bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inter‐ethnic comparisons of the pharmacokinetics of the HMG‐CoA reductase inhibitor cerivastatin
Authors: Mück W. , Unger S. , Kawano K. , Ahr G. 
Published: March 2003

Aims
During the world‐wide clinical development of the HMG‐CoA reductase inhibitor cerivastatin, pharmacokinetic data have been collected from studies performed in Europe, North America and Japan, covering different ethnic groups, mainly Caucasians and Japanese subjects, but also Black and Hispanics. The aim of the present investigation was to search for any inter‐ethnic differences in cerivastatin pharmacokinetics.
Methods
All concentration data were assessed by fully validated specific h.p.l.c. assays employing post‐column photochemical derivatization with ultra‐violet light and subsequent fluorescence detection. The comparability of analytical results was guaranteed by cross‐validations between all analytical laboratories. The inter‐ethnic comparison was based on retrospective analysis of the overall pharmacokinetic data pool (n=340 complete profiles) in the key parameters AUC, Cmax, tmax and t1/2, assessed via non‐compartmental methods.
Results
Based on the comparison of selected individual single‐ and multiple‐dose escalation studies in healthy young males, performed when starting the clinical development, exposure and disposition of the parent compound and its cytochrome P450‐mediated biotransformation products M‐1 and M‐23, and amounts of metabolites M‐1, M‐23 and M‐24 excreted in urine were comparable for US Americans, mainly Caucasians, and Japanese. Retrospective analysis of the complete pharmacokinetic data pool revealed that there are no statistically significant differences in dose‐normalized AUC‐ and Cmax‐values. The respective ratios of weight‐adjusted geometric least‐squares (LS) means (95% confidence intervals) between Japanese and Caucasians were: for AUCdose‐norm 0.96 (0.86–1.08) for single dose, and 1.04 (0.86–1.24) for multiple dose; for Cmax,dose‐norm 0.93 (0.83–1.05) for single dose, and 1.01 (0.82–1.25) for multiple dose. Half‐life was slightly, but statistically significantly shorter in Japanese than in Caucasian subjects following single dose: ratios (95% CI) were 0.68 (0.61–0.77) for single dose, and 1.00 (0.79–1.26) for multiple dose. Times to peak tended to be slightly greater in Japanese: differences of weight‐adjusted LS means (95% CI) were 0.60 h (0.28 h—0.92 h) for single dose, and 1.15 h (0.48 h—1.81 h) for multiple dose. Black and Hispanics did not differ in their pharmacokinetic characteristics from Caucasians.
Conclusions
Based on inter‐study comparisons and a retrospective analysis of the complete PK data pool there is no evidence for any clinically relevant inter‐ethnic differences in cerivastatin pharmacokinetics in Caucasians, Black and Japanese subjects after oral therapeutic doses.
A placebo‐controlled study of interaction between nabumetone and acenocoumarol
Authors: Pardo  , García‐Losa  , Fernández‐Pavón  , Del Castillo  , Pascual‐García  , García‐Méndez  , Dal‐Ré  
Published: March 2003

Aims The use of nonsteroidal anti‐inflammatory drugs (NSAIDs) in patients treated with oral anticoagulants is generally discouraged due to the risk of interactions that could increase the risk of bleeding complications. Available data suggest the NSAID, nabumetone, does not produce such an interaction. We investigated whether nabumetone would interact with acenocoumarol, an oral anticoagulant widely used in some European countries.Methods A double‐blind, randomized, placebo‐controlled study was conducted evaluating nabumetone (1–2 g daily for up to 4 weeks) in osteoarthritis patients with thromboembolic risk previously stabilized on acenocoumarol. The primary efficacy end point was the proportion of patients whose International Normalized Ratio (INR) remained within established margins and whose acenocoumarol dose was not changed. Fifty‐six patients were randomized to receive nabumetone (n=27) or placebo (n=29).Results Eighteen patients in each group (67% for nabumetone and 62% for placebo) completed the study without showing INR or acenocoumarol dose changes, and were considered as study successes. Nine patients (33%) with nabumetone and 11 (38%) with placebo were considered study failures in the intention‐to‐treat analysis (one patient on nabumetone and four on placebo did not complete the study due to reasons not related to INR and acenocoumarol dose changes). No significant differences were found between groups with regard to study successes. There were two minor bleeding complications, one in each group. Six patients per group presented with eight adverse experiences in each group.Conclusions Treatment with nabumetone did not alter INR levels compared with placebo in patients stabilized on oral acenocoumarol who require NSAID therapy. These results suggest that nabumetone does not produce a clinically relevant interaction with acenocoumarol. In orally anticoagulated patients without other associated risk factors, treatment with nabumetone for up to 4 weeks does not require increased monitoring of INR levels.
Auditory and electroencephalographic effects of midazolam and α‐hydroxy‐midazolam in healthy subjects
Authors: Hotz Michel A. , Ritz Rudolf , Linder Lilly , Scollo‐Lavizzari Giuseppe , Haefeli Walter E. 
Published: March 2003

