bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non‐antiarrhythmic drugs prolonging the QT interval:considerable use in seven countries
Authors: De Ponti Fabrizio , Poluzzi Elisabetta , Vaccheri Alberto , Bergman Ulf , Bjerrum Lars , Ferguson John , Frenz Kerry J. , McManus Peter , Schubert Ingrid , Selke Gisbert , Terzis‐Vaslamatzis Georgia , Montanaro Nicola 
Published: March 2003

Aims  Many drugs belonging to different therapeutic classes appear to share a potentially fatal side‐effect: ventricular tachyarrhythmias associated with QT prolongation. The aim of this study was to assess the relevance and the magnitude of the problem in seven countries by grouping all nonantiarrhythmic drugs according to the type of evidence on QT prolongation and analysing their sales data.Methods  We divided all nonantiarrhythmic QT‐prolonging agents into the following categories (in increasing order of clinical relevance): group A, drugs with published clinical or preclinical evidence on QT prolongation or with relevant official warnings; group B, drugs with published clinical or preclinical evidence; group C, drugs with published clinical evidence; group D, drug with published clinical evidence on torsades de pointes or ventricular arrhythmias associated with QT prolongation; group E, drugs belonging to group D with official warnings. We retrieved 1998 sales data from community pharmacies in seven countries (Australia, Denmark, England, Germany, Greece, Italy and Sweden). Data for individual agents were expressed as defined daily doses per 1000 inhabitants per day (DDD/1000/day). Overall use in each country was calculated for each drug group. Groups D and E were considered as the most clinically relevant.Results  Among the 102 nonantiarrhythmic agents meeting at least one of the inclusion criteria, 33 drugs had sales data ≥1 DDD/1000/day and 71 drugs had a use ≥0.1 DDD/1000/day in at least one country. Among the 37 nonantiarrhythmic agents with published reports of ventricular arrhythmias associated with QT prolongation, 12 compounds had sales data ≥1 DDD/1000/day. Total consumption in each country ranged: from 51.9 to 94.7 DDD/1000/day for group A; from 51.6 to 92.7 DDD/1000/day for group B; from 37.1 to 76.6 DDD/1000/day for group C; from 12.9 to 29.1 DDD/1000/day for group D; and from 5.8 to 15.3 DDD/1000/day for group E.Conclusions  In spite of wide variations in the sales of individual agents, the overall extent of use of nonantiarrhythmic QT‐prolonging drugs was of the same order of magnitude in all countries. The significant use of drugs belonging to categories D and E should prompt careful risk/benefit assessment of each agent.
Quinidine does not affect the renal clearance of moxonidine
Authors: Wise Stephen D. , Chan Clark , Schaefer Hans G. , He Minxia M. , Pouliquen Isabelle J. , Mitchell Malcolm I. 
Published: March 2003

Aims
To test the hypothesis that the renal clearance of moxonidine decreases when dosed with quinidine.
Methods
A randomized, two‐period study was conducted with six healthy, male subjects orally dosed with either 0.2 mg moxonidine alone or 1 h after 400 mg quinidine sulphate. Pharmacokinetic parameters were calculated using a noncompartmental analysis method.
Results
When coadministered, quinidine significantly increased moxonidine AUC and t1/2 by 11% and 15%, respectively, and decreased CL/F by 10% compared with the control dosing. CLR and Aeur were not significantly different. Clinically, both treatments were well tolerated.
Conclusions
Quinidine does not affect the renal clearance of moxonidine. The decrease  in  apparent  total  clearance  of  moxonidine  with  quinidine  coadministration was possibly due to metabolic inhibition, though not likely to be clinically significant.
The effects of St John's wort extract on heart rate variability, cognitive function and quantitative EEG: a comparison with amitriptyline and placebo in healthy men
Authors: Siepmann M. , Krause S. , Joraschky P. , Mück‐Weymann M. , Kirch W. 
Published: March 2003

