bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epidemiology of drug exposure and adverse drug reactions in two Swiss departments of internal medicine
Authors: Fattinger Karin , Roos Malgorzata , Vergères Patrice , Holenstein Clemens , Kind Brigitt , Masche Urspeter , Stocker David N. , Braunschweig Suzanne , Kullak‐Ublick Gerd A. , Galeazzi Renato L. , Follath Ferenc , Gasser Theo , Meier Peter J. 
Published: March 2003

Aims To explore drug exposure, frequency of adverse drug reactions (ADRs), types of ADRs, predisposing risk factors and ADR‐related excess hospital stay in medical inpatients. Methods Structured data regarding patient characteristics, ‘events’ (symptoms, laboratory results), diagnoses (ICD10) and drug therapy were collected using a computer‐supported data entry system and an interface for data retrieval from electronic patient records. ADR data were collected by ‘event monitoring’ to minimize possible bias by the drug monitor. The causality of each event was assessed in relation to disease(s) and drug therapy. Results The analysis included 4331 (100%) hospitalizations. The median observation period was 8 days. The median number of different drugs administered per patient and day was 6 and varied between 4 (Q1 ) and 9 (Q3 ) different drugs in 50% of all hospital days. In 41% of all hospitalizations at least one disease‐unrelated event could be possibly attributed to drug therapy. Clinically relevant ADRs occurred in 11% of all hospitalizations. In 3.3% of all hospitalizations ADRs were the cause of hospital admission. The incidence of possibly ADR‐related deaths was 1.4. Factors predisposing for clinically relevant ADRs were female gender and polypharmacy. ADR‐related excess hospital stay accounted for 8.6% of hospital days. Conclusions These data demonstrate the feasibility of the developed ‘event monitoring’ system for quantitative analysis of ADRs in medical inpatients. With increasing numbers of recorded patients the pharmacoepidemiological database provides a valuable tool to study specific questions regarding drug efficacy and safety in hospitalized patients.
Ziprasidone and the pharmacokinetics of a combined oral contraceptive
Authors: Muirhead G. J. , Harness J. , Holt P. R. , Oliver S. , Anziano R. J. 
Published: March 2003

Aims  To determine whether multiple doses of ziprasidone alter the steady‐state pharmacokinetics of the component steroids, ethinyloestradiol and levonorgestrel, of an oral contraceptive; to evaluate the tolerability of a co‐administered combined oral contraceptive and ziprasidone; and to compare plasma concentrations of prolactin in subjects taking a combined oral contraceptive with placebo or ziprasidone.Methods  Nineteen women taking a combined oral contraceptive (ethinyloestradiol 30 µg day− 1 and levonorgestrel 150 µg day− 1) were enrolled into a double‐blind, placebo‐controlled, two‐way crossover study. They received ziprasidone 40 mg day− 1 in two divided daily doses or placebo for 8 days (days 8–15) in one of two 21 day treatment periods separated by a 7 day washout period. Venous blood samples were collected immediately before and up to 24 h after the morning dose of oral contraceptive and ziprasidone or placebo on day 15 of each 21 day treatment period. These were assayed for ethinyloestradiol and levonorgestrel and the resulting data used to derive pharmacokinetic data for these steroids. Additional samples were collected immediately before and 4 h after the morning dose of oral contraceptive and ziprasidone or placebo on day 15 of each 21 day treatment period for prolactin assay. All observed and volunteered adverse events were recorded throughout the study.Results  The mean AUC(0,24 h), Cmax and tmax for ethinyloestradiol and the mean AUC(0,24 h) and Cmax for levonorgestrel during ziprasidone co‐administration were not statistically significantly different from corresponding values occurring during placebo co‐administration. The tmax for levonorgestrel was approximately 0.5 h longer. Concomitant therapy with a combined oral contraceptive and ziprasidone did not result in adverse events not previously seen with either preparation alone.Conclusions  The findings of this study suggest that, based on pharmacokinetic and tolerability data, ziprasidone may be co‐administered with ethinyloestradiol and levonorgestrel without loss of contraceptive efficacy or increased risk of adverse events.
The effects of ketoconazole on ziprasidone pharmacokinetics —a placebo‐controlled crossover study in healthy volunteers
Authors: Miceli J. J. , Smith M. , Robarge L. , Morse T. , Laurent A. 
Published: March 2003

