survey 1999–2000
Authors: Calder N. , Boyce M. , Posner J. , Sciberras D.
Published: December 2004

A comprehensive survey of UK‐based Phase 1 activity has been conducted by the Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI). The survey included studies done within pharmaceutical company in‐house units, by Clinical Research Organizations (CROs) and within academic centres. While the majority of institutions were members of AHPPI, some bodies outside of the organization were also contacted. The response rate was excellent (> 98%) and indicated that the vast majority of early drug research in humans is now CRO‐based (82%). The total number of studies (as indicated by protocol numbers) was notably similar across the 2 years –629 in 1999 and 606 in 2000. Turnaround time for ethics committee review was a mean of 14 days. These data set important benchmarks for early‐phase drug research in the UK where regulatory approval is not currently required. Furthermore, the information should be used as a guide if the competitive nature of such work in the UK is to be maintained as new national legislation is implemented following publication of the European Union (EU) Clinical Trials Directive.
Safety evaluation of fixed combination piperaquine plus dihydroartemisinin (Artekin®) in Cambodian children and adults with malaria
Authors: Karunajeewa Harin , Lim Chiv , Hung Te‐Yu , Ilett Kenneth F. , Denis Mey Bouth , Socheat Doung , Davis Timothy M. E.
Published: December 2004

Aims  To assess the haemodynamic, electrocardiographic and glycaemic effects of piperaquine‐dihydroartemisinin (Artekin®) fixed combination therapy in uncomplicated malaria.

Methods  Sixty‐two Cambodians (32 children and 30 adults) with falciparum or vivax malaria were given Artekin® given as four age‐based oral doses over 32 h. Supine and erect blood pressure, the electrocardiographic QT interval and plasma glucose were measured before treatment and then at regular intervals during a 4‐day admission period as part of efficacy and safety monitoring. QT intervals were rate‐corrected (QTc) using Bazett's formula.

Results  Artekin® therapy was well tolerated and all patients responded to treatment. Average parasite and fever clearance times were 19 and 12 h, respectively. The pretreatment mean fall in systolic blood pressure on standing was 8 ± 6 mmHg and 6‐hourly measurements over 72 h showed no significant change (P = 0.48). There was a significant lengthening of the mean QTc to a maximum of 11 ms0.5 (95% confidence interval 4–18 ms0.5) relative to baseline at 24 h (P = 0.003). The maximal QTc prolongation observed in any patient was 53 ms0.5. There was a mean 0.4 mmol l−1 reduction in the post‐absorptive plasma glucose during the first 48 h but no episodes of hypoglycaemia (plasma glucose < 3.0 mmol l−1) were observed at any time.

Conclusions  Artekin® is safe and effective combination therapy for uncomplicated malaria in children and adults. Although piperaquine is a long half‐life drug related to other quinoline compounds including chloroquine and quinine, no clinically significant cardiovascular or metabolic effects were observed.
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 events

Results  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.
Age‐related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications
Authors: Mangoni A. A. , Jackson S. H. D.
Published: December 2004

Advancing age is characterized by impairment in the function of the many regulatory processes that provide functional integration between cells and organs. Therefore, there may be a failure to maintain homeostasis under conditions of physiological stress. The reduced homeostatic ability affects different regulatory systems in different subjects, thus explaining at least partly the increased interindividual variability occurring as people get older. Important pharmacokinetic and pharmacodynamic changes occur with advancing age. Pharmacokinetic changes include a reduction in renal and hepatic clearance and an increase in volume of distribution of lipid soluble drugs (hence prolongation of elimination half‐life) whereas pharmacodynamic changes involve altered (usually increased) sensitivity to several classes of drugs such as anticoagulants, cardiovascular and psychotropic drugs. This review focuses on the main age‐related physiological changes affecting different organ systems and their implications for pharmacokinetics and pharmacodynamics of drugs.
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.