Volume 41, No. 12/2003(December)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Meta-analysis
Use of statins in primary and secondary prevention of coronary heart disease and ischemic stroke. Meta-analysis of randomized trials
Abstract
M. Vrecer, S. Turk, J. Drinovec and A. Mrhar
1Krka, Novo mesto and 2Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
Objective: To estimate the relative risk reduction of the clinical outcomes (coronary events, strokes, cardiovascular, non-cardiovascular and all-cause mortality) associated with statin therapy in primary and secondary prevention. Data sources: A literature search of the Medline and Cohrane databases for articles published from 1985 to July 2002 was performed. The data on systematic reviews and preliminary reports were also included in this study. Primary and secondary prevention trials and regression trials were eligible. Data extraction and statistical method: Data were extracted by 2 authors according to the defined inclusion criteria. Disagreements were resolved by consensus or by a third reviewer. Testing for heterogeneity was applied and on the basis of these results a fixed effect model or a random effect model was used for calculation of relative risk values (RR) and 95% confidence intervals (95% CI). Sensitivity analysis tested the impact of the individual study – duration of study, type of statin therapy and study size. The number of patients needed to treat was calculated as an absolute measure of clinical effectiveness of statin therapy when appropriate. Results: Data from 15 trials with 63,410 participants and mean duration of treatment of 3.6 years, were included in this overview. Tests for heterogeneity showed that the variability between study estimates is sufficiently small to assume that they are estimating the same underlying treatment effect. Statin therapy was associated with a 22% reduction in total cholesterol, 29% reduction in LDL cholesterol, 12% reduction in triglycerides and 6% increase in HDL cholesterol. Overall (primary and secondary studies) statin therapy significantly reduces relative risk of coronary events (RR, 0.73, 95% CI, 0.68, 0.77, *p < 0.0001), relative risk of cardiovascular disease mortality (RR, 0.78, 95% CI, 0.73, 0.84, *p < 0.0001), relative risk of non-fatal stroke (RR, 0.74, 95% CI, 0.67, 0.82, *p < 0.0001), relative risk of total (fatal and non-fatal) stroke (RR, 0.77, 95% CI, 0.70, 0.84, *p < 0.001) and relative risk of all-cause death (RR, 0.85, 95% CI, 0.81, 0.89, *p < 0.0001). There was a slight and insignificant reduction of relative risk in non-cardiovascular mortality (RR, 0.94, 95% CI, 0.86, 1.03, p = 0.1677) and fatal strokes (RR, 0.86, 95% CI, 0.70,1.07, p = 0.1912). Sensitivity analysis showed the robustness of our results for all outcomes. The results were not altered if an individual study was removed from meta-analysis. Conclusions: This overview indicates that statin treatment reduces the relative risk of occurrence of coronary events, cardiovascular disease mortality, non-fatal strokes and all-cause mortality. While secondary prevention with statins provides considerable improvement of cardiovascular morbidity/mortality, primary prevention with statins provides only small and clinically hardly relevant improvement of cardiovascular morbidity/mortality.
PK-PD evaluation
Serum carvedilol concentration and its relation to change in plasma brain natriuretic peptide level in the treatment of heart failure: a preliminary study
Abstract
H. Konishi, S. Nishio, T. Tsutamoto, T. Minouchi and A. Yamaji
1Department of Hospital Pharmacy, and 2Department of Cardiology,
Shiga University of Medical Science, Otsu, Japan
Objective: To examine the influence of carvedilol dose and concentration in serum on plasma brain natriuretic peptide (BNP), a measure of heart failure progression. Methods: 12 patients with New York Heart Association (NYHA) functional class II – III chronic heart failure were enrolled in the study. They received carvedilol at daily doses of 1 – 20 mg with a 1 – 2 weekly adjustment. Serum carvedilol trough concentrations were measured in steady-state using a specific fluorescence HPLC method. The degree of improvement in heart failure was assessed from the ratio of change in the plasma BNP concentration, 2 weeks, 1 month and 3 months after the commencement of carvedilol administration. Results: From the pharmacokinetic aspect, there was no valid correlation between the trough serum carvedilol concentration (Cmin) and daily dose per body weight (Dd/BW), indicating that there was a wide difference in the carvedilol elimination capacity among individuals. A significant decrease in the BNP was observed at the 3rd month in patients treated with the high dose (> 750 mg/3 months). On the other hand, in patients with a mean serum carvedilol level (Cmin) of less than 2.5 nmol/l up to 2 weeks after the start of carvedilol therapy, the degree of reduction in the BNP value after the 3rd month was significantly larger, relative to the patient group with Cmin over 2.5 nmol/l. Conclusions: The total carvedilol dose was confirmed to be one of the determinants for improvement in heart failure, and it was suggested that the initial serum level also plays an important role in therapeutic outcome. Therefore, it may be important to monitor the serum carvedilol level at the introductory period to determine the daily dose requirements because of the wide inter-individual variability in its metabolic clearance.
