Volume 44, No. 9/2006(September)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Drug Interactions
Valdecoxib does not interfere with the CYP2D6 substrate metoprolol
U. Werner*, C. Lamprecht*, D. Werner, S. Schaefer, H. Wuttke, B. Hinz, M.F. Fromm and K. Brune
Abstract
U. Werner1*, C. Lamprecht1*, D. Werner2, S. Schaefer3, H. Wuttke4, B. Hinz1, M.F. Fromm1 and K. Brune1
1Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University of Erlangen-Nuremberg, 2Clinic of Cardiology, Helios Hospital Schwerin, 3Clinic of Anaesthesiology, University of Essen, 4Institute of Pharmacology, University of Hamburg, Germany
Objective: We reported recently that celecoxib inhibits the metabolism of the cytochrome P450 (CYP)2D6 substrate metoprolol in volunteers. Valdecoxib, the active metabolite of parecoxib, has also been claimed to interfere with the metabolism of CYP2D6 substrates. However, little support for this contention is available despite the intensive use of parecoxib in the perioperative setting. Therefore, the objective of this study was to examine the effect of valdecoxib on the pharmacokinetics of the clinically relevant CYP2D6 substrate metoprolol. Methods: An open, randomized, 3-period crossover study was performed in 15 healthy male volunteers. Metoprolol (50 mg) was given in all 3 periods without, or following a 7-day pre-treatment with valdecoxib (20 mg, o.d.) or rofecoxib (25 mg, o.d.), to achieve steady state conditions of COX-2 inhibitors in Periods 2 and 3. In a small group of extensive metabolizers (EM/EM), short-term application of twice the dose was investigated. Results: No effect of valdecoxib (20 mg/d) or rofecoxib (25 mg/d) were detected on the area under the plasma concentration-time curve of metoprolol (323 ± 333 to 324 ± 296 or 309 ± 256 µg × h/l) or at a higher dose. No significant changes of pharmacokinetic or pharmacodynamic parameters of metoprolol were apparent. Conclusion: We conclude that, at therapeutic doses, valdecoxib and rofecoxib do not influence the CYP2D6 substrate metoprolol. Correspondence to:
PD Dr. U. Werner
Department of Experimental and Clinical Pharmacology and Toxicology
Friedrich Alexander University of Erlangen-Nuremberg
Fahrstraße 17
91054 Erlangen, Germany
Email: ulrike-werner@arcor.de
Pharmacokinetics
Bioavailability and pharmacokinetics of Echinacea purpurea preparations and their interaction with the immune system
K. Woelkart, E. Marth, A. Suter, R. Schoop, R.B. Raggam, C. Koidl, B. Kleinhappl and R. Bauer
Abstract
K. Woelkart1, E. Marth2, A. Suter3, R. Schoop3, R.B. Raggam2, C. Koidl2, B. Kleinhappl2 and R. Bauer1
1Institute of Pharmaceutical Sciences, Department of Pharmacognosy, Karl Franzens University, 2Institute of Hygiene, Medical University Graz, Austria, 3A. Vogel Bioforce AG, Roggwil, Switzerland
Echinacea is a widely used herbal remedy for the prevention and treatment of the common cold. Recently, many new insights concerning the molecular mode of action of the main lipophilic constituents, the alkamides, have renewed interest in this plant. In order to compare the bioavailability of alkamides from liquid and tablet preparations of E. purpurea (Echinaforce) in humans and to study the effects on ex vivo stimulated blood cells, a randomized, single-dose, crossover study with 10 (8 test, 2 placebo) volunteers has been performed. They received either 4 ml of the standardized E. purpurea (Echinaforce) tincture or 12 E. purpurea (Echinaforce) tablets or placebo. Both doses contained the same amount (0.07 mg) of the major alkamides, dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides. Liquid chromatography electrospray ionization ion-trap mass spectrometry was used to determine the content of alkamides in serum. It was found that the arithmetic mean Cmax of dodeca2E,4E, 8Z,10E/Z-tetraenoic acid isobutylamides absorbed after oral application of the Echinaforce tincture appeared after 30 min (0.40 ng/ml serum). In comparison, the tmax of tablets was 45 min with a Cmax of 0.12 ng/ml. An ex vivo stimulation of blood by LPS was carried out to measure the influence of E. purpurea on the innate and adaptive immune system. Both E. purpurea preparations led to the same effects on the immune system according to the concentration of pro-inflammatory cytokines TNF-a and IL-8. 23 hours after oral application a significant down-regulation of TNF-a and IL-8 in LPS pre-stimulated whole blood was found. However, no significant changes in the concentration of IL-6 were observed. Although a quarter of the dodeca-2E,4E,8Z, 10E/Z-tetraenoic acid isobutylamides was absorbed from the tablets, the study shows that the formulations trigger the same effects on the measured immune parameters.Correspondence to:
Univ.-Prof. Dr. R. Bauer
Institute of Pharmaceutical Sciences, Pharmacognosy
Karl Franzens University Graz
Universitätsplatz 4
8010 Graz, Austria
Email: rudolf.bauer@uni-graz.at
Drug Utilization
