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Abstract

R.H. Böger

Clinical Pharmacology Unit, Department of Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
Cholesterol-lowering drugs such as HMG-CoA reductase inhibitors (“statins”) are increasingly used in hypercholesterolemic patients who suffer from multiple concomitant diseases, and are therefore taking multiple drugs. The statins do not differ in their mechanism of action (pharmacodynamics), but there are differences in the affinity to the target enzyme as well as differences in pharmacokinetic properties, which need to be considered when choosing a statin for a specific patient. The most critical side effect of statins is development of myopathy, which becomes evident as muscle pain, weakness, and elevation of serum creatine kinase activity. The incidence of myopathy is usually low. However, myopathy and rhabdomyolysis are more frequent when statins are combined with other drugs that inhibit cytochrome P450-dependent metabolism of statins in the liver (e.g., itraconazole, erythromycin). Drug interactions can thus significantly increase the risk associated with statin therapy. Oral bioavailability of the statins varies considerably. Besides the absolute rate of oral bioavailability, it is important to know the relative difference between intestinal absorption rate and rate of oral bioavailability in order to assess the potential for drug-drug interactions. Statins that are not metabolized by a single cytochrome P450 isoenzyme, and have a high bioavailability, are the least prone to drug interactions.Correspondence to:
Prof. Dr. R.H. Böger; Clinical Pharmacology Unit, Department of Pharmacology Institute of Experimental and Clinical Pharmacology and Toxicology University Hospital Hamburg-Eppendorf, Martinistraße 52
D-20246 Hamburg, Germany
Email: boeger@uke.uni-hamburg.de

Abstract

T.J. Cleophas and A.H. Zwinderman

European College of Pharmaceutical Medicine, Lyon, France, and Department of Medicine, Albert Schweitzer Hospital, Dordrecht, The Netherlands
Background: Four large double-blind placebo-controlled studies have been performed to address mortality as a primary endpoint in patients with heart failure treated with b-blockers. Unfortunately, 2 of the studies were stopped in the interim stage, and so these trials may be somewhat underpowered for the estimation of the secondary endpoint, type of death. This endpoint is important, because if patients die for reasons other than progression of heart failure, e.g. arrhythmias, then alternative antiarrhythmic agents may serve equally well or better than b-blockers and with fewer side effects. Objectives and methods: We assessed hazard ratios of all-cause-deaths, sudden deaths, death due to progressive heart failure and serious adverse effects leading to discontinuation of double-blind treatment. Hazard ratio = risk of death in treatment group/risk of death in placebo group. Results: The pooled results showed a significant reduction in all-cause-deaths of 35% (p < 0.0001). The risk reduction of sudden death, reflecting the occurrence of fatal arrhythmias, similarly, showed a significant risk reduction of 37% (p < 0.0001). However, the risk reduction of death due to progression to heart failure was small (13%) and statistically non-significant, indicating that progression of heart failure, as estimated by numbers of deaths, was not beneficially influenced by the b-blocker therapy. Finally, the risk of serious adverse effects leading to discontinuation of treatment with b-blockers, was not significantly different from that for placebo. Conclusions: b-blockers do not reduce the risk of death due to progression of heart failure. The beneficial effect of b-blockers is mainly due to a reduced risk of fatal arrhythmias. The risk of serious adverse effects of b-blockers is not different from that of placebo and so there is little argument to withhold this treatment, even if it does not influence the progression of heart failure.Correspondence to:
Dr. T.J. Cleophas; Department of Medicine, Albert Schweitzer Hospital, P.O. Box 306, NL-3300 AH Dordrecht, The Netherlands
Email: ajm.cleophas@wxs.nl

Abstract

T. Zimmermann, H. Laufen, R.A. Yeates and F. Scharpf

Pfizer Research and Development, Illertissen, Germany
Concentrations of fluconazole in sebum and plasma were determined in 2 parallel groups, each consisting of 8 healthy subjects. Group 1 received a 150 mg fluconazole capsule once weekly over a period of 4 weeks, Group 2 was administered 2 capsules/ week, corresponding to 300 mg fluconazole/ week for 4 weeks. Sampling was performed immediately before and 5 hours after dosing, and at intervals up to 2 weeks after the last dose. Fluconazole concentrations were determined by a specific and highly sensitive gas chromatographic method. Both treatments were well tolerated. Maximum fluconazole concentrations (mean ± SD) in plasma were 3.5 ± 1.0 mg/ml (Group 1) and 5.5 ± 1.0 mg/ml (Group 2); maximum sebum concentrations were 11.0 ± 8.4 mg/g (Group 1) and 48.4 ± 37.0 mg/g (Group 2). Significant accumulation of fluconazole in sebum relative to plasma was observed. Sebum/plasma ratios ranged from 1.6 to 6.5 (Group 1) and from 4.3 to 27.9 (Group 2), with median ratios of 2.4 and 9.1, respectively. The overall accumulation factor was 7. The findings may be of particular relevance for the treatment of dermal mycoses involving the sebaceous glands, especially those associated with hair, such as tinea capitis.Correspondence to:
Dr. T. Zimmermann; Heinrich-Heine-Straße 24, D-10179 Berlin, Germany

