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Abstract

B. Schneider, R. Gerdsen, J. Plat, S. Dullens, I. Björkhem, U. Diczfalusy, P.J. Neuvonen, T. Bieber, K. von Bergmann and D. Lütjohann

¹Department of Clinical Pharmacology, ²Department of Dermatology, University of Bonn, Germany, ³Department of Human Biology, Maastricht University, Maastricht, The Netherlands, ⁴Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden and ⁵Department of Clinical Pharmacology, University of Helsinki, Finland
Objective: Epidemiological studies have convincingly demonstrated a positive association between LDL-cholesterol (LDL-C) and coronary artery disease but, in the case of HDL-C, there is an inverse association. Administration of high doses of the antifungal agent ketoconazole (800 mg/d) reduces serum concentrations of total cholesterol and LDL-C and there is a tendency for an increase in HDL-C. Our goal was to examine whether high-dose itraconazole raises HDL-C in subjects with normal levels of cholesterol. Patients and methods: 8 male patients with onychomycosis received 2 one-week cycles of treatment with itraconazole at a dose of 400 mg once daily in an open, prospective exploratory trial. Serum levels of itraconazole and its active metabolite hydroxyitraconazole were determined using high-performance liquid chromatography at the end of each treatment cycle. Fasting levels of serum lipoproteins and triglycerides were measured twice using routine enzymatic assays at the beginning and end of each cycle. The effects of itraconazole and hydroxyitraconazole on HDL-C metabolism were assessed in vitro using a human Caco-2 cell line and analyzing apoA-I levels with an enzyme-linked immunosorbent assay. Results: During itraconazole treatment total cholesterol and LDL-C decreased on average by 12% (p < 0.001) and 17% (p < 0.001), respectively, whereas HDL-C increased by 21% (p < 0.001). The ratio LDL : HDL-C, an index of atherogenic risk, decreased by 30% (p < 0.001). Incubation of Caco-2 cells in the presence of itraconazole and hydroxyitraconazole for 3 hours resulted in a significant increase in apoA-I concentration in the medium (913 and 412%, respectively) compared with control. Conclusion: In addition to its inhibitory effect on cholesterol synthesis, high-dose itraconazole (400 mg/d) causes a significant decrease in serum LDL-C and, in contrast to ketoconazole, a significant increase in HDL-C. In vitro studies with Caco-2 cells indicate that the latter observation might be caused by an increase in apoA-I levels.
Correspondence to:
D. Lütjohann, PhD Department of Clinical Pharmacology University of Bonn Sigmund-Freud-Straße 25 53105 Bonn, Germany
Email: dieter.luetjohann@ukb.uni-bonn.de

Abstract

S. Vossler, S. Füllert, F. Schneider, E. Haak, T. Haak, R. Samigullin, H. Tritschler, J.E. Tooke and T. Konrad

¹Institute for Metabolic Research, Academic Institute of the Medical Faculty of Johann Wolfgang Goethe University Frankfurt/Main, ²Research Institute of the Diabetes Academy Mergentheim, Bad Mergentheim, ³MEDA Pharma, Bad Homburg, Germany and ⁴Diabetes and Vascular Medicine, Peninsula Medical School, Exeter, United Kingdom
Objective: Diabetic endotheliopathy is the result of hyperglycemia and the production of oxygen-free radicals. In vitro and in vivo data have shown beneficial effects of dexlipotam (DEX), a tromethamine salt of R(+)-α-lipoic acid, on oxidative stress in hyperglycemic states, but no data are available on the effects of this agent on endothelial function. The purpose of this pilot study was to evaluate the impact of DEX on endothelial function in patients with type 2 diabetes (DM2) and to estimate the safety and tolerability of DEX. Material and methods: DEX 960 mg and DEX 1,920 mg were investigated in DM2 patients over a period of 4 weeks using a randomized, placebo- (PLA) controlled, double-blinded study with 3 parallel groups. The marker of arterial function after 4-week therapy with DEX was the maximum percentage change versus baseline in the flow-mediated dilation of the brachial artery (FMD) after reperfusion. Results: A total of 114 diabetic patients were randomized to the three study groups. DEX was safe and well tolerated. Dyspepsia appeared to be the most relevant side effect of DEX treatment. Systolic (p = 0.078) and diastolic blood pressure (p = 0.059) tended to be lower in patients treated with DEX at a dose of 1,920 mg. There were no significant differences in FMD between the placebo- and the DEX-treated groups. In patients with poorer glucose control (HbA1c > 6.5% Hb), FMD increased significantly after 4-week treatment with DEX: PLA –1.51 ± 2.98%, DEX 960 mg +1.22 ± 3.22, p = 0.027, DEX 1,920 mg +1.47 ± 3.78, p = 0.012. The magnitude of the mean change compared to placebo was 2.73% (DEX 920) and 2.98% (DEX 1,920) in patients with HbA1c > 7.5% Hb (DEX 960, p = 0.007, DEX 1,920, p = 0.032). The effects of treatment were usually statistically significant in subgroups with more severe vascular stress (longer duration of disease, pretreatment history, higher LDL-C, higher blood pressure). Conclusion: DEX therapy appears to reduce endothelial dysfunction in DM2, especially in men with long history of DM2 and having poor glucose control. These findings will be useful in patient selection in future prospective clinical trials with drugs to treat vascular stress.
Correspondence to:
Ass. Prof. Dr. T. Konrad, MD Institute for Metabolic Research Heidelberger Straße 13 60327 Frankfurt/Main, Germany
Email: t.konrad@em.uni-frankfurt.de