Safety and usage pattern of an over-the-counter ambroxol cough syrup: a community pharmacy-based cohort study
M. Schulz, A. Hämmerlein, U. Hinkel, G. Weis and A. Gillissen
Abstract
M. Schulz1,2, A. Hämmerlein1, U. Hinkel3, G. Weis3 and A. Gillissen4
1Center for Drug Information and Pharmacy Practice, ABDA – Federal Union of German Associations of Pharmacists, Berlin, 2Institute of Pharmacology, Johann Wolfgang Goethe University, Biocenter N260, Frankfurt, 3Medical Science Department, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, and 4St. George Medical Center, Robert Koch Hospital, Leipzig, Germany
Introduction: Mucoactive substances such as ambroxol, available in several countries as over-the-counter (OTC) medicines, are used for the treatment of acute and chronic bronchitis. Objective: This study was designed to evaluate the “real life” behavior of consumers with non-prescription access to an ambroxol cough syrup with special focus on tolerability and the pattern of product usage. Methods: Customers who bought the ambroxol syrup were recruited in 300 community pharmacies in Germany. Baseline data were collected from the participants in the pharmacy. Completing a self-administered questionnaire, participants provided information on tolerability, self-perceived effectiveness and usage pattern. Results: 2,707 participants were recruited in 266 pharmacies. 2,664 questionnaires were evaluable. At baseline, the respondents reported a complex pattern of symptoms. Productive cough, congested airways, dry cough, cough irritation in the throat and soreness in the throat were the most common ones. 67 patients (2.5%) reported a total of 81 adverse events (AE) which were usually mild in nature and mostly affecting the gastrointestinal tract (n = 53) followed by skin and subcutaneous tissue disorders (n = 9). No serious or unknown AE were reported. In general, 97% of the participants assessed the safety as “very good” (51%) or “good” (46%). Overall, the respondents complied with the indications for use and the recommended dosages, with only 0.7% of the participants using the maximum daily dose. 92% of the patients assessed the self-perceived effectiveness as “very good” (29%) or “good” (63%) and 89% were willing to purchase this ambroxol cough syrup again. Conclusions: This study confirms that ambroxol is used according to the advice given in the patients’ leaflet and supports the already established safety and efficacy of this product in acute bronchitis. It also demonstrates that the use of an OTC cough medication can be successfully monitored in a pharmacy-based cohort study.Correspondence to:
Prof. M. Schulz
Center for Drug Information and Pharmacy Practice (ZAPP), ABDA
Jägerstraße 49/50
10117 Berlin, Germany
Email: Schulz@em.uni-frankfurt.de
Pharmacodynamics
Increase in renal vascular resistance after intake of cyclosporin A and tacrolimus and reversal by nitroglycerin spray: a study in patients with stable renal allograft function*
C. Weingart , T. Leingärtner, T. Bergler, B. Krüger, C. Böger, M. Mack, B. Banas and B.K. Krämer
Abstract
C. Weingart , T. Leingärtner, T. Bergler, B. Krüger, C. Böger, M. Mack, B. Banas and B.K. Krämer
Clinic and Policlinic for Internal Medicine II – Nephrology, University of Regensburg, Regensburg, Germany
Purpose: Acute effects of drug administration on renal arterial resistance index (RI) are still discussed controversially. In our study we investigated the immediate effects of cyclosporin A (CyA) and tacrolimus (FK-506) on renal arterial resistance indices in patients with stable graft function after renal transplantation. Additionally we studied the effects of nitroglycerin spray on resistance indices. Methods: RI was measured by color Doppler sonography at baseline, at 1 and 2 hours after intake of medication and 30 minutes after administration of nitroglycerin spray which followed the 2-hour measurement. 34 renal transplant recipients were examined. 16 patients received CyA, 18 patients received FK-506. Whole blood levels of calcineurin inhibitors were taken at each time point. Arterial blood pressure and heart rate were measured to assess possible systemic hemodynamic effects. Results: Mean RI values increased significantly in both groups 1 hour after calcineurin inhibitor intake and remained still significantly elevated after 2 hours. There was no significant increase of mean arterial blood pressure nor was there any correlation between whole blood levels of calcineurin inhibitors and mean RI. 30 minutes after administration of nitroglycerin spray, mean RI values decreased significantly to a level even below baseline. Mean arterial blood pressure also decreased after administration of nitroglycerin. Conclusion: Renal RI values are markedly influenced by a recent intake of calcineurin inhibitors and vasoactive substances such as nitrates. This demonstrates the necessity of keeping standardized conditions when using RI as a tool in follow-up investigations after renal transplantation.