Aims
To compare the effects of multiple dosing with St John's wort (Hypericum perforatum) extract and amitriptyline on heart rate variability, cognitive function and quantitative EEG (qEEG) with placebo in healthy humans.
Methods
A randomized, double‐blind, cross over study of 12 healthy male volunteers. Subjects orally received capsules with 255–285 mg St John's wort extract (900 µg hypericin content), 25 mg amitriptyline and placebo three times daily for periods of 14 days each with at least 14 days between. The doses of amitriptyline and St John's wort extract are comparable with respect to their antidepressant activity. Compliance was confirmed by coadministration of 10 mg of riboflavin with each capsule and detection of urinary vitamin B2 on treatment day 11 with high performance liquid chromatography. Measurements of heart rate variability, psychometric tests and qEEG were performed before start of medication and repeatedly on the last treatment day.
Results
St John's wort extract did not affect heart rate variability (HRV) whereas amitripytline significantly decreased it: the difference in the percentage number of adjacent RR intervals> 50 ms (pNN50) was 8.6 (−2.6, 19.9; mean; 95% confidence interval) between St John's wort extract and placebo and −17.6 (−24.7, −10.4) between amitriptyline and placebo. Neither St John's wort extract nor amitriptyline had an influence on cognitive performance such as choice reaction, psychomotor coordination, short‐term memory and responsiveness to distractive stimuli. Amitriptyline but not St John's wort extract decreased self rated activity (P < 0.05). Both drugs caused significant qEEG changes. St John's wort extract increased theta power density. Amitriptyline increased theta as well as fast alpha power density.
Conclusions
Multiple doses of St John's wort extract do not affect heart rate variability    nor   cognitive   function.   Chronic   administration   of   amitriptyline   causes a decrement of HRV and subjective sedation but it does not impair cognitive performance.
Genetic polymorphisms in human CYP2A6 gene causing impaired nicotine metabolism
Authors: Yoshida Ryoko , Nakajima Miki , Watanabe Yuki , Kwon Jun‐Tack , Yokoi Tsuyoshi 
Published: March 2003

Aims  Previously, we determined the phenotyping of in vivo nicotine metabolism and the genotyping of the CYP2A6 gene (CYP2A6*1 A, CYP2A6*1B, CYP2A6*2, CYP2A6*3, CYP2A6*4 and CYP2A6*5 ) in 92 Japanese and 209 Koreans. In the study, we found one Korean and four Japanese subjects genotyped as CYP2A6*1B/CYP2A6*4 who revealed impaired nicotine metabolism, although other many heterozygotes of CYP2A6*4 demonstrated normal nicotine metabolism (CYP2A6*4 is a whole deletion type). After our previous report, several CYP2A6 alleles, CYP2A6*6 (R128Q), CYP2A6*7 (I471T), and CYP2A6*8 (R485L), have been reported. The purpose of the present study was to clarify whether the impaired nicotine metabolism can be ascribed to these CYP2A6 alleles. Furthermore, we also determined whether the subjects possessing CYP2A6*1×2 (duplication) reveal higher nicotine metabolism.Methods  Genotyping of CYP2A6 alleles, CYP2A6*6, CYP2A6*7, CYP2A6*8, and CYP2A6*1×2 was determined by PCR.Results  The five poor metabolizers were re‐genotyped as CYP2A6*7/CYP2A6*4, suggesting that a single nucleotide polymorphism (SNP) causing I471T decreases nicotine metabolism in vivo. Furthermore, we found that two subjects out of five with a lower potency of nicotine metabolism possessed SNPs of CYP2A6*7 and CYP2A6*8 simultaneously. The novel allele was termed CYP2A6*10. In the 92 Japanese and 209 Koreans, the CYP2A6*6 allele was not found. The allele frequencies of CYP2A6*7, CYP2A6*8, and CYP2A6*10 were 6.5%, 2.2%, and 1.1%, respectively, in Japanese, and 3.6%, 1.4%, and 0.5%, respectively, in Koreans. The CYP2A6*1×2 allele was found in only one Korean subject (0.5%) whose nicotine metabolic potency was not very high.Conclusions  It was clarified that the impaired in vivo nicotine metabolism was caused by CYP2A6*7 and CYP2A6*10 alleles.
In vitro–in vivo correlations for drugs eliminated by glucuronidation: Investigations with the model substrate zidovudine
Authors: Boase Sam , Miners John O. 
Published: March 2003