Vitamin E
Vitamin E and its effect on arterial stiffness in postmenopausal women – a randomized controlled trial
Abstract
A.H.G. Rasool1, A. Rehman2, W.N. Wan Yusuf1 and A.R.A. Rahman3
1School of Medical Sciences, 2School of Dental Sciences, and 3Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kelantan, Malaysia
Introduction: Arterial stiffness is emerging as a useful index of vascular health. Postmenopausal women have been shown to have stiffer arteries. Hormone replacement therapy and soy isoflavones improve arterial stiffness in these women. The aim of this study is to establish whether vitamin E improves arterial stiffness in postmenopausal women after 10 weeks of supplementation. Methods: Twenty postmenopausal women with a mean age of 54.59 ± 1.22 years participated in this randomized, crossover, double-blind, placebo-controlled clinical trial. All women received 400 IU of tocopherol daily for 10 weeks or a placebo capsule, before being crossed over for treatment. At intervals of 5 weeks, subjects attended sessions where measurements of arterial stiffness, blood pressure and plasma vitamin E level were taken. Pulse wave velocity measurement, using the automated Complior machine, was used as an index of arterial stiffness. Results: Plasma vitamin E level was 30.38 ± 1.56 mmol/l at baseline, after treatment it was 59.01 ± 3.30 mmol/l and 31.17 ± 1.37 mmol/l with vitamin E and placebo, respectively (p < 0.001). There was no significant difference in pulse wave velocity after 10-week treatment with placebo and vitamin E (9.14 ± 0.29 versus 9.04 ± 0.29 m/s, respectively). Similarly, no difference in systolic and diastolic blood pressure was seen between placebo and vitamin E at the end of 10 weeks. Conclusion: Supplementary vitamin E for 10 weeks at 400 IU daily has no effect on arterial stiffness in healthy postmenopausal women.
Bioavailability section
Comparative bioavailability of silibinin in healthy male volunteers
Abstract
Y.C. Kim, E.J. Kim, E.D. Lee, J.H. Kim, S.W. Jang, Y.G. Kim, J.W. Kwon, W.B. Kim and M.G. Lee
1College of Pharmacy and Research Institute of Pharmaceutical Sciences,
Seoul National University, Seoul, 2Research Laboratory, Dong-A Pharmaceutical Company, Yongin, and 3Department of Pharmacology, School of Medicine, Dankook University, Chunan, Korea
Aim: To study a comparative bioavailability of Liverman capsule to Legalon capsule and Silymarin tablet (which contain silibinin) in 24 healthy volunteers. Volunteers and methods: Twenty-four healthy male Korean volunteers received each medicine at the silibinin dose of 120 mg in a 3 × 3 crossover study. There was a 1-week washout period among the doses. Plasma concentrations of silibinin were monitored by a high-performance liquid chromatography for over a period of 12 hours after the administration. AUCinf (the area under the plasma concentration-time curve from time zero to time infinity) was calculated by the trapezoidal rule extrapolation method. Cmax (maximum plasma drug concentration) and tmax (time to reach a Cmax) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUCinf, AUC0-12h, and Cmax and untransformed tmax. Results: After an oral administration of Liverman capsule, the pharmacokinetic parameters of silibinin, such as AUC0-12h (5.59, 4.24 and 13.9 mg/ml × h for Legalon capsule, Silymarin tablet and Liverman capsule, respectively) and AUCinf (6.00, 4.63 and 15.1 mg/ml × h) were significantly greater, Cmax (1.33, 1.13 and 6.04 mg/ml) was significantly higher and tmax (1.83, 2.10 and 0.875 h) was significantly faster than those after Legalon capsule and Silymarin tablet. Conclusion: These results indicate that the absorption and the extent of relative oral bioavailability of silibinin after Liverman capsule were significantly faster and greater, respectively, than those after Legalon capsule and Silymarin tablet.