Aims  To assess the effects of multiple oral doses of ketoconazole on the single‐dose pharmacokinetics of oral ziprasidone HCl.Methods  This was a 14‐day, open‐label, randomized, crossover study in 14 healthy subjects aged 18–31 years. Group 1 received oral ketoconazole 400 mg once daily for 6 days, followed by a 2 day wash‐out period and 6 days of placebo administration. Group 2 received placebo followed by ketoconazole. Single oral doses of ziprasidone HCl 40 mg were administered on days 5 and 13 in both groups. Ziprasidone pharmacokinetic parameters were compared between placebo and ketoconazole administration periods.Results  Co‐administration of ziprasidone with ketoconazole was associated with a modest increase in ziprasidone exposure; mean ziprasidone AUC(0,∞) increased by 33%, from 899 ng ml− 1 h with placebo to 1199 ng ml− 1 h with ketoconazole. Mean Cmax increased by 34%, from 89 ng ml− 1 to 119 ng ml− 1, respectively. The treatment effect on both of these parameters was statistically significant (P< 0.02). Most adverse events were of mild intensity. There were no serious adverse events, laboratory abnormalities, abnormal ECGs, or clinically significant alterations in vital signs throughout the study.Conclusions  The concurrent administration of ketoconazole and ziprasidone led to modest, statistically significant increases in ziprasidone exposure, although the changes seen were not considered clinically relevant. This suggests that other inhibitors of CYP3A4 are unlikely to significantly affect the pharmacokinetics of ziprasidone.
The effect of carbamazepine on the steady‐state pharmacokinetics of ziprasidone in healthy volunteers
Authors: Miceli J. J. , Anziano R. J. , Robarge L. , Hansen R. A. , Laurent A. 
Published: March 2003

Aims  To evaluate the effect of steady‐state carbamazepine administration on the steady‐state pharmacokinetics of ziprasidone in healthy young adults, in an open, randomised, parallel‐group study.Methods  Twenty‐five subjects were randomized to one of two treatment groups. Group 1 received 20 mg ziprasidone twice daily on days 1 and 2, and a single dose on day 3. A single 100 mg dose of carbamazepine was given once daily on days 5 and 6 and twice daily on days 7 and 8, followed by 200 mg twice daily until day 28 and on the morning only on day 29. Ziprasidone 20 mg was also administered twice daily on days 26 and 27 and in the morning only on day 28. Group 2 received the same treatment regimen with carbamazepine replaced by placebo. Pharmacokinetic data were obtained on days 3 and 28.Results  Nine subjects in group 1 and 10 in group 2 completed all three treatment periods (ziprasidone, carbamazepine or placebo; and ziprasidone plus carbamazepine or placebo). Carbamazepine administration to group 1 was associated with modest reductions in ziprasidone exposure, with mean decreases in ziprasidone AUC(0,12 h) and Cmax values of 36% and 27%, respectively, on day 28 compared with day 3 (P<0.03). The mean differences between day 28 and day 3 ziprasidone AUC(0,12 h) and Cmax values were also statistically significantly greater in the carbamazepine group than in the placebo group. The mean half‐life of ziprasidone decreased by 1 h from day 3 to day 28 in the subjects receiving carbamazepine, compared with virtually no change in the placebo group. All adverse events were mild or moderate in severity and there were no serious adverse events, or clinically significant changes in ECGs and vital signs throughout the study.Conclusions  Induction of CYP3A4 with carbamazepine led to a modest reduction (<36%) in steady‐state exposure to ziprasidone that is believed to be clinically insignificant.
A discordance of the cytochrome P450 2C19 genotype and phenotype in patients with advanced cancer
Authors: Williams Marion L. , Bhargava Pankaj , Cherrouk Ilham , Marshall John L. , Flockhart David A. , Wainer Irving W. 
Published: March 2003