Aims  To investigate the effects of incubation conditions on the kinetic constants for zidovudine (AZT) glucuronidation by human liver microsomes, and whether microsomal intrinsic clearance (CLint) derived for the various conditions predicted hepatic AZT clearance by glucuronidation (CLH) in vivo.Methods  The effects of incubation constituents, particularly buffer type (phosphate, Tris) and activators (Brij58, alamethacin, UDP‐N‐acetylglucosamine (UDP‐NAcG)), on the kinetics of AZT glucuronidation by human liver microsomes was investigated. AZT glucuronide (AZTG) formation by microsomal incubations was quantified by h.p.l.c. Microsomal CLint values determined for the various experimental conditions were extrapolated to a whole organ CLint and these data were used to calculate in vivo CLH using the well‐stirred, parallel tube and dispersion models.Results  Mean CLint values for Brij58 activated microsomes in both phosphate (3.66 ± 1.40 µl min−1 mg−1, 95% CI 1.92, 5.39) and Tris (3.79 ± 0.74 µl min−1 mg−1, 95% CI 2.87, 4.71) buffers were higher (P < 0.05) than the respective values for native microsomes (1.04 ± 0.42, 95% CI 0.53, 1.56 and 1.37 ± 0.30 µl min−1 mg−1, 95% CI 1.00, 1.73). Extrapolation of the microsomal data to a whole organ CLint and substitution of these values in the expressions for the well‐stirred, parallel tube and dispersion models underestimated the known in vivo blood AZT clearance by glucuronidation by 6.5‐ to 23‐fold (3.61–12.71 l h−1vs 82 l h−1). There was no significant difference in the CLH predicted by each of the models for each set of conditions. A wide range of incubation constituents and conditions were subsequently investigated to assess their effects on GAZT formation, including alamethacin, UDP‐NAcG, MgCl2, d‐saccharic acid 1,4‐lactone, ATP, GTP, and buffer pH and ionic strength. Of these, only decreasing the phosphate buffer concentration from 0.1 m to 0.02 m for Brij58 activated microsomes substantially increased the rate of GAZT formation, but the extrapolated CLH determined for this condition still underestimated known AZT glucuronidation clearance by more than 4‐fold. AZT was shown not to bind nonspecifically to microsomes. Analysis of published data for other glucuronidated drugs confirmed a trend for microsomal CLint to underestimate in vivo CLH.Conclusions  AZT glucuronidation kinetics by human liver microsomes are markedly dependent on incubation conditions, and there is a need for interlaboratory standardization. Extrapolation of in vitro CLint underestimates in vivo hepatic clearance of drugs eliminated by glucuronidation.
Drug reimbursement: Indicators of inappropriate resource allocation
Authors: Bégaud Bernard , Bergman Ulf , Eichler Hans‐Georg , Leufkens Hubert G. M. , Meier Peter J. 
Published: March 2003

Aims  In many countries, governments and third parties find themselves paying for (reimbursing) unproven, inadequate products limiting their ability to invest in therapies with evidence of relevant patient benefit. We examined how three characteristics, level of therapeutic evidence, susceptibility of inappropriate prescribing, and intercountry variation can be used to identify inefficiencies in pharmaceutical reimbursement among four European Union countries, Austria, Belgium, the Netherlands and Sweden.Methods  Specific classes of medicines were chosen to provide useful examples of how healthcare resources could be reallocated. A high level of therapeutic evidence was defined as a substantial body of evidence in at least one indication with clear‐cut support of relevant patient benefit. The susceptibility of inappropriate prescribing was defined as the likelihood of prescribing a drug outside the scenario for which clear‐cut evidence (if any) has been documented to produce relevant benefit for the patient. The intercountry variation represents the variation in utilization of reimbursed drugs across the four countries.Results  The combination of these characteristics provides a useful tool for assessing appropriate reimbursement decisions. It would be beneficial to healthcare payers as well as patients to move resources from products that have a low level of therapeutic evidence and a high susceptibility of inappropriate prescribing to products with a high level of therapeutic evidence and low susceptibility of inappropriate prescribing, and to use intercountry variation as a signal of drug classes that should be subject to further scrutiny.Conclusions  A method is presented to help policy‐makers identify inefficiencies in the spending of limited health care resources, and to reallocate resources to products that have been shown to improve patient care through evidence‐based medicine.
Validation of a new fluorogenic real‐time PCR assay for detection of CYP2C9 allelic variants and CYP2C9 allelic distribution in a German population
Authors: Burian Maria , Grösch Sabine , Tegeder Irmgard , Geisslinger Gerd 
Published: March 2003

