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
Price
42.00 $
Volume 44 p. 31 - 37
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: [email protected]
Adverse Drug Reactions
Pharmacokinetics of oxaliplatin and non-hematological toxicity in metastatic gastrointestinal cancer patients treated with chronomodulated oxaliplatin, 5-FU and sodium folinate in a pilot investigat
U. Merkel, K. Farker, U. Wedding, M. Roskos, M. Hippius, K. Höffken and A. Hoffmann
Price
42.00 $
Volume 44 p. 128 - 134
Abstract
U. Merkel1, K. Farker1, U. Wedding2, M. Roskos3, M. Hippius1, K. Höffken2 and A. Hoffmann1
1Institute of Clinical Pharmacology, 2Clinic of Internal Medicine, 3Department of Clinical Chemistry and Laboratory Diagnostics, Friedrich Schiller University, Jena, Germany
Objective: To analyze in a pilot study the association between the pharmacokinetics of chronomodulated administered oxaliplatin and non-hematological toxicity in patients with metastatic gastrointestinal cancer. Methods: 16 patients received a 4-day chemotherapeutic regimen consisting of a 12-h chronomodulated infusion of oxaliplatin (25 mg/m2) followed by a 12-h chronomodulated infusion of 5-fluorouracil (750 mg/m2) and sodium folinate (150 mg/m2) daily. Plasma pharmacokinetics of oxaliplatin, measured as ultrafiltrable platinum, were determined. Results: Pharmacokinetics and non-hematological adverse events could be assessed in all patients included in the study. Pharmacokinetic parameters showed moderate interpatient variability. The occurrence of nausea and vomiting, but not diarrhea, was significantly associated with the pharmacokinetics of ultrafiltrable platinum. Thus, increased AUC values were observed in patients who experienced nausea or vomiting. No differences in pharmacokinetic parameters were found between patients with and without oxaliplatin-induced neurotoxicity or the other selected non-hematological toxicities. Conclusion: The preliminary results in this pilot study suggest an association between pharmacokinetics of ultrafiltrable platinum and non-hematological toxicity such as nausea and vomiting. Furthermore, although the sample size is limited, systemic exposure to ultrafiltrable platinum appears to predict the risk of non-hematological toxicity in patients treated with chronomodulated oxaliplatin combined with 5-FU and FS.
*Supported by Deutsche Krebshilfe(AZ 70-2445-Hö3)Correspondence to:
Dr. U. Merkel
Institute of Clinical Pharmacology
Friedrich Schiller University
Dornburger Straße 159
07740 Jena, Germany
Email: [email protected]
Übersicht
Der alte Patient mit terminaler Niereninsuffizienz – Behandlungsdefizite und Therapieoptionen
A. Hoffmann, R. Dikow, M. Zeier und V. Schwenger
Price
42.00 $
Jahrgang 33 p. 599 - 608
Abstract
Nieren- und Hochdruckkrankheiten, Jahrgang 33, Nr. 10/2004, S. 599–608
Der alte Patient mit terminaler Niereninsuffizienz – Behandlungsdefizite und Therapieoptionen
A. Hoffmann, R. Dikow, M. Zeier und V. Schwenger
Sektion Nephrologie, Medizinische Universitätsklinik Heidelberg
In den westlichen Ländern weist der alte Patient die höchste Inzidenz zur Nierenersatztherapie auf. Im Allgemeinen werden Patienten sehr spät zum Nephrologen überwiesen. Insbesondere der alte Patient wird einer nephrologischen Fachbetreuung noch später zugeführt. Diese späte Überweisung ist u.a. assoziiert mit höherer Mortalität, höheren Behandlungskosten und deutlich verminderter Lebensqualität. Um diese Defizite zu erfassen, wurden zwischen 1998 und 2001 alle Patienten erfasst, die in unserem Zentrum einer Nierenersatztherapie zugeführt wurden. 75-jährige oder ältere Patienten wurden im Median erst 4 Wochen vor Dialysebeginn zum Nephrologen überwiesen, jüngere Patienten (<75J.) wurden hingegen im Median 24,5 (Wilcoxon Test p=0.003) Wochen vor Dialysebeginn einem Nephrologen vorgestellt. Die Einjahresmortaliät der älteren Patienten betrug 31% gegenüber 16% bei den jüngeren Patienten. Diese hohe Mortalität ist bedingt durch die hohe Einjahresmortaltät der spätüberwiesenen alten Patienten (41% gegenüber 13% der frühüberwiesenen alten Patienten). Rechtzeitige Zuweisung zum Nephrologen auch oder insbesondere des alten Patienten ist nicht nur mit verminderter Mortalität assoziiert, sondern kann auch die Progression einer chronischen Niereninsuffizienz im Alter wirkungsvoll verzögern. Somit kann eine Dialyse oft um Monate bis Jahre hinausgeschoben werden. Bei adäquater Betreuung liegt die Hospitalisierungsrate des alten nierenkranken Patienten nur gering über der des jungen Patienten. Die adäquate Versorgung in der Prädialysephase hat somit einen erheblichen Einfluss auf die Lebensqualität des Patienten und somit auf entstehende Kosten im Gesundheitssystem.Correspondence to:
Dr. med. V. Schwenger
Sektion Nephrologie
Medizinische Universitätsklinik Heidelberg
Bergheimer Straße 56a
D-69115 Heidelberg
Email: [email protected]
Original
Assessment of ADRs associated with lipid- lowering agents recorded in the Department of Internal Medicine, University Hospital, Jena
M. Hippius, K. Farker, S. Helble and A. Hoffmann
Price
42.00 $
Volume 40 p. 97 - 101
Abstract
M. Hippius, K. Farker, S. Helble and A. Hoffmann
Department of Clinical Pharmacology, Friedrich Schiller University of Jena, Jena, Germany
Drug-related illness is an important cause of admission to hospital. Little information is available regarding the frequency of ADRs caused by antilipidemic agents classified as HMG-CoA reductase inhibitors (statins). Treatment with statins has been associated with the occurrence of myopathy or liver toxicity in case reports. Recent lipid intervention studies have involved the implementation of lipid lowering therapy with HMG-CoA reductase inhibitors in cardiovascular risk management. Since January 1997 we have been involved in a study, the aim of which was to improve the spontaneous drug information reporting system in Germany. The study was supported by the German Federal Institute for Drugs and Medical Devices, the “Bundesinstitut für Arzneimittel und Medizinprodukte”, Berlin BfArM. Between early 1997 and late 2000, as a result of this monitoring of ADRs, we analyzed all patient histories concerning therapy with statins. A total of 550 ADR patients were evaluated, (209 male, 341 female) with a mean age of 66.4 years. 27 (4.9%) of all patients had received statins (atorvastatin = 12, fluvastatin = 7, simvastatin as well as pravastatin = 3, lovastatin = 2). Only 2 of the 27 patients admitted to hospital for typical ADRs of statins such as skeletal muscle toxicity (e.g. myalgia, rhabdomyolysis) or disorders involving hepatic structure or function were receiving statins (atorvastatin). An increased risk of rhabdomyolysis has been reported in the case of several statins, following concomitant use with erythromycin, cyclosporine or itraconazole, all of which are potent inhibitors of CYP3A4 enzyme. But only 1 atorvastatin patient had received cyclosporine as a CYP3A4 inhibitor. After discontinuing medication, signs of intoxication disappeared. The antihyperlipidemic drugs available are generally safe and effective, and rate of ADRs is low if concomitant intake of other drugs and the differing pharmacokinetic profiles of the statins are considered.Correspondence to:
PD Dr. M. Hippius; Department of Clinical Pharmacology, Friedrich Schiller University of Jena, Dornburger Straße 159, D-07740 Jena, Germany
Email: Marion.Hippius@ med.uni-jena.de
Original
Assessment of frequencies of lifestyle factors and polymorphisms of drug-metabolizing enzymes (NAT2, CYP2E1) in human hepatocellular carcinoma (HCC) patients in a department of surgical medicine – a pilot investigation
K. Farker, U. Schotte, J. Scheele and A. Hoffmann
Price
42.00 $
Volume 40 p. 120 - 124
Abstract
K. Farker1, U. Schotte2, J. Scheele2 and A. Hoffmann1
1Institute of Clinical Pharmacology, and 2Surgical Clinic, Friedrich Schiller University Jena, Germany
The pathogenesis of human hepatocellular carcinoma (HCC) is a multistage process with the involvement of a multifactorial etiology. The role of drugs as risk factors has not been conclusively ascertained, but it appears that the use of oral contraceptives can be included. In the multifactorial etiology of human hepatocellular carcinoma (HCC), an association and interaction between genetic polymorssphisms of xenobiotic metabolizing enzymes, lifestyle factors and cancer risk has been postulated. This pilot investigation examines the frequency of polymorphisms in selected genes (NAT2, CYP2E1) coding for xenobiotic metabolizing enzymes, and lifestyle habits (cigarette smoking, alcohol consumption) in 38 HCC patients. Genotyping of xenobiotic metabolizing enzymes was carried out using polymerase chain reaction – restriction fragment length polymorphism methods and DNA extracted from peripheral blood cells. In addition, HCC patients were interviewed with regard to their cigarette smoking habits and alcohol consumption using a standardized questionnaire. The results of this pilot investigation showed that the majority of the HCC patients smoke and consume alcohol. We found no predominance of slow acetylators (45%) or rapid acetylators (55%). 