Volume 44, No. 1/2006(January)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Pharmacokinetics
Pharmacokinetic disposition of inhaled ciclesonide and its metabolite desisobutyryl-ciclesonide in healthy subjects and patients with asthma are similar
R. Nave, K.A. Gunawardena, K. Zech and T.D. Bethke
Abstract
R. Nave1, K.A. Gunawardena2, K. Zech1 and T.D. Bethke1
1ALTANA Pharma, Konstanz, Germany, and 2Chiltern International Limited, Chiltern House, Bells Hill, Stoke Poges, Buckinghamshire, UK
Objective: To evaluate whether the inflammatory process and bronchial constriction associated with asthma influence the pulmonary distribution and airway penetration of inhaled ciclesonide by investigating the pharmacokinetics of ciclesonide and its active metabolite, desisobutyryl-ciclesonide (des-CIC) in patients with asthma and matched healthy subjects. Methods: 12 patients with asthma (8 males, 4 females) and 12 healthy subjects matched for age, sex, height, and weight received a single inhaled dose of 1,280 µg (ex-actuator, equivalent to 1,600 µg ex-valve) ciclesonide by metered-dose inhaler in a parallel-group study. Timed blood samples were collected for measurement of serum concentrations of des-CIC and ciclesonide by liquid chromatography with tandem mass spectrometry. Results: There were no differences in the pharmacokinetics of des-CIC between healthy subjects and patients with asthma. Ratio analysis of the primary variable, the area under the concentration-time curve from time 0 to infinity (AUC(0–inf)) showed equivalence for des-CIC in healthy subjects and patients with asthma, with a ratio of 1.003 (90% confidence interval between 0.815 and 1.234). The mean terminal half-life (t1/2) for des-CIC was also similar in patients with asthma (3.15 hours) and healthy subjects (3.33 hours). Furthermore, the pharmacokinetic parameter estimates for ciclesonide were comparable between the study groups. Conclusion: After administration of a single dose of ciclesonide, the pharmacokinetic parameter estimates for des-CIC were equivalent between patients with mild-to-moderate asthma and healthy subjects, suggesting that there is comparable lung deposition and activation of ciclesonide in the 2 populations.Correspondence to:
R. Nave, PhD
Drug Metabolism and Pharmacokinetics
ALTANA Pharma AG
Byk-Gulden-Straße 2
78467 Konstanz, Germany
Email: ruediger.nave@altanapharma.com
Drug Utilization and Safety
Analysis of German package inserts
J. Fuchs, M. Hippius and M. Schaefer
Abstract
J. Fuchs, M. Hippius and M. Schaefer
1Institute of Clinical Pharmacology, Friedrich Schiller University Jena, 2Department for Drug Regulatory Affairs, Institute of Pharmacy, University of Bonn, and 3Institute of Clinical Pharmacology, Charité Humboldt University Berlin, Germany
Objective: Package inserts have an important impact on patients compliance and thus on the effectiveness of drug use. Despite efforts of the European or national regulatory authorities and manufacturers to improve the readability and comprehensiveness of package inserts, they are still the subject of critical discussion. Material and methods: 68 German package inserts were chosen for a detailed analysis of their quality and suitability based on a set of 104 quality criteria developed prior to the survey. Results: In many cases package inserts available on the German drug market did not include important information or were difficult to read or understand. In 73.5% of cases, the daily maximum dose was missing and 63.2% gave no information on the measures to take for each of the interactions. 66.2% of package inserts provided no instructions about the correct storage and 58.8% gave no instructions on the appropriate storage temperature. In 13 cases, dosage instructions were provided only in milligrams of active substance instead of a number of tablets or volume of liquid. 98.5% of the 68 package inserts included non-quantifiable statements such as “high dosage” or “take 2 – 4 tablets, 1 – 3 times daily”. 97.1% contained repetitious information, 83.8% included advertising elements and 8.8% contained contradictory information. Conclusion: Package inserts must be optimized and tested by selected groups of patients prior to approval of the drug. This will avoid misunderstandings and lack of information and ensure that use of the drug will give the best possible outcome and avoid safety risks.Correspondence to:
Dr. J. Fuchs
Magnus-Poser-Straße 6
07749 Jena, Germany
Email: jfuchs-jena@t-online.de
Pharmacodynamics
Disproportionately elevated proinsulin levels in type 2 diabetic patients treated with sulfonylurea
M. Dworacka, M. Abramczyk, H. Winiarska, S. Kuczynski, M. Borowska and K. Szczawinska
Abstract
M. Dworacka, M. Abramczyk, H. Winiarska, S. Kuczynski, M. Borowska and K. Szczawinska
Department of Pharmacology, Poznan University of Medical Sciences, Poznan, Poland
Objective: Hyperproinsulinemia in type 2 diabetic subjects has recently been accepted as an independent cardiovascular risk factor. Moreover, it has been confirmed that high proinsulin concentrations stimulate amylin secretion by pancreatic b-cells and amyloid accumulation within pancreatic islets leading to impairment of pancreatic islets secretory function. The association between sulfonylureas administration and secretory function of pancreatic b-cells, especially concerning insulin precursor peptides, is not sufficiently elucidated. Preliminary studies by our research group revealed that the fasting proinsulin serum concentration is significantly higher in type 2 diabetic patients treated with sulfonylureas than in a well-matched group treated with insulin only. Methods: A total of 101 subjects with type 2 diabetes were treated either with sulfonylureas (n = 32), with insulin (n = 40), with sulfonylureas + insulin (n = 17) or with diet alone (n = 12). Results: The basal secretory function in the four groups were comparable (C-peptide fasting serum level > 0.5 ng/l). An effect of fasting glycemia, long-term metabolic control (HbA1c), postprandial hyperglycemia (1,5-anhydro-D-glucitol), insulin resistance (HOMAIRscore) and diabetes duration on the fasting proinsulin serum level in the subjects treated could be excluded. Conclusion: The disproportionately high proinsulin levels are due to sulfonylureas therapy. The effect is independent of fasting glycemia, long-term metabolic control, postprandial hyperglycemia, diabetes duration and peripheral insulin resistance.Correspondence to:
M. Dworacka
Department of Pharmacology
Poznan University of Medical Sciences
Rokietnicka 5a str.