Aims  The aim was to develop a fast detection method for the polymorphic alleles related to impaired CYP2C9‐mediated metabolism.Methods  CYP2C9 genotypes were identified in 118 DNA samples using real‐time PCR (LightCycler) followed by melting curve analysis. All samples were re‐tested by validated PCR‐RFLP methodology.Results  The concordance between the two methods was 100% for two variant alleles. The frequencies of CYP2C9*1 (wild type), CYP2C9*2 and CYP2C9*3 (with 95% confidence intervals) were 0.81(0.05), 0.14(0.04) and 0.05(0.03), respectively, and are similar to those observed in other Caucasian populations.Conclusions  This assay is simple and rapid and may be used for CYP2C9‐genotyping in a clinical setting.
Determinants of undertreatment of hypercholesterolaemia in a population‐based study in The netherlands
Authors: Mantel‐Teeuwisse A. K. , Verschuren W. M. M. , Klungel O. H. , Porsius A. J. , De Boer A. 
Published: March 2003

Prevalence of undertreatment of patients with hypercholesterolaemia is high and it remains uncertain which patients receive treatment.The aim was to identify determinants of non‐use of lipid lowering drugs among those eligible for pharmacological treatment.Data were obtained from two population‐based surveys (n=65,428) on cardiovascular disease risk factors conducted from 1987–1997 in The Netherlands. All respondents (age 20–59 years) completed a questionnaire which contained questions on demographic variables, cardiovascular disease (CVD) risk factors and medication use. Blood pressure, total‐cholesterol and HDL‐cholesterol levels were measured. Treatment eligibility was established for all respondents according to the Dutch Consensus Cholesterol 1998. This standard indicates pharmacological treatment in secondary prevention (unless Tc<5 mmol l−1) and for primary prevention when the absolute level of risk exceeds an age‐ and gender‐specific cut‐off point (based on the Framingham risk function). Secondary prevention was defined as a history of myocardial infarction (MI), cerebrovascular accident (CVA), coronary artery bypass grafts (CABG) or percutaneous transluminal coronary angioplasty (PTCA).Multivariate logistic regression models were used to assess the association between demographic variables, CVD risk factors, medication use and treatment with lipid lowering drugs and to estimate odds ratios (OR) and their 95% confidence intervals.Of all respondents, 2719 were eligible for lipid lowering treatment (4.2%). In secondary prevention, 137 of the 1225 eligible respondents were treated (11.2%). Age (OR=0.96 per year; 0.93–1.00), calendar year (OR= 0.69 per year; 0.59–0.82), a history of MI (OR=0.34; 0.20–0.57), CABG (OR=0.28; 0.16–0.47) or PTCA (OR=0.44; 0.24–0.79) and antihypertensive drug use (OR=0.56; 0.34–0.90) were inversely related to non‐use of lipid lowering drugs. Non‐use in secondary prevention increased with untreated hypertension (OR=1.37), diabetes mellitus (OR=2.21) and male gender (OR=1.20), although not statistically significant.In primary prevention, 294 of the 1494 respondents eligible for treatment were treated (19.7%). Male gender (OR=12.2; 4.6–32.9), diabetes mellitus (OR=13.1; 6.6–25.8), untreated hypertension (systolic blood pressure >160 mmHg or diastolic blood pressure >95 mmHg) (OR=13.4; 7.0–25.8) current smoking (OR=11.7; 6.4–21.2) were most strongly associated with non‐use of lipid lowering drugs, while non‐use decreased with concomitant anticoagulant drug use (OR=0.05; 0.01–0.19). For age, we found an increase in risk of 1.26 (1.21–1.32) per year of age.This study indicates that many subpopulations of respondents eligible for treatment with lipid lowering drugs but not receiving medication can be identified. Attention should be focused on the elderly, men (especially in primary prevention), patients with diabetes mellitus and untreated hypertensives.
6‐Thioguanine in azathioprine and 6‐mercaptopurine intolerant patients with inflammatory bowel disease
Authors: Derijks L. J. J. , De Jong D. J. , Gilissen L. P. L. , Engels L. G. J. B. , Mulder C. J. J. , Bos L. P. , Lohman J. J. H. M. , Hooymans P. M. 
Published: March 2003