Aims Whereas cortical EEG effects of benzodiazepines are well characterized, information about benzodiazepine effects in other areas of the central nervous system is sparse. This study investigated the action of midazolam and its active metabolite α‐hydroxy‐midazolam on different parts of the auditory pathway in six healthy volunteers in a randomized, double‐blind, three‐way cross‐over study. Methods Acoustically evoked short (SLP) and middle (MLP) latency potentials, transitory evoked otoacoustic emissions (TEOAE), and EEG power spectra were analysed after short i.v. injections of placebo, or 0.15 mg kg−1 midazolam, or α‐hydroxy‐midazolam, respectively. Results All subjects fell asleep during the 4 min infusion of active drug. SLP showed a significant transient increase of Jewett wave V 10 min after injection for midazolam and α‐hydroxy‐midazolam while the latency of wave I was unchanged. Both benzodiazepines induced a marked and long‐lasting MLP amplitude decrease for 240 min with slow recovery over the following 360 min. No changes of TEOAE were observed. In agreement with earlier reports, increases in EEG beta activity and decreases in alpha activity were observed after administration of either drug. Conclusions Systemically administered benzodiazepines modulate the auditory pathway above the level of the cochlea. While SLP changes were closely associated with sedation and high plasma benzodiazepine concentrations, MLP effects persisted for hours after sedation even at low benzodiazepine plasma levels. Evoked potentials may therefore be more sensitive than EEG as a tool to monitor benzodiazepine effects.
Dramatic inhibition of amiodarone metabolism induced by grapefruit juice
Authors: Libersa, Christian C. , Brique Serge A. , Motte Kokou B. , Caron Jacques F. , Guédon‐moreau Laurence M. , Humbert Luc , Vincent A. , Devos Patrick , Lhermitte Michel A. 
Published: March 2003

Aims  Grapefruit juice increases blood concentrations of many drugs metabolized by CYP3A. Amiodarone is metabolized by CYP3A to N‐desethylamiodarone (N‐DEA). The aim of this study was to determine amiodarone kinetics when administrated with and without grapefruit juice.Methods  Eleven healthy adult volunteers took part in a single sequence, repeated‐measures design study. Each subject, who had been evaluated 6 months previously for amiodarone pharmacokinetics, was given a single oral dose of amiodarone (17 mg kg−1) with three glasses of 300 ml of grapefruit juice on the same day.Results  Grapefruit juice completely inhibited the production of N‐DEA, the major metabolite of amiodarone, in all subjects and increased the area‐under‐the‐curve (AUC) and maximum concentration of amiodarone (Cmax) by 50% and 84%, respectively, as compared with the control period during which water had been administrated instead of grapefruit juice (AUC: 35.9 ± 14.3 vs 23.9 ± 11.2 µg ml−1 h, P < 0.005 and Cmax: 3.45 ± 1.7 vs 1.87 ± 0.6 µg ml−1, P < 0. 02, respectively) (means ± s.d.). This inhibition of N‐DEA production led to a decrease in the alterations caused by amiodarone on PR and QTc intervals.Conclusions  Grapefruit juice dramatically alters the metabolism of amiodarone with complete inhibition of N‐DEA production. These results are in agreement with in vitro data pointing to the involvement of CYP3 A in the metabolism of amiodarone and suggests that this interaction should be taken into account when prescribing this antiarrhythmic drug.
Lack of adherence to lipid‐lowering drug treatment. A comparison of utilization patterns in defined populations in Funen, Denmark and Bologna, Italy
Authors: Larsen John , Vaccheri Alberto , Andersen Morten , Montanaro Nicola , Bergman Ulf 
Published: March 2003

