Volume 40, No. 4/2002(April)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Antiplatelet agents
Effects of antiplatelet agents on platelet-induced thrombin generation
W. Wegert, J. Graff, D. Kaiser, H.K. Breddin, U. Klinkhardt and S. Harder
Abstract
W. Wegert1, J. Graff1, D. Kaiser1, H.K. Breddin2, U. Klinkhardt1 and S. Harder1
1Institute for Clinical Pharmacology, University Hospital, Frankfurt am Main and 2International Institute for Thrombosis and Vascular Diseases, Frankfurt am Main, Germany
Objectives: The influence of antiplatelet agents on platelet-induced thrombin generation may increase the risk of bleeding. Assessment of the endogenous thrombin potential (ETP), is therefore a parameter deserving attention in early pharmacodynamic studies with antiplatelet drugs. The aim of this study was to assess whether an automated ETP-assay can be used to determine possible inhibitory effects of antiplatelet drugs on platelet-associated thrombin generation. Methods: We first characterized the in vitro dose-response relationship of several platelet agonists (ADP, collagen, U46619, TRAP (amino acid sequence: SFLLRNP) and tissue factor (TF) using the generation of ETP. One submaximal concentration of each agonist was then used to assess the influence of in vivo treatment with aspirin (single oral dose of 500 mg as inhibitor of thromboxane synthesis) and clopidogrel (given orally for 6 days, as an inhibitor of the purinergic P2Y12-receptor on platelets) and in vitro treatment with abciximab (which inhibits the platelet glycoprotein IIb/IIIa-receptor for fibrinogen), on the ETP. Results: The effect of TF and the other platelet inducers on thrombin generation was dose-dependent. Repeat measurements on samples from the same subject, with the same inducer concentration on 2 different occasions showed a variability of approx. 22% (absolute difference between 2 measurements as % of mean). The coefficient on variation of repeat measurements of one sample varied between 7% and 17%, depending on the inducer. After a single dose of aspirin, ETP was reduced by 25 – 40%, depending on the platelet activating agent used. The reduction in ETP with abciximab in vitro was more pronounced. In contrast, TF-induced ETP was not influenced by aspirin or abciximab. Clopidogrel, administered for 6 days, reduced the ETP by 60% when platelets were stimulated using 20 mM ADP, whereas collagen-induced ETP and TF-induced ETP remained unchanged. Conclusions: The ETP-method is a sensitive and reproducible method for the detection of drug effects on platelet-induced thrombin generation of high throughput, and can be recommended for studies on the pharmacodynamic profile of drugs interfering with platelet function.Correspondence to:
Prof. Dr. S. Harder; Institute for Clinical Pharmacology at the Pharmazentrum Frankfurt, University Hospital, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany
Email: harder@em.uni-frankfurt.de
Intensive-care patient therapy
Elimination of levofloxacin in critically ill patients with renal failure: influence of continuous veno-venous hemofiltration
R. Bellmann, P. Egger, W. Gritsch, R. Bellmann-Weiler, M. Joannidis, S. Dunzendorfer and C.J. Wiedermann
Abstract
R. Bellmann, P. Egger, W. Gritsch, R. Bellmann-Weiler, M. Joannidis, S. Dunzendorfer and C.J. Wiedermann
Department of Internal Medicine, Division of General Internal Medicine, University of Innsbruck, Innsbruck, Austria
Objectives: Pharmacokinetic data on levofloxacin in critically ill patients are sparse and conflicting. Aim of the study was to assess the clearance of levofloxacin in critically ill patients treated with continuous veno-venous hemofiltration (CVVH). Methods: Pharmacokinetics of levofloxacin were studied in 11 critically ill patients. Four patients were treated with CVVH because of renal failure, 4 patients had moderately impaired renal function but were not on hemofiltration, and 3 patients had approximately normal renal function. Patients received 0.5 g levofloxacin infused over 0.5 hours. Plasma levels of levofloxacin were determined by HPLC and pharmacokinetic parameters were calculated using a non-compartmental model. Results: Levofloxacin clearance in critically ill patients with approximately