Extended Abstracts
Preface
Extended Abstracts
The influence of liver metastases on the pharmacokinetics of doxorubicin – a population-based pharmacokinetic project of the CESAR-APOH
Abstract
H.J. Müller, R.E. Port, M. Grubert, R.A. Hilger, M. Scheulen and K. Mross
Extended Abstracts
Surrogate marker in clinical studies with anti-angiogenic drugs
Abstract
U. Zirrgiebel and J. Drevs
Extended Abstracts
DCE-MRI in clinical trials: data acquisition techniques and analysis methods
Abstract
R. Strecker, K. Scheffler, M. B
Extended Abstracts
Cerebrospinal fluid pharmacokinetics after different dosage regimens of intraventricular etoposide
Abstract
C. Sirisangtragul, G. Henke, G. Fleischhack, S. Reif, C. Kloft, U. Bode and U. Jaehde
Extended Abstracts
Two schedules of application for mesna and their influence on the thiol-metabolism
Abstract
B. Kempgens, J. Kisro, Y. Gruber, H. Bahrs and T. Wagner
Extended Abstracts
The role of hepatic Mrp2 in the interaction of flavopiridol and bilirubin: impact on therapy
Abstract
W. Jäger, E. Gehring, B. Hagenauer, S. Aust, A. Senderowicz and T. Thalhammer
Extended Abstracts
Assessment of platinum sensitivity human tumor cells
Abstract
J. Zisowsky, A. Becker, S. Weykam, M. Kassack and U. Jaehde
Extended Abstracts
Circadian rhythm in the regulation of the MAP kinase pathway – pitfall in the determination of surrogate parameters?
Abstract
R.A. Hilger, D. Díaz-Carballo, S. Bauer, S. Kredtke, M.E. Scheulen, S. Seeber and D. Strumberg
Extended Abstracts
Antitumor effect and potentiation or reduction in cytotoxic drug activity in human colon carcinoma cells by the Raf kinase inhibitor (RKI) BAY 43-9006
Abstract
M. Heim, M. Sharifi, R.A. Hilger, M.E. Scheulen, S. Seeber and D. Strumberg
Extended Abstracts
Drug-drug interaction pharmacokinetic study with the Raf kinase inhibitor (RKI) BAY 43-9006 administered in combination with irinotecan (CPT-11) in patients with solid tumors
Abstract
K. Mross, S. Steinbild, F. Baas, M. Reil, P. Buss, S. Mersmann, D. Voliotis, B. Schwartz and E. Brendel
Extended Abstracts
A phase I clinical and pharmacokinetic study of the Raf kinase inhibitor (RKI) BAY 43-9006 administered in combination with doxorubicin in patients with solid tumors
Abstract
H. Richly, P. Kupsch, K. Passage, M. Grubert, R.A. Hilger, S. Kredtke, D. Voliotis, M.E. Scheulen, S. Seeber and D. Strumberg
Extended Abstracts
Novel antitumoral compound isolated from Clusia rosea
Abstract
D. Díaz-Carballo, S. Seeber, D. Strumberg and R.A. Hilger
Extended Abstracts
Gene expression profiling of colon cancer reveals a broad molecular repertoire in 5-fluorouracil resistance
Abstract
W.M. Schmidt, M. Kalipciyan, E. Dornstauder, B. Rizovski, R. Sedivy, G.G. Steger, M.W. Müller and R.M. Mader
Extended Abstracts
Errata