Aims The objective was to explore differences in lipid‐lowering drug (LLD) prescribing in Italy and Denmark.Methods We used two geographical areas with computerized drug prescription records in defined populations, one in Funen, Denmark with 500 000 inhabitants, the other in Bologna, Italy with 400 000 inhabitants. Prescriptions for patients who had purchased a LLD from 1994 until 1996 were retrieved as well as coprescriptions of antidiabetic and cardiovascular drugs as markers for diabetes and cardiovascular disease. Only patients surviving and remaining in the area were included. Compliance was defined as percentage of DDDs purchased divided by the number of days within the time window. The limit between good and poor compliance was set at 82%.Results In Bologna, LLD consumption measured in DDD increased by 41% and in Funen by 129%. Annual prevalence increased from 36.9 to 46.3 users/1000 inhabitants from 1994 to 1996 and from 3.2 to 6.6 users/1000 inhabitants in Bologna and Funen, respectively. From 1995 to 1996, the incidence of use decreased slightly in Bologna from 19.3 to 18.8/1000 inhabitants/year, whereas in Funen the incidence increased from 1.8 to 2.3/1000 inhabitants/year. In Bologna 48% and in Funen 91% of users persisted with treatment for 2 years or longer. In Bologna, 7% and in Funen 45% were good compliers. In Bologna, 61% and in Funen, 72% received other drugs indicating cardiovascular or diabetic comorbidity.Conclusions Patterns of use differed substantially between the two areas. In contrast with Funen, where long‐term use was common, Bologna LLD use was sporadic. Based on a higher rate of coprescription, LLDs seemed to be used for secondary prevention to a higher extent in Funen than in Bologna. In Funen it appeared that the correct patients, but an insufficient number of them, were being treated adequately according to guidelines. The higher discontinuation rate of lipid lowering drugs in the Bologna area indicates that a large proportion of patients use these drugs for too short a period of time to benefit from treatment. Since society’s health care resources are limited it is difficult to justify public funding of these medications without at the same time giving appropriate attention to these problems.
Validation of a population pharmacokinetic model for adjunctive lamotrigine therapy in children
Authors: Chen Chao 
Published: March 2003

Aims
This analysis was performed to validate a previously developed population pharmacokinetic model for lamotrigine in order to establish a basis for dosage recommendations for children.
Methods
(a) The importance of the covariates in the final model was confirmed using the model validation dataset. Population and individual (Bayesian estimate) pharmacokinetic parameters were estimated using both the initial model, which included none of the covariates, and the final model. Accuracy and precision of parameter estimation and of concentration prediction were compared between the two models. (b) The performance in predicting the validation concentrations by the final model parameters obtained previously from the model development dataset was assessed. (c) The parameters of the final model were refined using a dataset combining both the development and validation data.
Results
Prediction performance of the final pharmacostatistical model was superior to that of the initial model. The results of the validation confirmed that concomitant antiepileptic drugs that increased or reduced lamotrigine clearance in adults had similar effects in children. The validation also verified the linear relationship between weight and clearance. The previously seen small sex effect on clearance was found statistically insignificant.
Conclusions
The current analysis confirmed the previous findings. To achieve the same concentrations, children receiving enzyme‐inducing antiepileptic drugs without valproate require higher doses than those receiving valproate; and heavier children require higher doses.
Effects of a medicine review and education programme for older people in general practice
Authors: Lowe Catherine J. , Raynor David K. , Purvis John , Farrin Amanda , Hudson Jocelyn 
Published: March 2003

Aims
To determine whether a medicine review and education programme influences the compliance and knowledge of older people in general practice.
Methods
Older people taking at least three medicines were randomly allocated to a control or intervention group. Both groups received three visits from a clinical pharmacist:Visit 1: Assessment and patients' medicines rationalized in intervention group.Visit 2: Intervention group given medicines education.Visit 3: Knowledge and compliance in both groups assessed by structured questionnaire
Results
Compliance in the intervention group was 91.3%, compared with 79.5% in the control group (P < 0.0001). The number of intervention group patients correctly understanding the purpose of their medicines increased from 58% to 88% on the second visit, compared with 67% to 70% in the control group (P < 0.0005).
Conclusions
A general practice based medication review and education programme improved medicine compliance and knowledge of older people in the short term.
Effects of policosanol treatment on the susceptibility of low density lipoprotein (LDL) isolated from healthy volunteers to oxidative modification in vitro
Authors: Menéndez Roberto , Más Rosa , Amor Ana MA. , González Rosa MA. , Fernández Julio C. , Rodeiro Idania , Zayas Mirta , Jiménez Sonia 
Published: March 2003

