Volume 40, No. 3/2002(March)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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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
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
Case Report
Severe hypoglycemia in an elderly patient treated with metformin
S. Zitzmann, I.R. Reimann and H. Schmechel
Abstract
S. Zitzmann1,2, I.R. Reimann2 and H. Schmechel1
1Clinic of Internal Medicine I, Sophien-und-Hufeland-Kliniken GmbH, Weimar, and 2Institute of Clinical Pharmacology, University of Jena, Germany
The following case of severe hypoglycemia was reported during a systematic evaluation of hospital admissions caused by adverse drug reactions (supported by BfArM). History and findings on admission: A 79-year-old diabetic woman was admitted to hospital in a stuporous and unresponsive state. The initial physical examination revealed no other abnormal findings. Serum blood glucose was found to be 2.0 mmol/l and HbA1c was 4.6%. The patient had been started on antidiabetic therapy with metformin 2 months earlier. Treatment with other drugs being taken at that time, an ACE inhibitor, an NSAID and nitrofurantoin, remained unchanged. Diagnosis, treatment and follow-up: Laboratory tests excluded lactic acidosis and renal insufficiency. Cerebral computed tomography findings were normal. The patient improved dramatically following administration of glucose. Other laboratory findings confirmed the diagnosis of hypoglycemia. Blood glucose concentrations ranged between 4.0 and 10.0 mmol/l in the subsequent days and the patient could be discharged in full health. Conclusions: Drug-induced hypoglycemia is possible even in diabetics not receiving insulin or oral antidiabetic agents increasing insulin secretion. The risk of drug-induced hypoglycemia should be particularly considered when drugs containing blood glucose-lowering components are combined. Metformin does not usually cause hypoglycemia when administered as monotherapy. We suspected that hypoglycemia in this patient was caused by additional blood glucose-lowering effects of the ACE inhibitor and the NSAID possibly combined with a suboptimal nutrition. The indications for metformin administration undergo critical scrutiny.Correspondence to:
Dr. I.R. Reimann; Institut für Klinische Pharmakologie der FSU Jena, Dornburger Straße 159, D-07740 Jena, Germany
Email: ilselore.reimann@med-uni-jena.de
Original
Results of systematic screening for serious gastrointestinal bleeding associated with NSAIDs in Rostock hospitals
M. Pietzsch, S. Theuer, G. Haase, F. Plath, M. Keyser and A.-K. Riethling
Abstract
M. Pietzsch1, S. Theuer1, G. Haase1, F. Plath2, M. Keyser3 and A.-K. Riethling1
1Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Rostock, 2Department of Gastroenterology, University Hospital of Internal Medicine, 3Hospital of Internal Medicine, Klinikum Südstadt Rostock, Rostock, Germany
Objectives: Gastrointestinal bleeding and ulcers may lead to life-threatening complications. One of the causes is use of non-steroidal anti-inflammatory drugs (NSAIDs). Methods: All hospital admissions in 1998 to the Departments of Internal Medicine, including the Intensive Care Unit and the Department of Surgery, in 2 hospitals in Rostock were prospectively screened for gastrointestinal bleeding. Whether the bleeding was due to an adverse drug reaction ADR or not was assessed using the rating scale of Begaud et al. [1985] for each drug taken. The risk profile and the drug history of all patients with gastrointestinal bleeding were registered. Results: A total of 58 patients with gastrointestinal bleeding due to NSAIDs were documented. Risk factors for bleeding were cardiac diseases, hypertension, diabetes, age over 60 years, history of ulcer, a Helicobacter pylori infection, smoking and consumption of alcohol together with drugs known to have a risk of causing gastrointestinal bleeding and ulcers (antiplatelet drugs, anticoagulants, corticosteroids). About 70% of these patients had 3 or more risk factors, but only 20% had been receiving effective prophylaxis with a proton pump inhibitor. Conclusion: Gastrointestinal problems resulting from the use of NSAIDs are clinically important. It is concluded, that individual risk profiles, as a criterion for the prophylactic use of effective protective drugs, would be helpful in patients management.Correspondence to:
Dr. M. Pietzsch; Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Rostock, Schillingallee 70, D-18057 Rostock, Germany
Original
Results of a systematic adverse drug reaction (ADR)-screening concerning bradycardia caused by drug interactions in departments of internal medicine in Rostock
G. Haase, M. Pietzsch, A. Fähnrich, W. Voss and A.-K. Riethling
Abstract
G. Haase1, M. Pietzsch1, A. Fähnrich2, W. Voss3 and A.-K. Riethling1
1Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Rostock, 2Division of Cardiology Department of Internal Medicine, Hospital South of Rostock and 3Division of Cardiology, Department of Internal Medicine, University of Rostock, Germany