normal renal function was similar to that in healthy subjects. In critically ill patients with impaired renal function not on CVVH, mean half-life was prolonged by a factor of about 3 (20 – 25 hours). The mean residence time and the volume of distribution were also increased. In renal failure treated with CVVH, a wide variability in pharmacokinetics was seen. The half-life was about 30 hours and the mean levofloxacin clearance was raised by a factor of 2. The area under the concentration-time curve was reduced by hemofiltration, while the volume of distribution was increased. There was a positive correlation between blood flow through the hemofilter and levofloxacin clearance. Variable amounts of the drug were recovered from the hemofilter. Most plasma levels, however, were in the therapeutic range and drug accumulation to toxic plasma concentrations was not observed in renal failure patients undergoing CVVH and receiving single daily administration of 0.5 g of levofloxacin i.v. Conclusions: During CVVH using polysulfone membrane hemofilters, plasma concentrations of levofloxacin are not easily predictable. Levofloxacin clearance may be affected by binding to secondary membranes formed in hemofilters during CVVH and blood flow rates have a significant impact on the pharmacokinetics of levofloxacin.Correspondence to:
Dr. R. Bellmann; Division of General Internal Medicine, Department of Internal Medicine, University of Innsbruck, Anichstraße 35, A-6020 Innsbruck, Austria
Email: romuald.bellmann@uibk.ac.at
Endothelial function
Effect of two oral contraceptives containing ethinylestradiol and levonorgestrel on serum and urinary surrogate markers of endothelial function
H. Seeger, G. Petersen, E. Schulte-Wintrop, A.T. Teichmann and A.O. Mueck
Abstract
H. Seeger1, G. Petersen2, E. Schulte-Wintrop2, A.T. Teichmann3 and A.O. Mueck1
1Department of Obstetrics and Gynecology, Section of Gynecological Endocrinology and Menopause, University of Tübingen, 2Wyeth-Pharma GmbH, Münster, and 3Department of Obstetrics and Gynecology, Aschaffenburg, Germany
Objective: To investigate the effect of two oral contraceptives containing 0.02 mg ethinylestradiol and 0.1 mg levonorgestrel (Formulation A, Leios), and the other containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel (Formulation B, Stediril 30) on the serum and urinary concentrations of various markers reflecting the status of vascular tone and development of atherosclerosis. The adhesion molecules E-selectin, inter-cellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and homocysteine were included as serum markers and cGMP, prostacyclin and its antagonist thromboxane as urinary markers. Methods: In a comparative, double-blind, randomized, parallel group study, 34 women received formulation A and 33 women formulation B. Serum samples were collected before treatment and after 3, 6 and 12 cycles. Nocturnal urine was collected before treatment and during cyclic treatment after 3 and 12 cycles. Serum and urinary markers were measured by enzyme immunoassays. Results: E-selectin levels were significantly reduced by both contraceptives after 3, 6 and 12 months compared to pretreatment levels. A slight increase in ICAM concentrations was observed for both contraceptives after 6 cycles, but this fell to pretreatment levels after 12 cycles. VCAM values were significantly lowered after 3, 6 and 12 months by both contraceptives. No significant changes were found in serum levels of homocysteine. No significant differences were found between treatment groups for the serum markers. Both contraceptives significantly enhanced urinary cGMP excretion after 12 cycles. The prostacyclin metabolite remained unchanged in the case of both formulations, but the excretion of the thromboxane metabolite was significantly decreased after 12 cycles. Thus, the ratio of prostacyclin to thromboxane, decisive for the resulting effect on vascular tone, increased significantly. Conclusion: These results indicate that the low-dose oral contraceptives can reduce the production of adhesion molecules which play a crucial role in the early stages of atherosclerosis. In addition, these contraceptives can shift the balance of vascular tone towards dominance of vasodilatory substances after 12 cycles of treatment. Thus, the positive influence of these contraceptives on the various markers investigated may improve vascular tone and impede development of atherosclerosis.Correspondence to:
Dr. A.O. Mueck; Head of Section of Gynecological Endocrinology and Menopause, Department of Obstetrics and Gynecology, Schleichstraße 4, D-72076 Tübingen, Germany
Email: endo.meno@ med.uni-tuebingen.de
Herbal clinical pharmacology
A review of the French maritime pine bark extract (Pycnogenol®), a herbal medication with a diverse clinical pharmacology
P. Rohdewald
Abstract
P. Rohdewald
Institute Pharmaceutical Chemistry, Westfälische Wilhelms-Universität Münster, Germany
Objectives: An increasing body of evidence indicates that Pycnogenol® (PYC), a standardized extract of French maritime pine bark, has favorable pharmacological properties. This is a review of studies with both PYC® and components of the preparation, that have helped to elucidate target sites and possible mechanisms for activity in men. Methods: Studies appearing in peer reviewed literature, as well as results presented at international meetings not yet available as published papers, are included in this review. Additional data from published sources in German and French languages that are not widely available are also included. Results: Chemical identification studies showed that PYC® is primarily composed of procyanidins and phenolic acids. Procyanidins are biopolymers of catechin and epicatechin subunits which are recognized as important constituents in human nutrition. PYC® contains a wide variety of procyanidins that range from the monomeric catechin and taxifolin to oligomers with 7 or more flavonoid subunits. The phenolic acids are derivatives of benzoic and cinnamic acids. The ferulic acid and taxifolin components are rapidly absorbed and excreted as glucuronides or sulphates in men, whereas procyanidins are absorbed slowly and metabolized to valerolactones which are excreted as glucuronides. PYC® has low acute and chronic toxicity with mild unwanted effects occurring in a small percentage of patients following oral administration. Clinical studies indicate that PYC® is effective in the treatment of chronic venous insufficiency and retinal micro-hemorrhages. PYC® protects against oxidative stress in several cell systems by doubling the intracellular synthesis of anti-oxidative enzymes and by acting as a potent scavenger of free radicals. Other anti-oxidant effects involve a role in the regeneration and protection of vitamin C and E. Anti-inflammatory activity has been demonstrated in vitro and in vivo in animals. Protection against UV-radiation-induced erythema was found in a clinical study following oral intake of PYC®. In asthma patients symptom scores and circulating leukotrienes are reduced and lung function is improved. Immunomodulation has been observed in both animal models as well as in patients with Lupus erythematosus. PYC® antagonizes the vasoconstriction caused by epinephrine and norepinephrine by increasing the activity of endothelial nitric oxide synthase. Dilation of the small blood vessels has been observed in patients with cardiovascular disease, whereas in smokers, PYC® prevents smoking-induced platelet aggregation and reduces the concentration of thromboxane. The ability to inhibit angiotensin-converting enzyme is associated with a mild antihypertensive effect. PYC® relieves premenstrual symptoms, including abdominal pain and this action may be associated with the spasmolytic action of some phenolic acids. An improvement in cognitive function has been observed in controlled animal experiments and these findings support anecdotal reports of improvement in ADHD patients taking PYC® supplements. Conclusions: There is much evidence showing that PYC® has beneficial effects on physiological functions. Results from ongoing clinical research are required to confirm and extend previous observations.Correspondence to:
Prof. Dr. P. Rohdewald; Institute Pharmaceutical Chemistry, Westfälische Wilhelms-Universität Münster, Hittorfstraße 58–62, D-48149 Münster, Germany
Email: rohdewa@ uni-muenster.de
Bioequivalence/Bioavailability Section