*This work was presented at the 9th NephroPharmacology meeting on October 8, 2005 in Ulm, GermanyCorrespondence to:
C. Weingart, MD
Clinic and Policlinic for Internal Medicine II – Nephrology
University of Regensburg
Franz-Josef-Strauß-Allee 11
93053 Regensburg, Germany
Email: christian.weingart@klinik.uni-regensburg.de
Therapeutics
Dosage adjustment of quinolone antibiotics and angiotensin-converting enzyme inhibitors in patients with renal dysfunction
H. Ohtani, Y. Kinoshita, Y. Nagasaki, H. Sata, A. Miki, M. Tsujimoto and Y. Sawada
Abstract
H. Ohtani, Y. Kinoshita, Y. Nagasaki, H. Sata, A. Miki, M. Tsujimoto and Y. Sawada
1Laboratory of Drug Informatics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, and 2Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
The aim of this study was to verify an approach for calculating pharmacokinetic parameters suitable for adjusting dosage regimens in patients with renal dysfunction. We carried out a retrospective analysis of the pharmacokinetic profiles of 12 new quinolone antibiotics and 11 angiotensin-converting enzyme inhibitors (ACEIs) in patients with normal and impaired renal function to obtain the renal excretion ratio (Rrenal) of each drug. We demonstrated that the pharmacokinetics of each drug in a patient with renal dysfunction can be adequately estimated using the Rrenal value of each drug together with the creatinine clearance as an index of the individual’s renal function. Using the Rrenal value obtained, we could successfully simulate pharmacokinetic profiles of the drugs in publications other than that used to obtain the Rrenal values. On the other hand, age-related changes in the pharmacokinetics of new quinolone antibiotics are not always adequately predicted using the Rrenal value compared to using creatinine clearance alone as an index, and the reasons for this are not fully understood. These results demonstrate that dosage regimens of quinolone antibiotics and ACEIs in patients with renal dysfunction can be adequately optimized using the Rrenal value for each drug using the present approach.Correspondence to:
Y. Sawada, PhD
Professor, Graduate School of Pharmaceutical Sciences
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Email: sawada@phar.kyushu-u.ac.jp
Therapeutics
Differences between prescribed daily doses and defined daily doses of antiepileptics – therapeutic drug monitoring as a marker of the quality of the treatment
B. Koristkova, M. Grundmann and H. BrozmanovaB. Koristkova, M. Grundmann and H. Brozmanova
Abstract
B. Koristkova, M. Grundmann and H. BrozmanovaB. Koristkova, M. Grundmann and H. Brozmanova
Department of Clinical Pharmacology, Ostrava University Hospital and Medico-Social Faculty, University of Ostrava, Czech Republic
Objective: Prescribed daily doses (PDDs) of antiepileptics (N03A ATC group) were recorded for drugs used in monotherapy or in combination therapy in the University Hospital in Ostrava, Czechia. Plasma levels were used as an indicator of the quality of treatment. Method: Request and reply forms for therapeutic drug monitoring (TDM) were used as a source of PDDs and plasma levels. The study included 1,144 in-patients examined in the period 1993 – 2004. The differences in PDD were tested by Mann-Whitney-U-test. ATC/DDD index 2005 was used. Doses given in mono- and polytherapy were compared. Results: Median PDDs in samples within the therapeutic range (in mg) in mono-/polytherapy were as follows (DDDs in parenthesis): carbamazepine 600/800 (1,000), clonazepam 2.0/2.0 (8), phenytoin 300/300 (300), ethosuximide –/1000 (1,250), lamotrigine 250/200 (300), phenobarbital –/200 (100), primidone 500/625 (1,250), topiramate –/300 (300), valproic acid 750/1,000 (1,500). Median PDDs in polytherapy with antiepileptics not analyzed for TDM were: gabapentin 900 (1,800), levetiracetam 1,500 (1,500), vigabatrin 1,500 (2,000). Conclusions: PDDs in monotherapy were similar or slightly lower than in combination therapy with an exception for lamotrigine, NS. The differences were significant in carbamazepine, p < 0.0001, and