70.6% of slow acetylators were smokers. 86.5% of all patients with homozygote PstI/RsaI genotype also carried the homozygote DraI genotype, whereas 10.8% of all subjects with heterozygote PstI/RsaI genotype also carried the heterozygote DraI genotype. These genotype frequencies remain to be confirmed in a larger ethnic group. Whether polymorphisms of xenobiotic metabolizing enzymes is an important risk factor in (cigarette smoking-/alcohol consumption) HCC or not is currently being investigated in a case-control study in the same ethnic group.Correspondence to:
Dr. K. Farker; Institute of Clinical Pharmacology, Friedrich Schiller University Jena, Dornburger Straße 159, D-07740 Jena, Germany
Email: katrin.farker@ med.uni-jena.de
Adverse drug reactions
Adverse drug reaction monitoring – digitoxin overdosage in the elderly
M. Hippius, B. Humaid, T. Sicker, A. Hoffmann, M. Göttler and J. Hasford
Price
42.00 $
Volume 39 p. 336 - 343
Abstract
M. Hippius1, B. Humaid1, T. Sicker1, A. Hoffmann1, M. Göttler2 and J. Hasford2
1Department of Clinical Pharmacology, Friedrich Schiller University of Jena, and 2Department of Medical Informatics, Biometry and Epidemiology, Pharmacoepidemiology Research Group, Ludwig Maximilians University, Munich
Drug-related illness is an everlasting universal problem and also an important cause of admissions to hospitals. Adverse reactions are still grossly underreported by medical professions. Little information is available regarding the frequency or type of ADRs managed in hospitals. Since January 1997, we have taken part in a study, supported by the German Federal Institute for Drugs and Medical Device to improve the spontaneous drug information reporting system in Germany. Three German regionalized Departments of Clinical Pharmacology – Jena, Dresden, Rostock – serve as Pharmacovigilance Centers in collaboration with the Pharmacoepidemiology Research Group of the University of Munich. Since January 1997, the regional group in Jena has been monitoring the University Clinic of Internal Medicine for admissions caused by adverse drug reactions. All emergency cases and patients on intensive care units were checked for adverse drug reactions. We present our results, including clinical and demographic data, concerning intoxications and especially those involving digitoxin in 210 patients with ADR. Forty patients with digitoxin toxicity had an average age of 81 years (81.1 ± 6.3), a low body weight (59.7 ± 12.7 kg) and 3 out of 4 were women. 75% of all patients with digitoxin side effects had elevated serum digitoxin levels with concentrations higher than 25 mg/ml. The relatively high frequency of digitoxin intoxications in our hospital may reflect the advanced age and low body weight of patients. Patients received digitoxin regardless of age, weight and, sometimes, clinical indication. Physicians should be aware of drugs having a high risk when used in elderly patients. The use of digitoxin assays and keeping serum levels within or near the therapeutic range will diminish the incidence of overdoses.Correspondence to:
Dr. M. Hippius; Department of Clinical Pharmacology, Friedrich Schiller University Jena, Dornburger Straße 159, D-07740 Jena, Germany
Email: [email protected]
Preface / Drugs: Prescription by the physician and use by the patient
A. Hoffmann
Price
42.00 $
Volume 39 p. 467 - 467
Editorial
Pharmacoepidemiology
A. Hoffmann
Price
42.00 $
Volume 39 p. 468 - 470
Original
Pattern of outpatient drug therapy in diabetics admitted to hospital – preliminary results
I.R. Reimann, S. Schilbach, M. Cercasov and A. Hoffmann
Price
42.00 $
Volume 39 p. 499 - 502
Abstract
I.R. Reimann, S. Schilbach, M. Cercasov and A. Hoffmann
