bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genotyping of four genetic polymorphisms in the CYP1A2 gene in the Egyptian population
Authors: Hamdy Samar I. , Hiratsuka Masahiro , Narahara Kaori , Endo Naomi , El‐Enany Mervat , Moursi Nadia , Ahmed Mohammed S.‐E. , Mizugaki Michinao 
Published: December 2004

Aims
The goal of this study was to determine the frequencies of CYP1A2*1C, *1D, *1E and *1F variants in the Egyptian population and compare frequencies with other populations.
Methods
Genotyping was performed in a total of 212 unrelated Egyptian subjects using polymerase chain reaction‐restriction fragment length polymorphism assay.
Results
The frequencies of CYP1A2*1C, *1D, *1E and *1F variants in the Egyptian population were 0.07, 0.40, 0.03 and 0.68, respectively. The Egyptians have a lower frequency of CYP1A2*1C, and CYP1A2*1E than the Japanese (0.07 vs 0.21 and 0.03 vs 0.08, respectively), while the frequencies of CYP1A2*1D and CYP1A2*1F did not differ significantly between the two groups. CYP1A2*1F (0.68) frequency in Egyptians was identical to that observed in Caucasians (0.68 among 236 German individuals).
Conclusions
The present study is the first to describe the frequencies of four known allelic variants of CYP1A2 among the Egyptian population. CYP1A2*1C and *1E occurred at frequencies significantly lower than that in Japanese, while similar frequencies were observed for CYP1A2*1D and *1F. The CYP1A2*1F frequency appeared to be identical to that of Caucasians. This does not exclude the possibility of the presence of new mutations relatively specific to the Egyptian population that have not been identified.
A placebo‐controlled pharmacodynamic and pharmacokinetic interaction study between tamsulosin and acenocoumarol
Authors: Rolan P. , Terpstra I. J. , Clarke C. , Mullins F. , Visser J. N. 
Published: December 2004

Aim
To evaluate pharmacokinetic and pharmacodynamic interactions between tamsulosin and acenocoumarol.
Methods
Twelve healthy volunteers received tamsulosin 0.4 mg or placebo once daily for 9 days in a double‐blind, cross‐over study. On day 5 of each study period, a single 10‐mg oral dose of racemic acenocoumarol was administered.
Results
The ratios (point estimates (90% confidence intervals)) of values in the presence and absence of tamsulosin were: AUCPT 1.01 (0.98, 1.03); maximum prothrombin time (Ptmax) 0.99 (0.94, 1.05); AUC (R)‐acenocoumarol 1.02 (0.90, 1.16), and AUC (S)‐acenocoumarol 1.03 (0.89, 1.20). Both combinations, tamsulosin and placebo with acenocoumarol, were well‐tolerated.
Conclusions
Multiple doses of tamsulosin had no effect on the pharmacokinetics or pharmacodynamics of a single high dose of acenocoumarol.
Dose–response relationship and reproducibility of urinary salbutamol excretion during the first 30 min after an inhalation
Authors: Tomlinson H. S. , Corlett S. A. , Chrystyn H. 
Published: December 2004

Aims  To determine the reproducibility and dose–response relationship for urinary salbutamol excretion post inhalation.Methods  Fifteen volunteers inhaled either one, two, three, four or five doses of 100 µg salbutamol on separate days and then seven of these also repeated each of the one, three and five doses on five occasions. After each study dose urine was collected 30 min post inhalation.Results  The mean (SD) 30 min urinary salbutamol after one, two, three, four and five doses was 2.61 (1.0.), 5.47 (1.59), 8.68 (2.73), 12.34 (3.96) and 15.99 (4.50) µg, respectively. Statistical analysis revealed a linear relationship (P < 0.001). Mean (SD) coefficient of variation after one, three and five doses was 10.5 (3.6), 10.1 (2.7) and 9.4 (2.3)%.Conclusions  The 30 min salbutamol urinary excretion post inhalation pharmacokinetic method, to compare inhaled products, is linear with inhaled dose and reproducible.
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.
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.
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.