valproic acid, p < 0.001. Patients with plasma levels within the therapeutic range were usually treated with similar or slightly higher doses than the remainder. In polytherapy the PDDs were similar to DDDs in carbamazepine, ethosuximide, phenytoin, and topiramate in samples within the therapeutic range when difference ± 20 per cent was considered as acceptable PDD of levetiracetam was also similar to actual DDD. In general plasma levels tended to be below the therapeutic range. The differences between PDD and DDD of antiepileptics have to be taken into account especially when utilization of different drugs is comparedCorrespondence to:
B. Koristkova, PharmD, PhD
Department of Clinical Pharmacology
Ostrava University Hospital and Medico-Social Faculty
University of Ostrava
17. listopadu 1790, 708 52 Ostrava, Czech Republic
Email: blanka.koristkova@fnspo.cz
Bioavailability Section
Ethanol does not significantly affect the bioavailability of almotriptan: an open, randomized, crossover, single-dose, phase I clinical trial in healthy volunteers
X. Cabarrocas, M. Salva, M. Pavesi and J. Costa
Abstract
X. Cabarrocas1, M. Salva1, M. Pavesi1 and J. Costa2
1Research Center, Almirall Prodesfarma, Barcelona, and 2Clinical Pharmacology Department, Hospital Universitario “Germans Trias i Pujol”, Universitat Autonoma de Barcelona, Badalona, Spain
Objective: A number of clinical reports have revealed a link between the use of alcohol and the onset or exacerbation of migraine headaches. This open, randomized, crossover, single-dose, phase I clinical trial evaluated the possible pharmacokinetic interactions between a single oral dose of almotriptan 12.5 mg, a 5-HT1B/1D receptor agonist for the acute treatment of migraine, and ethanol in 16 healthy male volunteers. Tolerability and safety of this combined treatment were also assessed. Methods: Subjects received a crossed oral dose of almotriptan (12.5 mg) with and without concomitant alcohol intake (target plasma concentration 0.8 g/kg) in two different treatment periods. Almotriptan was administered alone, while ethanol was diluted with orange juice, which was also given to the control group. There was a washout period of 7 days between treatments. Plasma levels of almotriptan were analyzed using a sensitive and specific liquid chromatographic-tandem mass spectrometry method. Results: The 90% non-parametric confidence interval for the median tmax of almotriptan plus ethanol compared to almotriptan alone (0.61/2.72) was outside the acceptable range (0.70 – 1.30), demonstrating that concomitant ethanol administration slightly increases the variability of absorption of almotriptan 12.5 mg. In contrast, the main bioavailability criteria parameters, Cmax and AUC, which show the rate and extent of systemic absorption, were not affected by alcohol ingestion. Therefore, it is unlikely that concomitant ethanol intake would produce clinically relevant differences in the therapeutic effect of almotriptan at the dose studied here. Tolerability of treatments was good throughout the entire study period. Conclusions: Almotriptan 12.5 mg, with or without concomitant alcohol ingestion, showed similar plasma concentrations after a single dose in healthy volunteers with no clinically relevant drug-to-drug interactions.Correspondence to:
J. Costa, MD
Clinical Pharmacology Department
University Hospital Germans Trias i Pujol
Ctra. de Canyet s/n; 08916 Badalona, Spain
Email: jcosta.germanstrias@gencat.net
Letters to the Editor
Sample size calculations and methacholine challenge tests
M.D. Inman and G. Norman
Abstract
M.D. Inman and G. Norman
Letters to the Editor
Reply to M. Inman and G. Norman
M. Neuhäuser and K.-H. Jöckel
Abstract
M. Neuhäuser and K.-H. Jöckel
Letters to the Editor
Successful treatment of anorexia with a combination of high-dose olanzapine, fluoxetine and mirtazapine
K.N. Fountoulakis, A. Iacovides, M. Siamouli, V. Koumaris and G.S. Kaprinis
Abstract
K.N. Fountoulakis, A. Iacovides, M. Siamouli, V. Koumaris and G.S. Kaprinis
Book Review
Clinical Pharmacokinetics
U. Klotz