Abstract

R. Kaaja, S. Kujala, K. Manhem, P. Katzman, A. Kibarskis, R. Antikainen, H. Ylihärsilä, R. Erkkola and J. Tuomilehto

¹Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, ²Helsinki University, Faculty of Pharmacy, Helsinki, Finland, ³Department of Medicine, Sahlgrenska University Hospital/Östra, Gothenburg, ⁴Department of Internal Medicine, Helsingborgs Lasarett, Helsingborg, Sweden, ⁵Department of Cardiology, Vilnus University, Vilnus, Lithuania, ⁶Oulu City Hospital, Oulu, ⁷Department of Public Health, University of Helsinki, Helsinki, ⁸Diabetes Genetic Epidemiology Unit, National Public Health Institute, Helsinki, and ⁹Department of Obstetrics and Gynecology, University of Turku, Turku, Finland
Cardiovascular risk factors are often ineffectively controlled in hypertensive postmenopausal women, and moreover, some antihypertensive drugs may increase particular risk factors such as insulin resistance. In a multicenter, multinational (Finland, Sweden, Lithuania), double-blind, prospectively randomized study hypertensive obese postmenopausal women without hormone therapy (n = 98) were randomly assigned to receive treatment with either the centrally acting agent moxonidine, 0.6 mg/day, or with the peripherally acting atenolol, 50 mg/day, for 8 weeks. In addition to blood pressure measurements, insulin sensitivity was estimated by the quantitative insulin sensitivity check index (QUICKI) and by the insulin sensitivity index (ISI-Matsuda). Subgroup analysis in insulin-resistant women (fasting P-insulin >= 10 mU/l) and blood pressure responders (diastolic blood pressure <= 90 mmHg and/or reduction of blood pressure >= 10 mmHg) were also carried out. Both atenolol and moxonidine led to a significant reduction in diastolic blood pressure of 9.5 mmHg and 6.2 mmHg, respectively. Among insulin-resistant women, an increase in the insulin sensitivity assessed by ISI was improved with moxonidine treatment (p = 0.025). A decrease in insulin sensitivity assessed by QUICKI was observed with atenolol treatment in women with fasting insulin level < 10 mU/l. In patients, in whom blood pressure was reduced, an improvement in insulin sensitivity (ISI) was associated with moxonidine treatment (p = 0.019), but not with atenolol treatment. The centrally acting sympatholytic agent moxonidine did reduce blood pressure somewhat less than atenolol, but it was associated with an improved metabolic profile in terms of decreased insulin resistance both in insulin-resistant postmenopausal women and in women with a significant blood pressure response.Correspondence to:
R. Kaaja, Associate Professor, MD, PhD Department of Obstetrics and Gynecology Helsinki University Hospital Haartmaninkatu Helsinki, Finland
Email: risto.kaaja@hus.fi

Abstract

J.H. Proost

Department of Pharmacokinetics and Drug Delivery, University Center for Pharmacy, University of Groningen, The Netherlands
Objective: Limited sampling models (LSM) for estimating AUC in therapeutic drug monitoring are usually validated in a separate group of patients, according to published guidelines. The aim of this study is to evaluate the validation of LSM by comparing independent validation with cross-validation using the patient data from the development group. Methods: The design of the Monte Carlo simulation study was similar to a study described in the literature, i.e. a development group of 20 patients receiving cyclosporine orally every 12 h. Blood samples were taken at 10 fixed time points. In total 20,000 patient data sets were generated by Monte Carlo simulation, taking into account interindividual variability and measurement errors. Accuracy (mean error, ME) and precision (root mean squared error, RMSE) were calculated for evaluation of the validation procedures, varying the time points of the samples used for the estimation of AUC to identify the optimal sampling time points. In addition, the influence of the number of samples and the number of subjects was investigated. Results: Cross-validation resulted in values for ME and RMSE almost identical to values using a separate validation group with the same number of subjects as the development group. Conclusion: A separate validation group is not needed. The most efficient method is to use all patient data for the development of the LSM, and to assess the accuracy and precision by cross-validation.Correspondence to:
Dr. J.H. Proost
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
Email: j.h.proost@rug.nl