Analysis of formulation and food effect on the absorption of metoclopramide
H. Vergin, U. Fisch, G. Mahr and B. Winterhalter
Abstract
H. Vergin1, U. Fisch1, G. Mahr2 and B. Winterhalter1
1Medical Affairs Arthritis/MDI, Pharmacia GmbH, and 2mcp, Erlangen
Objectives: Assessment of the relative and absolute bioavailability of immediate release and sustained release formulations of metoclopramide. Assessment of the effect of a high-fat meal on the pharmacokinetics of sustained release metoclopramide. Material and methods: In a balanced 4-way crossover study in 16 healthy male volunteers, a sustained release (SR) formulation of metoclopramide was compared with a solution for injection (A) and an immediate release tablet (B). The SR formulation was administered after a fasting period (C) as well as after a high-fat meal (D). A single dose of 30 mg metoclopramide was investigated in each treatment. Metoclopramide concentrations were determined by HPLC. Results: The absolute bioavailability of the sustained release formulation (fasting state) was 58% and thus about 17% lower than the bioavailability of the immediate release formulation. Comparing the treatments C (sustained release, fasting state) and D (sustained release, high-fat meal) no significant influence of food on the absorption of sustained release metoclopramide could be detected.Correspondence to:
Dr. H. Vergin; Medical Affairs Arthritis/ MDI, Pharmacia GmbH, Am Wolfsmantel 46, D-91058 Erlangen, Germany
Email: hartmut.vergin@pharmacia.com
Bioequivalence/Bioavailability Section
Methylphenidate bioavailability from two extended-release formulations
M.A. González, H.S. Pentikis, N. Anderl, M.F. Benedict, H.H. DeCory, S.J. Hirshey Dirksen and S.J. Hatch
Abstract
M.A. González1, H.S. Pentikis2, N. Anderl3, M.F. Benedict4, H.H. DeCory5, S.J. Hirshey Dirksen5 and S.J. Hatch5
1GloboMax Américas, Weston, FL, USA, 2Globomax LLC, Hanover, MD, USA, 3PPD Development, Richmond, VA, USA, 4PPD Development, Austin, TX, USA, 5Celltech Americas, Rochester, NY, USA
Objective: The objective of these studies was to compare the rate and extent of absorption of d,l-threo-methylphenidate (MPH) from two extended-release products – a capsule formulation containing coated beads and an OROS® tablet formulation – in healthy male and female subjects under fasted conditions. Materials: Metadate® CD (methylphenidate HCl, USP) Extended-Release Capsules and Concerta® (methylphenidate hydrochloride) Extended-Release Tablets. Methods: Two studies were conducted: (1) A single dose, randomized, two-way crossover study in 36 adults comparing a 20 mg capsule and an 18 mg tablet, and (2) a single dose, randomized, four-way crossover study in 24 adults comparing 2 × 20 mg capsules, one 36 mg tablet, 3 × 20 mg capsules and one 54 mg tablet. Blood samples were collected over 24 hours and MPH plasma concentrations were used to calculate pharmacokinetic parameters for each treatment. Equivalence of pharmacokinetic parameters for comparable doses of the formulations was concluded if the 90% confidence intervals (CI) for the ratio between test and reference means were within the 80 – 125% equivalence criterion. Results: Both formulations exhibited biphasic plasma concentration-time profiles and were equivalent in terms of total exposure (AUC0–last and AUC0–¥). However, early exposure (AUC0–4 and AUC0–6), the first maximum measured plasma concentration (Cmax–1), and early plasma MPH concentrations (1.5, 3 and 4 hours) were greater with the capsule formulation, while later plasma MPH concentrations (8, 10 and 12 hours) were greater with the tablet formulation (the CIs were outside the 80 – 125% required for equivalence and p < 0.001 for all). Similar results were obtained whether or not the data were normalized for the difference in total dose. Conclusions: The two formulations are not bioequivalent. The capsule formulation produces greater exposure to MPH and higher MPH concentrations during the first 6 hours following dosing. MPH is frequently used in school children, and this period would correspond to a major part of the school day.Correspondence to:
H.H. DeCory, Ph.D; Celltech Americas, Inc., P.O. Box 31710, 755 Jefferson Road Rochester, NY 14603, USA
Email: heleen.decory@celltechgroup.com