Aims  To examine the relationship between cytochrome P450 2C19 (CYP2C19) genotype and expressed metabolic activity in 16 patients with advanced metastatic cancer.Methods  Individual CYP2C19 genotypes were determined by PCR‐based amplification, followed by restriction fragment length analysis, and compared with observed CYP2C19 metabolic activity, as determined using the log hydroxylation index of omeprazole.Results  All 16 patients had an extensive metabolizer genotype. However, based on the antimode in a distribution of log omeprazole hydroxylation indices from healthy volunteers, four of the patients had a poor metabolizer phenotype and there was a general shift of the remaining 12 patients towards a slower metabolic phenotype. This suggests a reduction in metabolic activity for all patients relative to healthy volunteers. A careful analysis of patient medical records failed to reveal any drug interactions or other source for the observed discordance between genotype and phenotype.Conclusions  There are no previous reports of a ‘discordance’ between genotype and expressed enzyme activity in cancer patients. Such a decrease in enzyme activity could have an impact on the efficacy and toxicity of chemotherapeutic agents and other drugs, used in standard oncology practice.
CYP2D6 and CYP2C19 genotypes of patients with terodiline cardiotoxicity identified through the yellow card system
Authors: Ford Gary A. , Wood Susan M. , Daly Ann K. 
Published: March 2003

Aims
Terodiline has concentration dependent QT prolonging effects and thus the potential for cardiotoxicity. Pharmacogenetic variation in terodiline metabolism could be responsible for cardiotoxicity. We sought to determine whether CYP2D6 (debrisoquine hydroxylase) or CYP2C19 (S‐mephenytoin hydroxylase) status is a risk factor for terodiline cardiotoxicity.
Methods
Using the UK Yellow Card scheme to identify patients, blood samples were obtained from eight patients who survived ventricular tachycardia or torsades de pointes suspected to be due to terodiline, for determination of CYP2D6 and CYP2C19 genotypes. Genotype prevalence was compared with that in published general population groups.
Results
One patient was a CYP2D6 poor metaboliser (CYP2D6*4 homozygous) and a second was heterozygous for CYP2D6*4, a slightly lower frequency for these genotypes compared with the general population (P = 0.31). In the case of CYP2C19, one patient was a poor metaboliser and four were heterozygous for the variant CYP2C19*2 allele, compared with general population frequencies of 2% and 23%, respectively (P = 0.035).
Conclusions
These findings suggest that debrisoquine poor metaboliser status is not primarily responsible for terodiline cardiotoxicity. However, possession of the CYP2C19*2 allele appears to contribute to adverse cardiac reactions to terodiline. The present study demonstrates the feasibility of using spontaneous adverse drug reaction reporting schemes to determine the contribution of genotype for metabolizing enzymes to uncommon adverse drug reactions.
Kinetics and inhibition of the formation of 6β‐naltrexol from naltrexone in human liver cytosol
Authors: Porter Susan J. , Somogyi Andrew A. , White Jason M. 
Published: March 2003

Aims  To determine the kinetics of the formation of 6β‐naltrexol from naltrexone in human liver cytosol, and to investigate the role of potential inhibitors.Methods  The kinetics of the formation of 6β‐naltrexol from naltrexone were examined in eight human liver cytosol preparations using h.p.l.c. to quantify 6β‐naltrexol and, the extent of inhibition of 6β‐naltrexol formation was determined using chemical inhibitors. The formation of 6β‐naltrexol and the back reaction of 6β‐naltrexol to naltrexone were also examined in a microsomal preparation.Results  The Vmax, Km and CLint values for the formation of 6β‐naltrexol from naltrexone were in the ranges of 16–45 nmol mg−1 protein h−1, 17–53 µm and 0.3–2.2 ml h−1 mg−1 protein, respectively. The steroid hormones testosterone (Ki = 0.3 ± 0.1 µm) and dihydrotestosterone (Ki = 0.7 ± 0.4 µm) were the most potent competitive inhibitors of 6β‐naltrexol formation, with naloxone, menadione and corticosterone also producing > 50% inhibition at a concentration of 100 µm. The opioid agonists morphine, oxycodone, oxymorphone and hydromorphone, and a range of benzodiazepines showed < 20% inhibition at 100 µm. In the microsomal preparation, there was no formation of naltrexone from 6β‐naltrexol nor any formation of 6β‐naltrexol from naltrexone.Conclusions  The intersubject variability in the kinetic parameters of 6β‐naltrexol formation could play a role in the efficacy of and patient compliance with naltrexone treatment. This variability could be due in part to a genetic polymorphism of the dihydrodiol dehydrogenase DD4, one of the enzymes reported to be responsible for the formation of 6β‐naltrexol from naltrexone. DD4 also has hydroxysteroid dehydrogenase activity which could account for the potent inhibition by the steroid hormones testosterone and dihydrotestosterone. The clinical significance of the latter finding remains to be established.
Risk factors in the development of adverse reactions to N‐acetylcysteine in patients with paracetamol poisoning
Authors: Schmidt L. E. , Dalhoff K 
Published: March 2003