Institute of Clinical Pharmacology, Friedrich Schiller University, Jena, Germany
The prevalence of outpatient treatment with various drug groups is significantly higher in diabetics than in non-diabetic control patients. In addition to the specific diabetes-related prescriptions, diabetics were more frequently treated with drugs acting on the alimentary tract or used in metabolic disorders (ATC code A), drugs used in disorders of the blood and blood-forming organs (ATC B), cardiovascular system (ATC C), musculo-skeletal system (ATC M) and nervous system (ATC N) – resulting in markedly higher outpatient costs in this patient group. Objective of this investigation was to analyze the pre-hospital prescription pattern of diabetics and non-diabetic controls at the time of admission to hospital. Method: A sample survey of a total of 189 general medical and 68 surgical admissions involving diabetics and 676 and 143 non-diabetic control patients – corresponding in age, sex and main diagnosis – were analyzed with regard to selected medical and demographic characteristics and pharmacotherapy. Results and discussion: The prevalence of non-diabetic drug treatment in diabetics was highest for ATC C (87.8% and 69.1%), ATC A (40.7% and 27.9%; without A10) and ATC B (39.2% and 29.4%) in internal and surgical admissions, respectively. A substantially higher prevalence was found for ATC groups B and C in diabetics and controls admitted to medical wards than in epidemiological prescription analyses. Conclusion: Data indicate that the need for treatment with cardiovascular drugs and drugs used to treat disorders of the blood and blood-forming organs may be associated with a higher risk of hospitalization in general medical wards.Correspondence to:
Dr. I. R. Reimann; Institut für Klinische Pharmakologie der Friedrich-Schiller-Universität Jena, Dornburger Straße 159, D-07740 Jena, Germany
Original
Analysis of point mutation in exon 2 of CYP2E1 gene in renal cell/urothelial cancer patients in comparison with control population
K. Farker, M.H. Lehmann, R. Kästner, J. Weber, V. Janitzky, J. Schubert and A. Hoffmann
Price
42.00 $
Volume 38 p. 30 - 34
Abstract
K. Farker1, M.H. Lehmann1, R. Kästner1, J. Weber3, V. Janitzky2, J. Schubert2 and A. Hoffmann1
1Institute of Clinical Pharmacology, 2Clinic for Urology, Friedrich Schiller University Jena, 3Department of Genome Analysis, Institute of Molecular Biotechnology, Jena, Germany
Objective: Genetic polymorphisms of human cytochrome P450s have been implicated to be of importance for susceptibility to different cancers. Recently, a point mutation was found in the exon 2 of the CYP2E1 gene (CYP2E1*2) [Hu et al. 1997]. In order to evaluate a possible link between the point mutation in exon 2 of the CYP2E1 gene and the susceptibility to renal cell/ urothelial cancer, we developed a screening method based on the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Material: DNA of peripheral white blood cells was isolated from 158 renal cell/urothelial cancer patients as well as from 150 controls. Method: Primers for PCR were designed by the Primer 3 release 0.1 program. The PCR yield a product of 215 base pairs (bp), which was digested with the restriction enzyme Hha I. The DNA fragments were separated on a 3% agarose gel stained with ethidium bromide. Restriction enzyme digestion of the PCR product obtained from the wild-type DNA resulted in the appearance of a 66 bp, a 43 bp, a 40 bp, a 39 bp and a 28 bp DNA fragment. In contrast to the wild-type, the digestion of the PCR product from DNA carrying the point mutation resulted in the loss of the 39 bp and 40 bp fragments and the appearance of an additional 79 bp fragment. Therefore, the loss of one Hha I restriction site caused by a single nucleotide exchange is suitable for the identification of the point mutation in exon 2 of CYP2E1 gene. Results: However, we could not detect any point mutation in any of the 158 renal cell/urothelial cancer patients or the 150 controls. The distribution of the point mutation in exon 2 of CYP2E1 gene did not show any difference in renal cell/urothelial cancer patients and controls. Conclusion: This might indicate a lack of association between this CYP2E1 polymorphism (CYP2E1*2) and renal cell/urothelial cancer.Correspondence to:
Dr. K. Farker; Institute of Clinical Pharmacology, Friedrich Schiller University Jena, Dornburger Straße 159, D-07740 Jena, Germany
Original
Bioavailability of a new effervescent tablet of diclofenac
B. Terhaag, A. Hoffmann, M. Barkworth and B. Vens-Cappell
Price
42.00 $
Volume 38 p. 546 - 551
Abstract
B. Terhaag1, A. Hoffmann1, M. Barkworth2 and B. Vens-Cappell2
1Corporate Research and Development, ASTA Medica Group, Arzneimittelwerk Dresden, Radebeul, and 2Phoenix International McKnight, Hamburg,Germany
Objective: The bioavailability of a newly developed effervescent tablet containing 50 mg diclofenac Na (DIC-effervesc) was investigated and compared with an enteric-coated dragée (DIC-enteric). Subjects and method: 24 healthy, male and informed volunteers (mean body weight 78.8 kg, mean age 31.9 years) received in a randomized cross-over design a single dose of 50 mg diclofenac as DIC-effervesc and DIC-enteric. A total of 19 blood samples were obtained before and up to 12 h after administration according to the different properties of the galenic formulation. Diclofenac was analyzed by a sensitive HPLC method with a lower limit of quantification of 20 ng/ml. The bioavailability was compared as ratios of the geometric means of AUC0-¥ and Cmax. Results: DIC-effervesc shows no lag time, a tmax within 30 min and a double peak of Cmax in 15/24 subjects. The mean Cmax (arithm. mean ± SD) for DIC-effervesc is 950 ± 341 ng/ml (first Cmax) and for DIC-enteric 1364 ± 335 ng/ml. The mean AUC0-¥ (arithm. mean ± SD) amounts to 1097 ± 210 ng/ml´h for DIC-effervesc and 1262 ± 220 ng/ml´h for DIC-enteric. Based on the point estimator and the 90% interval DIC-effervesc is bioequivalent in respect to amount absorbed (86.4%; 81.8 – 91.3%). DIC-effervesc was well tolerated. Conclusion: The new effervescent tablet of diclofenac Na shows a rapid absorption without lag time, the same amount of absorption and a slightly lower Cmax (caused by a double peak phenomenon) in comparison to the enteric-coated dragée. A rapid onset of therapeutic effect is postulated in acute pain disorders.Correspondence to:
Prof. Dr. B. Terhaag; Arzneimittelwerk Dresden GmbH, Department of Medical Research, Meißner Straße 35, D-01445 Radebeul, Germany
Übersicht
Zur Doping-Epidemiologie in Fitnessstudios im Raum Kitzingen und Würzburg
C. Raschka und A. Hoffmann
Price
42.00 $
Jahrgang 29 (2017) p. 14 - 20
Abstract
Prävention und Rehabilitation, Jahrgang 29, Nr. 1/2017, S. 14-20
Zur Doping-Epidemiologie in Fitnessstudios im Raum Kitzingen und Würzburg
C. Raschka und A. Hoffmann
Institut für Sportwissenschaft der Julius-Maximilians-Universität Würzburg
Der Leistungssport wird immer wieder von nationalen wie internationalen Doping- Fällen erschüttert. Inzwischen ist die Einnahme von Doping-Substanzen allerdings auch unter Freizeitsportlern weit verbreitet. Um den Doping-Konsum im Kitzinger und Würzburger Raum zu erforschen, wurde eine Befragung unter 284 Mitgliedern von 7 Fitnessstudios durchgeführt. 3,3% der befragten Kraftsportler gaben an, schon einmal Doping-Mittel eingenommen zu haben. Ein aktueller Konsum konnte lediglich bei 0,6% der Studienteilnehmer festgestellt werden. Unter den Frauen befand sich keine Athletin, die ihr Training jemals durch leistungssteigernde Medikamente unterstützt hat. Der Vergleich zwischen privaten Studios und Ketten zeigte einen höheren prozentualen Anteil an Abusern in den Ketten. Bei den konsumierten Substanzen handelte es sich zu 83,3% um anabole Steroide und zu 33,3% um Stimulanzien. Die Medikamente wurden in den meisten Fällen über den Schwarzmarkt bezogen. Außerdem fiel auf, dass verhältnismäßig viele Doping-Konsumenten auch Kontakt zu illegalen Drogen hatten. Ebenso war das Bildungsniveau unter diesen Personen niedriger als bei den anderen Sportlern. Fazit: Doping bei Freizeitsportlern im Kitzinger und Würzburger Raum scheint nicht so weit verbreitet zu sein wie in anderen Regionen. Ein generelles Problem stellt allerdings der stetig wachsende und schwer kontrollierbare Schwarzmarkt dar.Correspondence to:
Prof. Dr.med. Dr. rer. nat. Dr. Sportwiss. Christoph Raschka
Internist und Facharzt für Allgemeinmedizin – Sportmedizin
Im Igelstück 31
36088 Hünfeld
Email: [email protected]
