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Abstract

R. Siekmeier¹,², W. Groß² and W. März³

¹Institut für Klinische Chemie und Laboratoriumsmedizin, Klinikum Carl Gustav Carus der Technischen Universität, Dresden, ²Labor für Angewandte Biochemie, Klinikum der Johann-Wolfgang-Goethe Universität, Frankfurt/Main, and ³Zentrallabor, Medizinische Klinik der Albert-Ludwigs-Universität, Freiburg, Germany
Background: Pravastatin is a hydrophilic liver-specific inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase. It effectively lowers plasma cholesterol and low-density lipoprotein concentrations in humans. Pharmacokinetic studies of pravastatin have been mostly performed by means of radioactively labelled drug or by measuring plasma concentrations with gas chromatography and mass spectrometry. Aims of the study: Aim of our study was to develop a simple, but reliable method which allows the determination of pravastatin plasma concentrations under clinical routine conditions. Subjects, materials and methods: Samples were prepared by solid-phase extraction on cyclohexyl bond elut cartridges. Chromatography was carried out on an octyl matrix. Triamcinolone acetonide was used as internal standard. The method was linear within the range of 5 to 200 mg/l pravastatin. The coefficient of variation depended on the pravastatin concentration, but was less than 10% throughout. The pharmacokinetics of pravastatin were determined in healthy individuals. Five healthy subjects received single oral doses of pravastatin (60 mg) and one of these subjects additionally received a dose of 80 mg at three different study days. In all subjects blood was sampled 0, 30, 60, 90, 120, 150, 180, 240 and 300 min after drug intake. Results: Peak plasma concentrations of pravastatin were found between 60 min and 120 min after oral administration of 60 mg and reached values between 37 mg/l and 126 mg/l. The calculated AUCs were between 52 ng/ml×h and 311 ng/ml×h and the corresponding plasma elimination half-life times were between 95 min and 165 min. In all subjects plasma concentrations of pravastatin 5 hours after oral drug administration were near the detection limit of the method (5 mg/l). Intraindividually, there was only little variation in the kinetics of pravastatin. However, marked differences were encountered between the subjects studied. Conclusion: The data suggest that the determination of pravastatin plasma concentrations by means of a HPLC system can be used for routine analysis of pravastatin plasma concentrations. The obtained pharmacokinetic data in healthy individuals stand in ample agreement with the results of prior studies in which the concentrations of pravastatin were determined by other more sophisticated methods.Correspondence to:
Dr. R. Siekmeier; Bundesinstitut für Arzneimittel und Medizinprodukte, Friedrich-Ebert-Allee 38, D-53113 Bonn, Germany

Abstract

E. Anzenbacherová¹, P. Anzenbacher¹, F. Perlík² and J. Kvetina¹

¹Institute of Experimental Biopharmaceutics, PRO.MED.CS Praha a.s. – Academy of Sciences Joint Institute, Hradec Králové, and ²Clinical Pharmacology Unit, ¹st Department of Medicine, Faculty of Medicine, Charles University, Prague, Czech Republic
Aim: The antiarrythmic drug propafenone is metabolized to its main metabolite by CYP2D6, suggesting that its metabolic ratio may be used for CYP2D6 phenotyping. However, reported ratios obtained from plasma concentrations did not reflect the phenotype. The objective of this paper was to find optimal conditions for plasma sampling based on pharmacokinetic data and to investigate whether propafenone/metabolite ratios reflect the CYP2D6 phenotype. Patients, materials and methods: The present study was conducted in 14 healthy volunteers phenotyped for CYP2D6 activity by a sparteine test. A single dose of oral propafenone (Profenorm PRO.MED.CS Praha a.s.) was administered, and venous blood samples were taken up to 24 hours thereafter. Propafenone and hydroxypropafenone were measured by HPLC. Results: The individual data for the respective propafenone/metabolite metabolic ratio in plasma samples taken at tmax correlated well with the sparteine metabolic ratio used routinely for CYP2D6 phenotyping. However, when the samples were taken 4 hours after drug intake, the correlation was poor. Conclusion: The results indicate a possibility to use the propafenone metabolic ratio for determination of the CYP2D6 phenotype in plasma samples taken at single time point (close to the Cmax, i.e. 2 hours after drug intake).Correspondence to:
Dr. E. Anzenbacherová; Institute of Experimental Biopharmaceutics, PRO.MED.CS Praha a.s. – Academy of Sciences Joint Institute, Heyrovského 1207, 50002 Hradec Králové, Czech Republic