Aims  To identify risk factors in the development of side‐effects to N‐acetylcysteine (NAC) in patients with paracetamol poisoning.Methods  A retrospective study was carried out based upon the hospital charts of 529 consecutive patients admitted with paracetamol poisoning, all treated with NAC, at the Department of Hepatology, Copenhagen University Hospital (the tertiary care centre of liver disease in Denmark).Results  Forty‐five patients (8.5%; 95% confidence intervals (CI) 6.4, 11%) developed side‐effects to NAC and 18 patients (3.4%; 95% CI 2.1, 5.4%) developed systemic side‐effects. Asthmatics were 2.9 times (95% CI 2.1, 4.7) more likely to develop side‐effects (Chi‐square: P = 0.004). Side‐effects were of similar severity in asthmatics and nonasthmatics. A history of medical allergy was not a risk factor. Serum paracetamol was lower in patients with side‐effects than in those without (Mann–Whitney: P = 0.00006).Conclusions  Asthma must be considered a risk factor in the development of side‐effects to NAC. However, the side‐effects are easily managed and there is no reason to withhold NAC from any patient with paracetamol poisoning. Paracetamol itself seems to offer some protection against the development of side‐effects to NAC.
Neuroimaging of histamine H1‐receptor occupancy in human brain by positron emission tomography (PET): A comparative study of ebastine, a second‐generation antihistamine, and (+)‐chlorpheniramine, a classical antihistamine
Authors: Tagawa Masaaki , Kano Michiko , Okamura Nobuyuki , Higuchi Makoto , Matsuda Michiaki , Mizuki Yasuyuki , Arai Hiroyuki , Iwata Ren , Fujii Toshihiko , Komemushi Sadao , Ido Tatsuo , Itoh Masatoshi , Sasaki Hidetada , Watanabe Takehiko , Yanai Kazuhiko 
Published: March 2003

Aims  Sedation induced by antihistamines is widely recognized to be caused by their penetration through the blood–brain‐barrier and the consequent occupation of brain histamine H1‐receptors. We previously studied the mechanism of sedation caused by antihistamines using positron emission tomography (PET). Recently, we revealed the nonsedative characteristic of ebastine, a second‐generation antihistamine, with cognitive performance tests. In the present study, H1‐receptor occupation by ebastine was examined in the human brain using PET.Methods  Ebastine 10 mg and (+)‐chlorpheniramine 2 or 6 mg were orally given to healthy male volunteers. PET scans with [11C]‐doxepin, a potent H1‐receptor antagonist, were conducted near tmax of respective drugs. Other volunteers in the control group also received PET scans. The binding potential of doxepin (BP=Bmax/Kd) for available brain H1‐receptors was imaged on a voxel‐by‐voxel basis through graphical analysis. By setting regions of interest, the H1‐receptor occupancy of drugs was calculated in several H1‐receptor rich regions.Results  Brain distribution of radioactivity after ebastine treatment was similar to that without any drugs. However, after the oral administration of 2 mg (+)‐chlorpheniramine, the level was lower than after ebastine and nondrug treatments. Graphical analysis followed by statistical parametric mapping (SPM96) revealed that H1‐receptor rich regions such as cortices, cingulate gyrus and thalamus were regions where the BPs after ebastine were significantly higher than after (+)‐chlorpheniramine (2 mg). H1‐receptor occupancies in cortex were approximately 10% by ebastine and ≥50% by either dose of (+)‐chlorpheniramine (95% confidence interval for difference in the mean receptor occupancies: 27%, 54% for 2 mg and 35%, 62% for 6 mg vs ebastine, respectively). Receptor occupancies increased with increasing plasma concentration of (+)‐chlorpheniramine, but not with concentration of carebastine, an active metabolite of ebastine.Conclusions  Ebastine (10 mg orally) causes brain histamine H1‐receptor occupation of approximately 10%, consistent with its lower incidence of sedative effect, whereas (+)‐chlorpheniramine occupied about 50% of brain H1‐receptors even at a low but sedative dose of 2 mg; occupancy of (+)‐chlorpheniramine was correlated with plasma (+)‐chlorpheniramine concentration.
Development and validation of limited sampling strategies for prediction of the systemic exposure to the novel anticancer agent E7070 (N‐(3‐chloro‐7‐indolyl)‐1,4‐benzenedisulphonamide)
Authors: Van Kesteren Charlotte , Mathôt R. A. A. , Raymond E. , Armand J. P. , Fumoleau P. , Punt C. , Ravic M. , Wanders J. , Beijnen J. H. , Schellens J. H. M. 
Published: March 2003

