Volume 38, No. 5/2000(May)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Overview
Trospium chloride: an effective option for medical treatment of bladder overactivity
I. Füsgen and D. Hauri
Abstract
I. Füsgen1 and D. Hauri2
1Department of Geriatric Medicine, University of Witten/Herdecke, Velbert, Germany, and 2Department of Urology, University of Zürich, Zürich, Switzerland
This article provides an overview on pharmacological and clinical trials with trospium chloride (TCl) in the treatment of urinary incontinence. A total of 19 clinical trials and post-marketing surveillance studies including more than 10,000 patients is reported. Selected pharmacological and clinical pharmacokinetic data are discussed as a basis for a better interpretation and understanding of the clinical trial results. The efficacy and safety of trospium chloride in the treatment of detrusor overactivity is well proven. Given a favorable risk/benefit ratio trospium chloride qualifies as a first choice drug for the treatment of urge incontinence and reflex incontinence.Correspondence to:
Prof. Dr. I. Füsgen; Geriatrische Medizin, Universität Witten/Herdecke, Tönisheider Straße 24, D-42553 Velbert, Germany
Original
Variation of CYP1A2-dependent caffeine metabolism during menstrual cycle in healthy women
M. Zaigler, S. Rietbrock, J. Szymanski, J.S.E. Dericks-Tan, A.H. Staib and U. Fuhr
Abstract
M. Zaigler1,2, S. Rietbrock1,2, J. Szymanski2, J.S.E. Dericks-Tan3, A.H. Staib2 and U. Fuhr1,2
1Institute for Pharmacology, Clinical Pharmacology, Universität zu Köln, 2Institute for Clinical Pharmacology, and 3Department of Gynaecological Endocrinology, Centre for Gynaecology and Obstetrics, University Hospital, Frankfurt am Main, Germany
Background and objectives: The activity of the human cytochrome P450 CYP1A2 is decreased by female sex hormones during pregnancy or treatment with oral contraceptives. However, the influence of menstrual cycle on CYP1A2 activity is not clear. Methods: CYP1A2 activity was monitored in 15 women (13 with confirmed ovulatory cycles, 2 smokers, age (mean ± SD) 27.8 ± 3.8 years, body mass index 23.8 ± 3.8 kg × m–2) using the specific substrate caffeine (mean doses 149 mg). After a run-in period started one week prior to expected onset of menses, daily saliva samples were taken 7.3 ± 0.7 hours after caffeine intake throughout the cycle, and caffeine clearance was estimated from the paraxanthine to caffeine ratio therein. Ovulation was confirmed by progesterone serum concentration above 3 ng/ml in the second half of the cycle. Results: Initial (day 2) caffeine clearance (n = 15, geometric mean) was 1.37 ml/min/kg body weight (coefficient of variation (CV) 48%). The ratio of caffeine clearance for the luteal (day –9 to –4 prior to onset of the next menses) to the follicular phase (days 5 – 10) was (n = 13, point estimate) 1.03 (90% CI 0.95 – 1.12), indicating that there was no difference in CYP1A2 activity between these cycle phases. The median intraindividual CV in ovulatory cycles (n = 13) was 23% (range 11% to 39%). As an additional finding, there was evidence for long-term fluctuations of CYP1A2 activity in most individuals. Conclusions: A dose adaptation according to the phase of menstrual cycle based on pharmacokinetics is not required for CYP1A2 substrates.Correspondence to:
Prof. Dr. med. U. Fuhr; Institute for Pharmacology, Clinical Pharmacology, Universität zu Köln, Gleueler Straße 24, D-50931 Köln, Germany
Original
Effect of chronic renal failure on the disposition of highly hepatically metabolized drugs
R. Yuan and J. Venitz
Abstract
R. Yuan1 and J. Venitz2
1CDER-OPS-OCPB-DPE-I, Food and Drug Administration, Rockville, MD, and 2Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, USA