60-806 Poznan, Poland
Email: mdworac@am.poznan.pl
Pharmacodynamics
Effects of a fenofibrate/losartan combination on the plasma concentration and urinary excretion of purine bases
T. Ka, T. Inokuchi, Z. Tsutsumi, S. Takahashi, Y. Moriwaki and T. Yamamoto
Abstract
T. Ka, T. Inokuchi, Z. Tsutsumi, S. Takahashi, Y. Moriwaki and T. Yamamoto
Division of Endocrinology and Metabolism, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
Objective: To assess the effects of a combination of fenofibrate and losartan on the plasma concentrations and urinary excretion of purine bases in healthy male subjects. Methods: 5 healthy males participated in a fenofibrate plus losartan combination study. The plasma concentrations and urinary excretion of purine bases (hypoxanthine, xanthine, uric acid) were measured before and after administrations of losartan (100 mg o.d.) alone for 2 weeks, losartan and fenofibrate together for 2 weeks and fenofibrate (300 mg o.d.) alone for 2 weeks, which were given consecutively over a 6-week period. Results: Losartan alone significantly reduced the serum uric acid concentration and increased uric acid excretion, whereas the combination of losartan and fenofibrate reduced serum uric acid concentrations further with a concomitant increased uric acid excretion. Fenofibrate alone also reduced plasma uric acid concentration with an increase in urinary excretion, although the effect was weak when compared with the combination treatment. The plasma concentrations and urinary excretion of oxypurines remained unchanged throughout the entire study. Conclusion: A combination of fenofibrate and losartan demonstrated an additive urate-lowering effect which may be beneficial in the treatment of patients with gout and hypertriglyceridemia.Correspondence to:
Y. Moriwaki, MD
Division of Endocrinology and Metabolism
Department of Internal Medicine
Hyogo College of Medicine
Mukogawa-cho 1-1
Nishinomiya, Hyogo 663-8501, Japan
Email: moriwaki@hyo-med.ac.jp
Clinical Trials
Methacholine challenge tests: sample sizes required in crossover trials
M. Neuhäuser and K.-H. Jöckel
Abstract
M. Neuhäuser and K.-H. Jöckel
Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Germany
Objective: Methacholine challenge testing is common for assessing the pharmacodynamic properties of anti-asthma drugs. In order to design studies and to interpret published studies, sample size calculations are essential. Unfortunately, wrong sample sizes were previously reported in the literature. We present correct sample sizes required for the comparison of two treatments based on methacholine challenge testing in a crossover study. Methods and results: Formulas for sample size calculations and the resulting number of subjects required for a specified power are presented for studies designed to show a difference as well as for equivalence and non-inferiority studies. Conclusions: A much larger sample size is required for methacholine challenge testing than previously reported.Correspondence to:
M. Neuhäuser
Institute for Medical Informatics, Biometry and Epidemiology
University Hospital Essen
Hufelandstraße 55
45122 Essen, Germany
Email: markus.neuhaeuser@medizin.uni-essen.de
Therapeutics
Chronomodulated chemotherapy with oxaliplatin, 5-FU and sodium folinate in metastatic gastrointestinal cancer patients: analysis of non-hematological toxicity and patient characteristics in a
K. Farker, U. Merkel, U. Wedding, M. Hippius, K. Höffken and A. Hoffmann
Abstract
K. Farker1, U. Merkel1, U. Wedding2, M. Hippius1, K. Höffken2 and A. Hoffmann1
1Institute of Clinical Pharmacology, 2Clinic of Internal Medicine, Friedrich Schiller University Jena, Germany
Objective: Several clinical trials have demonstrated that oxaliplatin is a useful agent in combination with 5-fluorouracil (5-FU) and folinic acid (FA) for the treatment of patients with colorectal carcinoma. The aims of this pilot study were to evaluate non-hematological toxicity and patient characteristics in gastrointestinal cancer patients treated with chronomodulated chemotherapy consisting of oxaliplatin, 5-FU and sodium folinate. Methods: Patients with metastatic gastrointestinal cancer received a chronomodulated regimen with oxaliplatin (25 mg/m2), 5-FU (750 mg/m2) and sodium folinate (150 mg/m2). Non-hematological toxicities were evaluated and analyzed in relation to patient characteristics, i.e. age, sex, body weight, body mass index (BMI), body surface area and smoking status. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria. Results: The severity of non-hematological toxicity was generally moderate. Grade 4 toxicity was only found in 2 patients with diarrhea (12.5%). The most frequent common adverse events were nausea, Grades 1 – 2 in 13 patients (81.3%), followed by motor neuropathy, Grades 1 – 3 in 11 patients (68.9%). The analyses showed that patient characteristics such as BMI and smoking status were associated with mucositis/stomatitis, vomiting or mood alteration. Furthermore, there was a relationship between smoking status and the overall non-hematological toxicity. Smokers had significantly higher overall toxicity than non-smokers and body mass index correlated significant with overall toxicity. Conclusion: The results of this pilot investigation suggest that a chronomodulated regimen with oxaliplatin, 5-FU and sodium folinate has a manageable non-hematological toxicity profile and that toxicity of the chronomodulated schedule studied depends on the patient characteristics. In further investigations, risk factors determining chemotherapeutic toxicity should be considered. Because of the small number of patients in this pilot investigation, the findings need to be confirmed in a larger clinical study.Correspondence to:
PD Dr. K. Farker
Institute of Clinical Pharmacology
Friedrich Schiller University Jena
Dornburger Straße 159
07740 Jena, Germany
Email: katrin.farker@med.uni-jena.de
Biavailability Section
Significant food interactions observed with a nifedipine modified-release formulation marketed in the European Union
M. Wonnemann, B. Schug, K. Schmücker, E. Brendel, P.A. van Zwieten and H. Blume
Abstract
M. Wonnemann1, B. Schug1, K. Schmücker1, E. Brendel2, P.A. van Zwieten3 and H. Blume1
1SocraTec R&D GmbH, Oberursel, 2Institut für Klinische Pharmakologie, Pharmaforschungszentrum, Bayer HealthCare AG, Wuppertal, Germany, and 3Departments of Pharmacotherapy, Cardiology and Cardio-Thoracic Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
The objective of this study was to compare the rate and extent of nifedipine bioavailability after single dose administration of Adalat OROS 30 (Reference) and Nifedipine Sandoz retard 30 tablets (Test). Both modified release formulations are marketed in Member States of the European Union. Prior to the clinical study the in vitro dissolution characteristics were investigated. There was a significant pH dependency observed with the Test product but drug release with the Reference product was almost independent of the experimental conditions used. In the subsequent open, randomized, controlled, 4-way crossover study both pharmaceutical products were administered to 28 healthy male volunteers, either after fasting overnight or immediately after a high-fat American breakfast. Blood sampling was performed over 48 hours post-dose for the determination of pharmacokinetic profiles of nifedipine. Considerable differences were observed between the two formulations when administered to fasted subjects where maximum nifedipine plasma concentration (Cmax) were higher in the case of the Test formulation. Differences were even more pronounced after a high-fat American breakfast. Under these conditions a significant food interaction was detected in the case of Nifedipine Sandoz retard 30 with a three-fold increase in the mean Cmax when compared to values obtained in fasting subjects. In contrast, food intake had no clinically relevant effect on bioavailability of nifedipine (rate and extent) in the case of Adalat OROS 30. The pharmacokinetic findings in this study were reflected in the adverse event pattern which indicated a potential tolerability problem in the case of Nifedipine Sandoz retard 30. The results confirm the relationship between the in vitro dissolution profile results and the effects of the drug in vivo. Dose dumping after intake of a high-fat meal could be shown. Nifedipine Sandoz retard 30 is not bioequivalent to Adalat OROS 30 and produced highly variable and poorly predictable nifedipine plasma concentrations. The differences observed between the two products investigated may have direct therapeutic relevance when switching from one formulation to the other and, in particular, when administration conditions change i.e. administration in the fasting state and administration with a meal, since the pharmacological and therapeutic actions of nifedipine are closely associated with the concentration. Correspondence to:
Dr. M. Wonnemann
SocraTec R&D GmbH
Feldbergstraße 27-29
61440 Oberursel, Germany
Email: meinolf.wonnemann@socratec-pharma.de
Book review
Calcium in human health
M. Igel
Letters to the Editor
Evaluation of prescribing errors in primary care
S. Panthee
Letters to the Editor
Response to Mr. Panthee’s comments on “Evaluation of prescribing errors in primary care”
K.A.J. Al Khaja, T.M. Al-Ansari and R.P. Sequeira
Abstract
K.A.J. Al Khaja, T.M. Al-Ansari and R.P. Sequeira