Abstract

I. Kraus¹, D. Vitezic² and R. Oguic³

¹Department of Gastroenterology, University Hospital Center Rijeka, ²Department for Science and Clinical Pharmacology, University Hospital Center Rijeka and Department of Pharmacology, University of Rijeka Medical School, and ³Department of Urology, University Hospital Center Rijeka, Rijeka, Croatia
Objective: To describe the characteristics of 3 patients hospitalized in the Department of Gastroenterology, University Hospital Center, Rijeka, as the result of acute hepatitis, a rare adverse drug reaction to flutamide. Patients and results: All 3 patients with advanced prostate carcinoma were treated with oral flutamide at a dose rate of 250 mg 3 times daily. The patients developed clinical signs (jaundice, anorexia, nausea, dark urine etc.) and laboratory liver function test changes (high aminotransferase and bilirubin level), indicative of acute hepatitis, 20 – 22 weeks after commencing flutamide treatment. The flutamide therapy was immediately discontinued and this resulted in spontaneous remission (clinical and liver function test results returned to normal) during the next 8 weeks. Conclusion: Our data clearly suggest that flutamide causes acute hepatitis and that the monitoring of the patients’ liver function tests in order to detect these changes as early as possible, is important.Correspondence to:
Dr. D. Vitezic; Department for Science and Clinical Pharmacology, University Hospital Center, Rijeka, and Department of Pharmacology, University of Rijeka Medical School, Brace Branchetta 20, CRO-51000 Rijeka, Croatia
Email: Dinko.Vitezic@mamed.medri.hr

Abstract

S.R. Penzak¹, W.D. Lawhorn² and P.O. Gubbins¹

¹Southern School of Pharmacy, Mercer University, Atlanta, Georgia, and ²College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Ritonavir is an HIV-1 protease inhibitor that is often used to improve the systemic availability of concurrently administered protease inhibitors by impairing their metabolism through cytochrome P450 (CYP) 3A4. Pharmacodynamic relationships between plasma ritonavir concentrations and efficacy and toxicity have also been described. To date, published high-performance liquid chromatographic (HPLC) methods for the determination of ritonavir in human plasma are often complex, requiring the use of a buffered mobile phase that contains amine-modifiers (i.e. diethylamine, triethylamine). In the method herein, ritonavir was precipitated with acetonitrile plus barium hydroxide and zinc sulphate. Chromatographic separation was accomplished using a C-18 base-deactivated (250 × 4.6 mm I.D., 5 mm particle size) analytic column with a mobile phase composed of acetonitrile : water (52 : 48, v/v). Quantification was performed at 239 nm. Calibration curves were linear from 0.5 – 25 mg/ml (R2 > 0.999); percent errors, as a measure of accuracy, were < 12.7%. Intra- and inter-assay relative standard deviations (RSD) were below 12.8%. This method provides a rapid and simple means for the accurate and precise analysis of ritonavir in human plasma. Furthermore, the assay requires neither the use of a buffered mobile phase adjusted to a specific pH, nor the addition of amine modifiers. This method has been successfully used to determine plasma ritonavir concentrations in drug interaction studies.Correspondence to:
Dr. S.R. Penzak; Mercer University, Southern School of Pharmacy, 3001 Mercer University Drive, Atlanta, Georgia 30341-4155, USA
Email: Penzak_SR@Mercer.edu

Abstract

H.A. Wieland and B.S. Hamilton

Department of Cardiovascular and Metabolic Disease, Boehringer Ingelheim Pharma KG, Biberach, Germany
In industrial nations the most common form of malnutrition is obesity. Obesity is a chronic disease associated with increased morbidity and mortality. Unfortunately, the simplest treatment for obesity, increasing physical activity and reducing caloric intake, for the vast majority of patients is completely ineffective over the long term. Weight lost is quickly regained, and body weights after intervention often exceed pretreatment levels. Early pharmacotherapy had been successful in reduction and maintenance of weight loss; unfortunately, unforeseen side effects contributed to an unacceptable risk/benefit balance that necessitated the withdrawal of many of these agents. Current pharmacotherapy is limited, with only 2 compounds accepted for long-term use for the treatment of obesity. Both sibutramine and orlistat contribute to modest weight loss and maintenance and reduce obesity-associated risk factors. Beginning with the discovery of leptin in the mid-1990s, a renaissance in obesity research has taken place. This research has provided more detailed insights into the regulation of energy homeostasis. The central feedback regulation loops involving the leptin and melanocortinergic pathways have provided several targets for therapeutic intervention, including leptin analogs and melanocortin agonists. Several peripheral targets including uncoupling proteins and b3-adrenergic receptor are also being explored for their anti-obesity potential. Therefore, it can be expected that new pharmacotherapies will be available to help combat the epidemic of obesity.Correspondence to:
Dr. H.A. Wieland; Boehringer Ingelheim Pharma KG, Aventis Pharma Deutschland GmbH, DG Thrombotic Diseases/Degenerative Joint Diseases, H821, D-65926 Frankfurt M., Germany

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Volume 39, No. 9/2001(September)