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Abstract

M. Baumhäkel¹, D. Kasel¹, R.A. Rao-Schymanski¹, R. Böcker², K.T. Beckurts³, M. Zaigler¹, D. Barthold¹ and U. Fuhr¹

¹Clinical Pharmacology, Institute for Pharmacology, University of Köln, ²Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen, and ³Department of Visceral and Vascular Surgery, University of Köln, Germany
Background: The human cytochrome P450 enzyme CYP3A4 is involved in the metabolism of many anticancer drugs. Since these drugs are usually administered in a polychemotherapy regimen, the objective of this study was to examine their inhibitory potency on CYP3A4 with regard to possible mutual drug interactions. Method: CYP3A4 activities in human liver microsomes from 2 donors were determined using the oxidation of the dihydropyridine denitronifedipine, a specific CYP3A4 substrate, at a concentration of 50 mM (= KM). Formation of the pyridine metabolite was measured using HPLC. Inhibitor concentrations used were 0.5, 5 and 50 mg/ml, except for cyclophosphamide and ifosfamide (0.5, 2.5 and 5 mg/ml) and for paclitaxel (0.05, 0.15, 0.5, 1.5 and 5 mg/ml). Results: The following substances showed an inhibitory effect on CYP3A4 (IC50 values for the 2 microsome samples are parenthesized): cyclophosphamide (12.3/9.2 mmol/l), mafosfamide generated 4-OH-cyclophosphamide (152/163 mmol/l), ifosfamide (3.6/2.5 mmol/l), vinblastine sulfate (20/44 mmol/l), vincristine sulfate (67/176 mmol/l), daunorubicin hydrochloride (206/200 mmol/l), doxorubicin hydrochloride (160/215 mmol/l), teniposide (64/84 mmol/l) and docetaxel (6.4/12.7 mmol/l). No inhibitory effect on CYP3A4 was observed with epirubicin, etoposide, paclitaxel, cytarabine, 5-FU, 6-mercaptopurine, methotrexate, cisplatin, carboplatin, bleomycin, busulfan, chlorambucil and mitomycin. Conclusion: Comparing IC50 values with plasma concentrations present during antineoplastic therapy, the agents cyclophosphamide, ifosfamide, vinblastine, teniposide and docetaxel could possibly cause clinical drug interactions by inhibition of CYP3A4. Some recently described clinical interactions with antineoplastic agents may be explained by these results.Correspondence to:
Prof. Dr. U. Fuhr; Institut für Pharmakologie, Klinische Pharmakologie, Universität zu Köln,
Gleueler Straße 24, D-50931 Köln, Germany
Email: uwe.fuhr@medizin.uni-koeln.de

Abstract

P. Biswas, L.V. Wilton and S.A.W. Shakir

Drug Safety Research Unit, Burseldon Hall, Southampton and School of Medicine, University of Southampton, UK
Objective: Montelukast is an orally administered cysteinyl receptor antagonist, approved for the treatment of asthma. There is pharmacological plausibility of its effectiveness in the treatment of other immunologically mediated conditions such as eczema and urticaria. The objective of this study was to determine whether there are any beneficial effects of montelukast on eczema and urticaria. Method: A non-interventional observational cohort study was conducted between February 1998 and December 1998 using Prescription-Event Monitoring (PEM). During PEM studies, patients are systematically identified from dispensed prescription data and questionnaires are sent to the prescribing general practitioner (GP) asking them to report events occurring during and after treatment. In this study, events reported as eczema or urticaria improved were identified. A simple questionnaire was sent to the GPs for additional information. Results: The cohort comprised 15,612 patients, in which 16 reports of eczema or urticaria improved were identified. Questionnaires were sent to the GPs for additional information. Fifteen of the 16 questionnaires were returned. In 5 cases the GPs thought that there was an improvement of eczema or urticaria with montelukast treatment in patients who had history of long-standing eczema or urticaria. Of the remaining 11 cases there was an alternative explanation for the improvement of eczema or urticaria in 10 cases and one was unassessable. Conclusion: PEM is conducted to monitor the safety of medicines, and doctors report events including improvement in pre-existing conditions. Although the number of cases of improvement of eczema or urticaria in this cohort is small, there is a possibility that leukotriene inhibitors may be helpful in the treatment of these diseases. Further studies are needed to provide evidence as to whether montelukast will have a role in the treatment of these conditions.Correspondence to:
Dr. P. Biswas Drug Safety Research Unit, Burseldon Hall, Blundell Lane, Southampton, SO31 1AA, Hants, UK
Email: pipasha.biswas@dsru.org