Azathioprine (AZA) and 6‐mercaptopurine (6‐MP) are frequently used in the treatment of inflammatory bowel disease (IBD). However, about 10–20% of IBD‐patients are unable to tolerate AZA and/or 6‐MP due to side‐effects. 6‐Thioguanine (6‐TG), the active metabolite of AZA and 6‐MP, may be an alternative in these cases.We measured 6‐TG levels in erythrocytes 4 weeks after start of 6‐TG therapy in nine out‐patients with IBD. 6‐TG concentrations were considered to reach steady state in 4 weeks having a half‐life of approximately 5 days. The mean age of the patients was 41 years (range 24–59), three were male, six were female. Two patients were intolerant to 6‐MP, 5 to AZA and two to both drugs. Five patients received a daily dose of 20 mg, four were given 40 mg. The results are summarized in Table 1.

Patient characteristics.

Number
Sex
Age  (years)
IBD
Intolerance
Dose  (mg)
6‐TG (*)

1
M
59
UC
6‐MP
20
552 (#)

2
M
51
UC
AZA
20
270 (##)

3
F
24
CD
6‐MP
20
1013

4
F
35
CD
AZA
20
819

5
F
46
UC
AZA/6‐MP
20
1072

6
F
24
CD
AZA
40
986

7
M
44
UC
AZA
40
1359

8
F
51
CD
AZA
40
703

9
F
34
CD
AZA/6‐MP
40
1666

* 6‐TG concentrations at t=4 weeks, at t=2 weeks (

#) and at t=1 week (

##) in pmol/8×10
8 RBC.
UC=ulcerative colitis, CD=Crohn's disease.

Poor correlation was found between dose and 6‐TG concentration (r : 0.34). 6‐TG concentrations after 6‐TG intake are relatively high compared with blood concentrations measured in AZA or 6‐MP treated patients (mean: 276, range: 0–792) [1]. Beside drug efficacy 6‐TG concentrations are also associated with bone marrow suppression, especially when these concentrations are high; Dubinsky et al. [1] measured a mean 6‐TG concentration of 490 in a pediatric leukopenic population treated with AZA or 6‐MP [2].No leukopenia was observed in our 6‐TG treated group.One of our patients showed an early allergic reaction to 6‐TG and developed high fever and erythema nodosum within the first week (patient 2). Another patient discontinued 6‐TG after 3 weeks because of total malaise (patient 1). Late, pharmacological explainable adverse reactions due to high 6‐TG concentrations did not occur in the 4 week period.These results suggest that 6‐TG may serve as a safe alternative in AZA and 6‐MP intolerant IBD‐patients. Frequent 6‐TG concentration measurement and leukocyte counts are mandatory in determining optimal dose and guaranteeing safety. Further data are needed to establish safety and efficacy in the long term. We therefore initiated a prospective multicenter clinical trial.
Interaction of ibuprofen and probenecid with drug metabolizing enzyme phenotyping procedures using caffeine as the probe drug
Authors: Vrtic Fatima , Haefeli Walter E. , Drewe Jürgen , Krähenbühl Stephan , Wenk Markus 
Published: March 2003