Aims
The aim of this study was to investigate the effect of policosanol on the susceptibility of LDL‐C to in vitro lipid peroxidation in human healthy volunteers.
Methods
The effect of policosanol (5 and 10 mg day−1) on LDL‐C oxidation was studied in a double‐blind, randomized, placebo‐controlled trial conducted in 69 subjects. LDL‐C samples isolated at baseline and after 8 weeks were subjected to in vitro tests of LDL‐C oxidation. We tested the susceptibility of LDL‐C to lipid peroxidation in a cell‐free system by the addition of copper ions as well as in a more physiological system, macrophage‐mediated oxidation.
Results
At baseline all groups were well matched regarding all variables. After 8 weeks of therapy policosanol administered at 5 and 10 mg, significantly and in a dose‐dependent manner increased the lag phase of conjugated diene generation (mean ± s.d.) from 83.79 ± 29.16 min to 94.90 ± 25.50 min (5 mg day−1) and from 82.74 ± 17.16 min to 129.89 ± 35.71 min (10 mg day−1), while in the placebo group LDL‐C oxidation did not change significantly. Policosanol (10 mg day−1), but not placebo, significantly decreased the rate of conjugated diene generation. Comparison with placebo after therapy also showed significant differences. Macrophage mediated‐oxidation was also inhibited by policosanol as evident by measuring thiobarbituric acid reactive substances (TBARS). Policosanol (10 mg day−1) significantly lowered malondialdehyde (MDA) generation from 8.50 ± 0.91 to 5.76 ± 1.01 nmol mg−1 protein. Comparison with placebo after 5 and 10 mg day−1 showed significant differences. Policosanol significantly lowered total cholesterol by 10.5% (5 mg day−1) and 12.4% (10 mg day−1) and LDL‐C by 16.7% and 20.2%, respectively. Also, policosanol (10 mg day−1) increased HDL‐C by 15.2%. Five subjects withdrew from the study, none because of adverse experiences. No clinical or blood biochemical drug‐related disturbances were found.
Conclusions
The present study demonstrated that policosanol administered within its therapeutic dosage for lowering cholesterol (5 and 10 mg day−1), decreased the susceptibility of LDL‐C to lipid peroxidation in vitro.
In vitro evaluation of potential in vivo probes for human flavin‐containing monooxygenase (FMO): metabolism of benzydamine and caffeine by FMO and P450 isoforms
Authors: Lang Dieter H. , Rettie Allan E. 
Published: March 2003

Aims
To determine the FMO and P450 isoform selectivity for metabolism of benzydamine and caffeine, two potential in vivo probes for human FMO.
Methods
Metabolic incubations were conducted at physiological pH using substrate concentrations of 0.01–10 m
m with either recombinant human FMOs, P450s or human liver microsomes serving as the enzyme source. Products of caffeine and benzydamine metabolism were analysed by reversed‐phase h.p.l.c. with u.v. and fluorescence detection.
Results
CYP1A2, but none of the human FMOs, catalysed metabolism of caffeine. In contrast, benzydamine was a substrate for human FMO1, FMO3, FMO4 and FMO5. Apparent Km values for benzydamine N‐oxygenation were 60 ± 8 µm, 80 ± 8 µm, > 3 m
m and > 2 m
m, for FMO1, FMO3, FMO4 and FMO5, respectively. The corresponding Vmax values were 46 ± 2 min−1, 36 ± 2 min−1, < 75 min−1 and < 1 min−1. Small quantities of benzydamine N‐oxide were also formed by CYPs 1A1, 1A2, 2C19, 2D6 and 3A4.
Conclusions
FMO1 and FMO3 catalyse benzydamine N‐oxygenation with the highest efficiency. However, it is likely that the metabolic capacity of hepatic FMO3 is a much greater contributor to plasma levels of the N‐oxide metabolite in vivo than is extrahepatic FMO1. Therefore, benzydamine, but not caffeine, is a potential in vivo probe for human FMO3.
Benzydamine N‐oxidation as an index reaction reflecting FMO activity in human liver microsomes and impact of FMO3 polymorphisms on enzyme activity
Authors: Störmer Elke , Roots Ivar , Brockmöller Jürgen 
Published: March 2003