Abstract

J.K. Coller, C. Joergensen, D.J.R. Foster, H. James, D. Gillis, L. Christrup and A.A. Somogyi

¹Discipline of Pharmacology, University of Adelaide, Australia, ²Department of Pharmacology and Pharmacotherapy, Danish University of Pharmaceutical Sciences, Copenhagen, Denmark, ³School of Pharmacy and Medical Sciences, University of South Australia, ⁴Division of Human Immunology, Institute of Medical and Veterinary Sciences and ⁵Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, Australia
Objective: To investigate the influence of CYP2D6 genotype on the oral clearance of (R)-, (S)- and rac-methadone. Methods: In this retrospective study, CYP2D6 genotypes were identified in 56 methadone maintained subjects. Plasma concentrations of (R)-, (S)- and rac-methadone were determined by stereoselective HPLC and sufficient data were available to estimate the apparent oral clearances of (R)-, (S)- and rac-methadone using a population kinetic model in 37 of the genotyped subjects. Results: The CYP2D6 allele frequencies were similar to those previously reported in Caucasians, the most common being: CYP2D6*1 (35.2%), CYP2D6*2 (12.0%) and CYP2D6*4 (22.2%). Three unknown SNPs were found in four subjects: 1811G > A (n = 1), 1834C > T (n = 1) and 2720G > C (n = 2). The oral clearances of (R)-, (S)- and rac-methadone varied 5.4-, 6.8- and 6.1-fold, respectively. No significant differences in methadone oral clearance were found between CYP2D6 genotypic PM, IM and EM (p = 0.57, 0.40 and 0.43 for (R)-, (S)- and rac-methadone, respectively). Only 1 subject had duplication of functional CYP2D6 alleles and the oral clearance of the three analytes was not markedly altered. Conclusions: CYP2D6 poor, intermediate and extensive metabolizer genotypes did not appear to impact on the oral clearance of (R)-, (S)- or rac-methadone. In addition, methadone dosage requirements were not influenced by CYP2D6 genotypes in these subjects. However, the impact of duplication of functional CYP2D6 alleles on oral clearance and dosage requirements requires further investigation.Correspondence to:
Dr. J.K. Coller Discipline of Pharmacology, Level 5 Medical School North University of Adelaide Adelaide SA 5005, Australia
Email: janet.coller@adelaide.edu.au

Abstract

Y.-X. Chen, B. Cabana, N. Kivel, H. Pieniaszek, S. Gilman and A. Michaelis

¹ActivBiotics, Inc., Lexington, MA, ²HPP Consulting and Services, Inc., Darlington, MD, USA
Rifalazil, a second-generation rifamycin, is being evaluated for the treatment of sexually transmitted disease and gastrointestinal infections. We determined whether rifalazil influences CYP3A4 metabolism by studying the effect of a single oral, 25 mg dose of rifalazil administered to healthy postmenopausal women, on the steady-state pharmacokinetics (PK) of ethinyl estradiol (EE) during administration of Ortho-Novum 1/35 (EE/NET). Noncompartmental PK and sequential statistical analyses were performed to establish if and when subjects achieved steady-state EE plasma concentrations and to determine whether this steady state was altered by rifalazil administration. The geometric mean ratios for the difference between EE alone and following rifalazil for EE Cmax, AUC(0-24) and Cmin were 105.9, 104.4 and 105.0, respectively. The 90% confidence intervals for each ratio fell within 80 – 125% of the reference treatment indicating no significant difference in the PK of EE before or after rifalazil administration. The posterior probabilities for the true treatment differences of Cmax or AUC(0-24) being less than 20% were > 99.99% in both cases. Based on the results of this study, there is no CYP3A4-metabolic interaction between a single oral, 25 mg dose of rifalazil and EE for either induction or inhibition. Consequently, there is minimal threat of contraceptive failure when single doses of rifalazil are administered with EE/NET. A single dose of rifalazil 25 mg was well tolerated when administered concomitantly with a combination oral contraceptive (EE/NET) by healthy postmenopausal females.Correspondence to:
Y. Chen, PhD
Millennium Pharmaceuticals Inc.
35 Landsdowne Street
Cambridge, MA 02139, USA
Email: Ying.Chen@MPI.com

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Volume 45, No. 7/2007(July)