Aims  E7070 is a novel, sulphonamide anticancer agent currently under clinical development for the treatment of solid tumours. The aim of this study was to develop and validate limited sampling strategies for the prediction of E7070 exposure in two different treatment schedules for phase II studies using the Bayesian estimation approach.Methods  Data from two phase I dose finding studies were used in which E7070 was administered either as a single 1 h infusion or as a daily 1 h infusion for 5 days. Plasma concentration‐time data from 75 patients were randomly divided into an index data set, used for the development of the strategies, and a validation data set. Population pharmacokinetic parameters were derived on the basis of the index data set. The D‐optimality algorithm was used for the selection of optimal time points for both treatment schedules. The developed strategies were compared by assessment of their predictive performance of exposure, expressed as AUC (area under the plasma concentration vs time curve), in the validation data set.Results  The developed population pharmacokinetic model comprised three compartments, with saturable distribution to one peripheral compartment and both linear and saturable elimination from the central compartment. For the 1 h infusion, a four sample strategy was selected which resulted in unbiased and accurate predictions of AUC (bias 0.74%, precision 13%). A five sample strategy was generated for the daily times five schedule yielding unbiased (bias 3.2%) and precise (12% precision) predictions of AUC.Conclusions  Optimal sampling strategies were developed and validated for estimation of E7070 exposure in two different treatment schedules. Both schedules enabled accurate and unbiased predictions of AUC.
Is quinine a suitable probe to assess the hepatic drug‐metabolizing enzyme CYP3A4?
Authors: Wanwimolruk Sompon , Paine Mary F. , Pusek Susan N. , Watkins Paul B. 
Published: March 2003

Aims To evaluate the antimalarial agent quinine as a potential in vivo probe for hepatic cytochrome P450 (CYP) 3A4 activity.Methods Ten healthy adult volunteers received, by randomized crossover design, either a single oral dose of quinine sulphate (600 mg) alone, or quinine sulphate (600 mg) plus the CYP3A4 inhibitor troleandomycin (TAO; 500 mg every 8 h). Plasma and urine samples were collected before quinine administration, and up to 48 h thereafter, then analysed by h.p.l.c. for both quinine and its CYP3A4‐generated metabolite, 3‐hydroxyquinine. During both phases, the erythromycin breath test (ERMBT) was administered at specific times to assess hepatic CYP3A4 activity.Results Compared with control, TAO treatment significantly decreased the mean time‐averaged ERMBT result by 77% (95% CI, 68, 85%), the mean apparent oral clearance of quinine (CL/F ) by 45% (95% CI, 39, 52%), and the mean apparent formation clearance of 3‐hydroxyquinine (CL3‐OH) by 81% (95% CI, 76, 87%). There was no correlation between the TAO‐mediated percent decrease in the time‐averaged ERMBT result and the percent decrease in CL/F or in CL3‐OH. When TAO and control treatments were analysed separately, there were no significant correlations between the time‐averaged ERMBT result and CL/F, CL3‐OH, or single plasma quinine concentration at 12, 24, and 48 h.Conclusions Quinine may be a useful probe to detect inhibition of liver CYP3A4 activity within an individual. Further studies are needed to determine whether it can provide a quantitative measure of CYP3A4 activity suitable for intersubject comparison.