Aims  The role of flavin containing monooxygenases (FMO) on the disposition of many drugs has been insufficiently explored. In vitro and in vivo tests are required to study FMO activity in humans. Benzydamine (BZD) N‐oxidation was evaluated as an index reaction for FMO as was the impact of genetic polymorphisms of FMO3 on activity.
Methods
BZD was incubated with human liver microsomes (HLM) and recombinant enzymes. Human liver samples were genotyped using PCR‐RFLP.
Results

BZD N‐oxide formation rates in HLM followed Michaelis‐Menten kinetics (mean Km = 64.0 µm, mean Vmax= 6.9 nmol mg−1 protein min−1; n = 35). N‐benzylimidazole, a nonspecific CYP inhibitor, and various CYP isoform selective inhibitors did not affect BZD N‐oxidation. In contrast, formation of BZD N‐oxide was almost abolished by heat treatment of microsomes in the absence of NADPH and strongly inhibited by methimazole, a competitive FMO inhibitor. Recombinant FMO3 and FMO1 (which is not expressed in human liver), but not FMO5, showed BZD N‐oxidase activity. Respective Km values for FMO3 and FMO1 were 40.4 µm and 23.6 µm, and respective Vmax values for FMO3 and FMO1 were 29.1 and 40.8 nmol mg−1 protein min−1. Human liver samples (n = 35) were analysed for six known FMO3 polymorphisms. The variants I66M, P135L and E305X were not detected. Samples homozygous for the K158 variant showed significantly reduced Vmax values (median 2.7 nmol mg−1 protein min−1) compared to the carriers of at least one wild type allele (median 6.2 nmol mg−1 protein min−1) (P < 0.05, Mann–Whitney‐U‐test). The V257M and E308G substitutions had no effect on enzyme activity.
Conclusions

BZD N‐oxidation in human liver is mainly catalysed by FMO3 and enzyme activity is affected by FMO3 genotype. BZD may be used as a model substrate for human liver FMO3 activity in vitro and may be further developed as an in vivo probe reflecting FMO3 activity.
The pharmacokinetics of methadone in HIV‐positive patients receiving the non‐nucleoside reverse transcriptase inhibitor efavirenz
Authors: Clarke Susan M. , Mulcahy Fiona M. , Tjia John , Reynolds Helen E. , Gibbons Sara E. , Barry Michael G. , Back David J. 
Published: March 2003

Aims  Methadone is predominantly metabolized by cytochrome P450 3A4 and the non nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz is a recognized inducer of this enzyme. We evaluated the pharmacokinetics of methadone in the presence and absence of efavirenz when administered to HIV infected patients with a history of injection drug use (IDU).Methods  Eleven patients on stable methadone maintenance therapy, due to commence antiretroviral therapy (ART), participated in this study. Steady state methadone kinetic profiles were obtained on two occasions 0, 1, 2, 3, 4, 5, 6, 7, 8 and 24 h post dosing. Following centrifugation, separated plasma was heated at 58 °C for 30 min to inactivate HIV and stored at −80 °C until methadone analysis by high performance liquid chromatography.Results  When combined with efavirenz there was a marked decrease in the maximum plasma concentration (Cmax) of methadone from 689 (range 212–1568) to 358 (range 205–706) ng ml−1, P = 0.007 : 95% confidence interval (CI) 112–549. The mean area under the methadone concentration curve 0–24 h (AUC(0,24 h)) was also significantly reduced from 12341 (range 3682–34147) to 5309 (range 2430–10349) ng ml−1 h in the presence of efavirenz, P = 0.012 : 95% CI 1921–12143. Nine patients described symptoms of methadone withdrawal and received a dose increase. Although methadone AUC(0,24 h) was reduced by over 50% following efavirenz the mean increase in methadone dose required was 22% (range 15–30 mg).Conclusion  The inclusion of the NNRTI efavirenz in once daily ART for HIV patients with a history of IDU receiving methadone maintenance results in a significant reduction in methadone plasma concentrations mediated by enzyme induction. It is important to distinguish efavirenz neurological effects which were observed between days 1–5 of therapy from symptoms of methadone withdrawal which occurred from day 8 onwards. The dose of methadone was adjusted by increments of 10 mg to counteract the efavirenz inducing effect.