Abstract

S. Harder¹, O. Mohr¹ and H. Klepzig²

¹Institute of Clinical Pharmacology, University Hospital, Frankfurt/Main, and ²Städtische Kliniken Offenbach, Germany
Objectives: In controlled trials, HMG-CoA reductase inhibitors (statins) effectively reduced cardiovascular events in patients with coronary artery disease (CAD). However, recent pharmacoepidemiological studies indicate an underuse of statins in the target population. The objective of this study was to examine the extent to which CAD patients in Germany actually received statins under field conditions. Methods: We evaluated the medical records of 296 patients referred to the cardiology outpatient clinic of the Frankfurt University Hospital by their general practitioner (GP) in the period 1995 to 1998. All patients had symptomatic, angiographically proven CAD, 142 had previous myocardial infarction. A diagnosis of dyslipidemia was taken from the records. Most patients were visited on more than 1 occasion. In all, we were able to access 296 records for a 1st visit, 76 records for a 2nd visit and 29 records for a 3rd visit and 16 records for > 3 visits. Results: According to the entry criteria of the 4S Trial (total cholesterol 5.5 – 8.0 mmol/l or 212 – 311 mg/dl), 108 patients were deemed as eligible for lipid-lowering treatment, criteria of the LIPID Trial (4.0 – 7.0 mmol/l or 154 – 270 mg/dl) gave a yield of 190 patients. The actual treatment rate with a statin at the 1st visit was 34% (LIPID Group) and 40% (4S Group). At later visits, the treatment rates with statins increased to 63% (LIPID Group) and 79% (4S Group), due to advice given to the GP by the outpatient clinic. When the observation period was devided into 2 periods (04/95 – 01/97; 02/97 – 09/98), actual treatment rates (all visits) for the 4S Group were 43% and 38%, respectively, indicating no further “penetration” of the 4S Study in the therapy decision-making of the GPs. Conclusions: The data indicate that necessary treatment with a HMG-CoA reductase inhibitor is often withheld in the ambulatory setting.Correspondence to:
PD Dr. S. Harder; Institute of Clinical Pharmacology at the Pharmazentrum Frankfurt, University Hospital, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany
Email: harder@em.uni-frankfurt.de

Abstract

H.S. Cha, J.H. Koh, C.H. Jeon, C.K. Lee, J.S. Kim and E.M. Koh

Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Objective: To compare the safety and efficacy of naproxen CR (1,000 mg once daily) with that of nabumetone (1,000 mg once daily) in the treatment of patients with symptomatic knee osteoarthritis (OA). Methods: A total of 159 Korean patients (80 in the naproxen CR group and 79 in the nabumetone group) were enrolled in this 4-week, single-blind, controlled, randomized, parallel study and an intention-to-treat model was used for data analysis. Six efficacy parameters were measured: Lequesne index, visual analogue pain scale at rest and at activity, patient’s and physician’s global assessment, and time to walk 50 feet. Results: Significant improvement in all efficacy parameters except time to walk 50 feet occurred at Week 2 and Week 4 in both groups. The mean improvement from baseline at Week 2 and Week 4 for the efficacy variables was not different between naproxen CR and nabumetone group. Twenty-four patients (30%) in the naproxen CR group and 18 patients (22.8%) in the nabumetone group withdrew from the study. Among them, only 1 patient in the naproxen CR group terminated the study prematurely due to an adverse event of dyspepsia. No statistically significant difference in the frequency of adverse events, including gastrointestinal symptoms, was observed between these 2 groups during the treatment period. Significant laboratory abnormalities also did not occur during the study period in both groups. Conclusions: Naproxen CR is an effective and tolerable drug in the treatment of knee OA. Efficacy and safety profiles are comparable to those of nabumetone.Correspondence to:
Dr. E.M. Koh; Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Kangnam-Ku, Seoul 135-710, Korea
Email: chahs@samsung.co.kr

Abstract

M. Ritzerfeld¹, M. Klasser² and H. Mann¹

¹Dialysezentrum Aachen, and ²gwd consult, Mühlheim/Main

Parathyroid hormone increases due to hypocalcemia even in the early phases of renal insufficiency. At the same time, hyperphosphatemia develops due to decreasing renal excretion which, in turn, intensifies secondary hyperparathyroidism. The cornerstones for prevention and therapy of renal osteopathy are, therefore, efficient lowering of phosphate levels and the early substitution of vitamin-D3 metabolites. In a post marketing surveillance (PMS) of almost 2000 dialysis patients with renal osteopathy, the course of therapy with Alfacalcidol (Bondiol®) was observed over a 6-month period. In 55.9% of cases, Alfacalcidol was administered at a daily dose of 0.25 mg. In 26.6% of patients, Alfacalcidol was administered every second day at a dose of 0.25 – 1 mg/d. In 16.1% of patients, Alfacalcidol was administered as pulse-therapy, mostly at a dose of 1 – 2 mg once or twice per week. To lower phosphate levels, 54.8% of patients received calcium compounds, 9.2% aluminium compounds, and 21.7% aluminium compounds in combination with calcium compounds. 14.3% of patients did not receive phosphate binding agents. Two thirds of patients had received active vitamin-D3-metabolites prior to commencing therapy with alfacalcidol, most frequently calcitrol. In 58.1%, the dialysis solution used had a calcium concentration of 1.5 mmol/l (44.8%) or lower; whereas in 41.9%, a higher calcium concentration was used – mostly 1.75 mmol/l (38%). During the observation period, serum concentrations of calcium and phosphate remained constant, suggesting that the risk of hypercalcemia due to therapy with Alfacalcidol was not increased. It was found that elevated alkaline phosphatase and parathyroid hormone levels could be significantly lowered (statistically). These effects could be observed both in patients who had been previously treated with vitamin-D3-metabolites and in patients without prior therapy. Efficacy and tolerability of therapy with Alfacalcidol was assessed to be very high by the attending nephrologists.Correspondence to:
Dr. med. M. Ritzerfeld; Dialysezentrum, Schurzelter Straße 564, 52074 Aachen, Germany