Aims To examine the suspected inhibitory potential of the over‐the‐counter (OTC) drug ibuprofen on N‐acetyltransferase 2 (NAT2) in vitro and in vivo and the possible implications for phenotyping procedures using caffeine as probe drug.Methods We first studied the inhibitory effect of ibuprofen on NAT2 in vitro, using human liver cytosol and sulfamethazine as substrate. In vivo 15 fast and 15 slow acetylating healthy volunteers were treated with a single dose of ibuprofen (800 mg) orally and phenotyped for NAT2, CYP1A2, and xanthine oxidase (XO) with caffeine as probe drug before and during drug treatment. Because of unexpected in vivo results with ibuprofen this study was repeated in 20 healthy volunteers with probenecid, a model substrate of renal organic anion transport (OAT). For phenotyping tests a urine sample was collected 6 h after caffeine (200 mg) intake. The caffeine metabolites acetyl‐6‐formylamino‐3‐methyluracil (AFMU), 1‐methylxanthine (1MX), 1‐methyluric acid (1MU), and 1,7‐dimethyluric acid (17MU) were quantified by HPLC, and the corresponding metabolic ratios for CYP1A2, NAT2, and XO were then calculated. Genotyping for NAT2 was performed with standard PCR‐RFLP methods.Results In vitro, with human liver cytosol an inhibition by ibuprofen of the acetylation of sulfamethazine with Ki values between 2.2 and 3.1 mm was observed. Surprisingly, in vivo a significant (P < 0.001) increase of the acetyl‐6‐formylamino‐3‐methyluracil/1‐methylxanthine (AFMU/1MX) urinary ratio from 0.97 ± 0.16 to 1.08 ± 0.18 (95% CI on the difference 0.049, 0.170) was found, indicating an apparent elevation of NAT2 activity. In contrast, no change was observed for the ratios used for XO and CYP1A2. Because an induction of NAT2 could be excluded, an interaction of ibuprofen with the tubular secretion of some of the caffeine metabolites was assumed. To prove this assumption, the in vivo study was repeated with probenecid, a model substrate of the renal OAT system. Again, a prominent elevation of the AFMU/1MX ratio from 0.97 ± 0.21 to 1.53 ± 0.35 was found (P < 0.002; 95% CI on the difference 0.237, 0.876), but also the XO ratio 1MU/1MX was significantly (P < 0.0001) increased from 1.34 ± 0.09 to 2.24 ± 0.14 (95% CI on difference 0.735, 1.059) due to a reduction of 1MX excretion.Conclusions Substrates of OAT interact with renal excretion of caffeine metabolites and may falsify NAT2 and XO phenotyping results. Other phenotyping procedures, which are based on urinary metabolic ratios, should also be validated in this respect, especially in patients under polymedication.
Effect of short‐term administration of garlic supplements on single‐dose ritonavir pharmacokinetics in healthy volunteers
Authors: Gallicano Keith , Foster Brian , Choudhri Shurjeel 
Published: March 2003

Aims  To evaluate the effect of acute dosing of garlic supplements on the single‐dose pharmacokinetics of ritonavir.Methods  Ten healthy volunteers (five male, five female) were equally randomized in a crossover design to receive 400 mg of a single dose of ritonavir within 10 min after eating breakfast either alone or with 10 mg of Natural Source Odourless Garlic. They received a total of eight doses of garlic extract (2 × 5 mg capsules) taken twice daily for 4 days. Ritonavir and the seventh garlic dose were administered simultaneously.Results  Coadministration of garlic nonsignificantly decreased area under the plasma concentration‐time curve (AUC(0,∞)) by −17% (90% confidence interval (CI), −31% to 0%; range −46% to 68%) and peak plasma concentration of ritonavir by −1% (90% CI, −25% to 31%; range −51% to 136%).Conclusions  Acute dosing of the garlic capsules over 4 days did not significantly alter the single‐dose pharmacokinetics of ritonavir in healthy volunteers. Given the complex effects of both ritonavir and garlic on drug metabolism, the results of our study should not be extrapolated to steady‐state conditions, where the possibility of an interaction still needs to be evaluated.