Objective: The objective of this study was to investigate the effect of renal impairment on the disposition of an extensively metabolized drug, i.e., drug X. Drug X has a hepatic extraction ratio of less than 0.1 and free fraction in plasma of less than 1% in healthy volunteers. Methods: Pharmacokinetic (PK) parameters of drug X were obtained from subjects with normal renal function (I, n = 6), as well as in subjects with mild (II, n = 5), moderate (III, n = 7) and severe renal impairment (IV, n = 5). Disease-PK models were developed to describe the changes of PK parameters with respect to renal function measured by creatinine clearance. While experimentally observed data are presented for drug X, additional simulations were performed for other drugs that are extensively metabolized (extensive metabolism is defined as metabolism that accounts for more than 90% of total drug elimination). The simulated scenarios included drugs that have a low extraction ratio (ER) and with high plasma protein binding (PPB), low ER and with low PPB, high ER and with high PPB, or high ER and with low PPB. Results: Systemic clearance of drug X, a low ER and high PPB drug, in renal patients depended on the simultaneous effects of renal disease on protein binding and intrinsic metabolic clearance. Protein binding of drug X was related to creatinine clearance in an inverse hyperbolic relationship, while the unbound intrinsic metabolic clearance declined linearly with creatinine clearance. Because the disease effects on these two factors offset each other in terms of total systemic clearance, the lowest total systemic clearance was not observed in the severely renal impairment patients, but rather in the moderately impaired group. Additional simulations showed that for low ER drugs that are highly metabolized, the pattern and magnitude of systemic clearance change in renal patients depended on how the disease affected PPB and/or intrinsic metabolic clearance. But the systemic clearance of high ER drugs would not be as susceptible to the effect of renal disease as that of low ER drug. Conclusions: Chronic renal disease should not be considered as an isolated event that affects only renally excreted drugs. Uremia may also modify the disposition of a highly metabolized drug by changes in plasma protein binding and/or hepatic metabolism.Correspondence to:
Dr. R. Yuan; Building 1-3C39, 340 Kingsland Street, Nutley, NJ 07110, USA
Original
Pharmacokinetics of reboxetine in elderly patients with depressive disorders
I. Poggesi, C. Pellizzoni and J.C. Fleishaker
Abstract
I. Poggesi1, C. Pellizzoni1 and J.C. Fleishaker2
1Pharmacokinetics and Metabolism Department, Pharmacia and Upjohn S.p.A., Milano, Italy, and 2Clinical Pharmacokinetics Unit, Pharmacia and Upjohn Inc, Kalamazoo, MI, USA
Objectives: To examine the pharmacokinetic characteristics of the selective norepinephrine reuptake inhibitor, reboxetine, in elderly patients with depression. Patients: Twelve female inpatients (mean age 80 ± 4 years) with major depressive or dysthymic disorder were enrolled in a 4-week uncontrolled study of oral reboxetine 2 – 8 mg/day. Methods: After a one-week washout period, patients were randomized into two groups (groups A and B, n = 6/group). Reboxetine was given twice daily, starting with 2 mg/day during week 1 and increasing by 2 mg/day each week to 8 mg/day in week 4. Pharmacokinetic evaluations were carried out at two dosage levels in each group: at the end of weeks 1 and 3 in group A (2 and 6 mg/day), and at the end of weeks 2 and 4 in group B (4 and 8 mg/day). Blood and urine samples were taken for determination of reboxetine pharmacokinetics. Results: Reboxetine displayed linear pharmacokinetics, with dose-proportional changes, in elderly depressed patients. Mean total urinary recovery ranged from 4.06 to 6.17%. The mean area under the plasma concentration-time curve (AUCt) and the maximum plasma drug concentration (Cmax) showed considerable variation between patients; at a dosage of 4 mg/day, AUCt was 1466 – 6866 ng×h/ml and Cmax ranged from 169 to 663 ng/ml. Conclusions: The pharmacokinetics of reboxetine are linear across the dosage range of 2 – 8 mg/day in elderly depressed patients, although Cmax and AUCt values are higher (and more variable) than in young adults. These results support the use of a lower starting dose (4 mg/day) of reboxetine in the elderly.Correspondence to:
Dr. I. Poggesi; Pharmacokinetics and Metabolism Department, Pharmacia and Upjohn S.p.A., Viale Pasteur, 10-20014 Nerviano, Milano, Italy
Original
Ethnic differences in response to non-selective b-blockade among racial groups in Malaysia
A.H.G. Rasool, A.R.A.Rahman, R. Ismail, S. Hatim, A.R.W Abdullah, R. Singh and R. Haron
Abstract
A.H.G. Rasool, A.R.A.Rahman, R. Ismail, S. Hatim, A.R.W Abdullah, R. Singh and R. Haron
Departments of Pharmacology, Physiology and Biostatistics, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
Objective: To determine whether racial differences in response to blockade of b receptors occur among racial groups in Malaysia that are the Malays, Indians and Chinese. Subjects, materials and method: 35 healthy male volunteers representing the 3 main racial groups in Malaysia (12 Malays, 12 Chinese and 11 Indians) were studied in a randomized, placebo-controlled, crossover and single-blind design. Propranolol 80 mg 12-hourly was given orally for 48 hours. Six hours after the last dose subjects attended an exercise session where resting and exercise heart rate, blood pressure, plasma potassium and glucose levels, resting FEV1 and plasma propranolol concentrations were recorded. Results: No significant difference in plasma propranolol (mean ± SEM) levels was seen between races six hours after the last dose (Malays, 59.7 ± 8.8 ng/ml, Indians, 67.6 ± 19.3 ng/ml, Chinese, 58.4 ± 7.9 ng/ml). Chinese were least sensitive to the bradycardic and hypotensive effects of propranolol at rest and exercise. Indians and Malays had significant reduction of supine systolic blood pressure with propranolol but not Chinese. Comparison of percentage reductions of systolic blood pressure at supine, sitting and exercise by repeated measure analysis showed the Malays to have significantly higher change compared to the Chinese (p = 0.022). Similarly, comparison of percentage reductions of heart rate at supine, sitting and exercise by repeated measure analysis showed the Malays to have significantly higher change compared to the Chinese (p = 0.040). Average change in potassium concentrations at peak exercise and recovery showed the Indians to have significantly higher increase in potassium levels with propranolol compared to the Malays (p = 0.038). However, no significant interethnic difference was seen in the reduction of glucose levels at rest, peak exercise or recovery. Also, no significant interethnic difference was seen in reduction of FEV1 values. Conclusion: We, therefore, conclude that ethnic differences in response to blockade of b-receptors exist among racial groups in Malaysia. These differences were seen at similar plasma drug levels between races suggesting ethnic differences in drug sensitivity, rather than differences in drug disposition.Correspondence to:
Dr. A. Hanum bt Ghulam Rasool; Pharmacology Department, Universiti Sains Malaysia, 16150 Kelantan, Malaysia
Short Communication
Fluvastatin increases prostacyclin and decreases endothelin production by human umbilical vein endothelial cells
H. Seeger, A.O. Mueck and T.H. Lippert
Abstract
H. Seeger, A.O. Mueck and T.H. Lippert
Section of Clinical Pharmacology, Department of Obstetrics and Gynecology, University of Tübingen, Tübingen, Germany
Fluvastatin, an agent of a class of lipid-lowering drugs, the “statins”, significantly enhanced prostacyclin synthesis at the concentrations of 0.1 mM and 1 mM and significantly reduced endothelin production at the concentrations 0.01, 0.1 and 1 mM in cell cultures of human umbilical endothelial veins. Since prostacyclin is a vasodilator and endothelin a vasoconstrictor, fluvastatin may have a significant effect on hemodynamics by favoring the balance towards vasodilation. This mechanism may contribute to the prevention of cardiovascular diseases.Correspondence to:
Prof. Dr. T.H. Lippert; Section of Clinical Pharmacology, Department of Obstetrics and Gynecology, Schleichstraße 4, D-72076 Tübingen, Germany