Abstract

B. Okopien¹, L. Cwalina¹, M. Lebek¹, J. Kowalski¹, M. Zielinski¹, M. Wisniewska-Wanat², Z. Kalina² and Z.S. Herman¹

¹Department of Clinical Pharmacology, and ²Department of Internal Diseases and Clinical Pharmacology, Medical University of Silesia, Katowice, Poland
Objective: Increased levels of fibrinogen and plasminogen activator inhibitor 1 (PAI-1) are associated with an increased risk of ischemic coronary disease and its complications. Since atherogenic dyslipidemias are well-known risk factors for coronary heart disease, this study aimed to determine whether Type IIb dyslipidemia, one of the most atherogenic dyslipidemias, is accompanied by increased PAI-1 and fibrinogen synthesis. The additional aim of this study was to evaluate the effect of micronized fibrates on the levels of PAI-1 and fibrinogen in patients with Type IIb dyslipidemia. Subjects: Thirty patients with Type IIb dyslipidemia and 12 age-matched control subjects were studied. Fourteen patients were treated with fenofibrate and 16 were treated with ciprofibrate for 1 month. Methods: Plasma PAI-1 levels were measured by the ELISA method with Diagnostica Stago kit. The level of fibrinogen was measured by the Clauss method. Results: PAI-1 levels in dyslipidemic patients before treatment differed significantly in both the fenofibrate and ciprofibrate treatment groups (101.18 ± 36.47 ng/ml, 87.64 ± 32.06 ng/ml, respectively) from those in the control group (32.32 ± 7.39 ng/ml, p < 0.001). Compared with the control subjects (2.91 ± 0.35 g/l), fibrinogen levels before treatment were higher in patients with dyslipidemia treated with ciprofibrate (3.42 ± 0.59 g/l, NS) and fenofibrate (3.65 ± 1.10 g/l, p < 0.05). One-month ciprofibrate treatment resulted in an insignificant decrease in PAI-1 levels (76.28 ± 21.60 ng/ml, NS) and in a significant decrease in fibrinogen levels (2.73 ± 0.40 g/l, p < 0.01). After one-month fenofibrate treatment PAI-1 levels (81.22 ± 25.01 ng/ml, p < 0.01) and fibrinogen levels (2.95 ± 0.72 g/l, p < 0.01) decreased significantly. Conclusion: Type IIb dyslipidemic patients have increased levels of PAI-1 and fibrinogen. Micronized fibrates decreased not only lipid levels but also the levels of fibrinogen and PAI-1 in these patients.Correspondence to:
Dr. B. Okopien; Department of Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland

Abstract

H. Takikawa, T. Ogasawara, A. Sato, M. Ohashi, Y. Hasegawa and M. Hojo

Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
Colestimide is a new anion-exchange resin which is used to lower serum cholesterol levels in Japan. Because of its excellent compliance, colestimide can replace cholestyramine in the treatment of pruritus. However, there may be an interaction in cholestatic patients undergoing treatment with ursodeoxycholic acid (UDCA). Therefore, we studied the effect of colestimide on the absorption of UDCA in men. Five healthy men took two 100 mg tablets of UDCA after a test meal following an overnight fast, and blood samples were collected every 30 min for 3 h. Two weeks later, the same study was repeated just after taking colestimide granules (1.5 g). Bile acid subfractions in serum were measured by HPLC. Serum UDCA levels after 30 min (mainly unconjugated), which reflect the initial absorption, were decreased > 50% by colestimide in 4 out of 5 subjects. Serum total bile acid levels after 30 min, which reflect the initial absorption of bile acids due to postprandial bile secretion, were decreased by colestimide in all subjects. These results indicate that colestimide administration before the meal inhibits UDCA absorption.Correspondence to:
H. Takikawa, MD; Department of Medicine, Teikyo University School of Medicine, Kaga 2-11-1, Itabashi-ku, Tokyo 173-8605, Japan
Email: takikawa@med.teikyo-u.ac.jp

Abstract

F.P. Meyer

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Volume 39, No. 12/2001(December)