Objectives: The concomitant intake of drugs, which is frequently needed, may be associated with drug interactions. We report results on the screening of ADRs responsible for hospital admissions involving bradycardia. This investigation was part of a BfArM pilot project with the objective of monitoring and reporting ADRs. Method: Beginning in 1997, a trained medical staff member of the Pharmacovigilance Center, Rostock, prospectively screened all hospital admissions to the Departments of Internal Medicine of the 2 hospitals in Rostock (40,000 hospital admissions). ADRs leading to hospital admission were registered, evaluated and reported. Results: A total of 1,441 ADRs were recorded by the Pharmacovigilance Center Rostock in the period up to December 2000. 12% (n = 173) of all ADRs involve the cardiovascular system; 83 patients (5.7% of all ADRs) suffered from bradycardia. Bradycardia was the most frequent cardiovascular ADR observed. Of these patients, 88% were receiving 3 – 10 different drugs. Drugs suspected of causing bradycardia were: digitalis (n = 62), b-blockers (n = 47), calcium channel blockers with negative chronotropic effect (n = 45), and antiarrhythmic drugs (n = 3). 54 patients had received more than 1 of these drugs concomitantly as outpatients, increasing the risk of drug interactions: 18 patients received digitalis + calcium channel blocker; 14 patients digitalis + b-blocker; 7 patients b-blocker + calcium channel blocker; 12 cases digitalis + b-blocker + calcium channel blocker. Conclusion: The results show that special attention should be given to patients who receive more than 1 drug when there is a high risk of bradycardia. Drug combinations which may cause drug interactions should be avoided, especially when other equivalent therapeutic options are available.Correspondence to:
Dr. G. Haase; Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Rostock, Schillingallee 70, D-18057 Rostock, Germany
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
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
Abstract
Drug Utilization Conference Abstracts II
W. Rathmann, B. Haastert and G. Giani
Abstract
W. Rathmann, B. Haastert and G. Giani
Short Report
Treatment behavior of doctors regarding Helicobacter pylori infections
E. Perez, D. Schröder-Bernhardi and G. Dietlein
Abstract
E. Perez, D. Schröder-Bernhardi and G. Dietlein
IMS HEALTH, Frankfurt am Main, Germany
Objective: Since the detection of the gastric acid resistant bacterium Helicobacter pylori in the year 1982 there has been a fundamental change regarding the therapy of ulcers. According to expert opinion these infections should be treated and eradicated, whereby the so-called triple-therapies are considered to be the most effective ones. Whether such recommendations to eradicate Helicobacter pylori can be put to use in daily practice is an important question that is frequently asked. Methods: All analyses described in the study here were done using mediplus, a longitudinal patient database with anonymous access to a representative and valid panel of physicians and patients within Germany. A total of more than 1,000 medical practices and over 75 million prescriptions can be analyzed in a cross- and/or longitudinal section. The longest time period per patient is more than 10 years starting in 1989 with monthly updates. Results: With regard to existing recommendations, doctors overestimate their own compliance with the recommendations because only a fraction of traceable Helicobacter pylori infections are actualy eradicated. Within the period of observation the therapy behavior has changed significantly in favor of the triple-therapies, but there are relevant differences between practitioners and internal specialists. Discussion: Only a fraction of traceable Helicobacter pylori infections are adequately treated by doctors. The results show a very alarming situation due to the gap between “state of the art” and what is being achieved and carried out in daily practice. The potential for possible cost reductions and saving on resources is probably high. Conclusion: The results lead to the conclusion that in the treatment of Helicobacter pylori infections there is a potential for cost saving which is unused from the pharmacoeconomical point of view.Correspondence to:
Dr. G. Dietlein; IMS HEALTH, Hahnstraße 30 – 32, D-60528 Frankfurt/Main, Germany
Email: gdietlein@de.imshealth.com
Short Report
Use of the mediplus® patient database in healthcare research
G. Dietlein and D. Schröder-Bernhardi
Abstract
G. Dietlein and D. Schröder-Bernhardi
IMS Health, Frankfurt/Main, Germany
Objective: Public health systems require fast and precise analyses of physicians’ day-to-day diagnoses and therapy behavior regarding qualitative, safety or economical aspects. A partnership between physicians in practices and a database organization (IMS Health, Frankfurt, Germany) which has been in existence for more than 10 years has developed a procedure for documenting various types of studies with regard to diagnosis and therapy behavior. This endeavor has facilitated scientific progress by providing precise analytical information and guidelines. Methods: The database used has the name mediplus®. It is a longitudinal patient database with anonymous access to a representative and valid panel of physicians and patients in Germany. A total of more than 1,000 medical practices and over 75 million prescriptions have been documented in a cross and/or longitudinal section. The longest time period per patient is more than 10 years starting in 1989, with monthly updates. Results: Analyses have been obtained detailing prescription behavior of doctors regarding diabetes therapy and enable recommendations to be made regarding the therapy of migraine and the eradications of Helicobacter pylori infections. Information is also retrievable on drug safety studies in general and the extent to which hospitals influence the prescription behavior of doctors treating patients after discharge. Discussion: The mediplus® patient database combines all decision relevant information on physicians, patients, diagnoses and course of therapies and thus makes possible the investigation of the courses of diseases and therapy patterns. The monthly update enables trends to be identified at an early stage. The mediplus® database is an ideal instrument for the enforcement of quantitative and qualitative analyses of patient histories because it directly links the individual diagnoses with the corresponding therapies. The database is currently undergoing extension with additional specialist groups such as pediatricians, neurologists, orthopedists, urologists, ENT specialists, surgeons and pulmonologists.Correspondence to:
Dr. G. Dietlein; IMS Health, Hahnstraße 30 – 32, D-60528 Frankfurt/Main, Germany
Email: gdietlein@de.imshealth.com