Abstract

M. Grossmann¹ and H. Schmidramsl²

¹Department of Neurology, Municipal Hospital, München-Harlaching, and ²Krankenhaus für Naturheilwesen, München, Germany
Objective: Migraine is still an unsolved problem. This clinical trial investigates the efficacy and tolerance of Petasites hydridus in the prophylaxis of migraine. Methods: A randomized, group-parallel, placebo-controlled, double-blind clinical study was carried out with a special CO2 extract from the rhizome of Petasites hybridus. Following a 4-week run-in phase, 60 patients received either the special Petasites hybridus extract petadolex or placebo at a dosage of 2 capsules (each capsule contains 25 mg) twice daily over 12 weeks. Outcome variables included the frequency, intensity and duration of migraine attacks as well as any accompanying symptoms. Results: The frequency of migraine attacks decreased by a maximum of 60% compared to the baseline. This reduction in migraine attacks with petadolex was significant (p < 0.05) compared to placebo. No adverse events were reported. Petasites was exceptionally well tolerated. Conclusions: The results suggest that migraine patients can benefit from prophylactic treatment with this special extract. The combination of high efficacy and excellent tolerance emphasizes the particular value that Petasites hydridus has for the prophylactic treatment of migraine.Correspondence to:
Prof. Dr. W. Grossmann; Städtisches Krankenhaus München-Harlaching, Abteilung Neurologie, Sanatoriumsplatz 2, D-81545 München, Germany

Abstract

M. Tripkovic¹, F. Kozjek², I. Krizman¹, J. Jereb¹, I. Francetic³, I. Grabnar² and A. Mrhar²

¹Department of Gastroenterology, Clinical Centre of Ljubljana, ²Department of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia, and ³Clinical Medical Centre Rebro, Zagreb, Croatia
Objective: The double-blind randomized pilot study was undertaken to compare the effects of a 10-day course of ondansetron 8 mg/day and propranolol 80 mg/day perorally in treating portal hypertension. Subjects and methods: 16 patients with liver disease were enrolled in the study. Measurements of portal vein diameter, portal blood flow velocity and portal blood flow volume were done at days 1, 5 and 10 of treatment using duplex Doppler sonography. Results: The propranolol group demonstrated a decrease in portal venous diameter, while patients treated with ondansetron exhibited reduced portal blood flow velocity values. A decreased portal blood flow volume was found in both groups after 10 days of therapy. Conclusion: No statistically significant differences were found between the groups with the exception of portal venous diameter which is significantly lower at the end of the treatment in the case of propranolol.Correspondence to:
Dr. F. Kozjek; Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia

Abstract

R. Vrhovac, N. Rojnic-Putarek and B. Jaksic

Department of Medicine, University Hospital “Merkur”, Zagreb, Croatia
Objective: To analyze different aspects of patients’ knowledge and attitudes to pharmacotherapy in medical inpatients. Patients: 183 patients hospitalized in the Department of Medicine of University Hospital “Merkur”, Zagreb, Croatia were investigated. Methods: A questionnaire was designed to investigate patients’ knowledge of drugs they were taking before admission to the hospital and drugs they are receiving during hospitalization. Patients were asked to give drug names, dosage and reasons for their prescription. Patients’ rating of the importance of some drug characteristics (dosage, indication, precautions, side-effects, mode of action) was evaluated. Results: A representative group of patients (mean age 55.5 years, range 17 – 86, SD 16.1; 89 men, 94 women; 50 hematological, 44 cardiological, 50 gastroenterological and 39 nephrological patients) showed a significantly better (p < 0.000001) overall knowledge of drugs taken prior to admission compared to the knowledge of drugs that they were receiving during hospitalization. Overall drug knowledge did not differ significantly between groups of patients stratified according to gender, ward, number of drugs they were taking or duration of treatment. In older patients (p < 0.0001) and in those with lower education (p < 0.001) a significantly worse overall knowledge was observed. On a 1 – 5 semiquantitative scale patients rated dosage as the most important and mode of action as the least important drug characteristic (average 3.62 and 2.08, respectively). Of all patients, 94.5% pointed out physicians as one of their sources of drug information, written drug information followed in 40.4% and pharmacists in only 11.5% of patients. Conclusions: Our results agree with the results of the few similar studies published to date. A need for better health education of patients is underlined and possible ways of providing drug information for patients are discussed. The need for improvement of physician-patient transfer of drug information as well as the need for written drug information tailored according to patients’ needs is underlined.Correspondence to:
Dr. R. Vrhovac; Department of Medicine, University Hospital “Merkur”, Zajceva 19, 10000 Zagreb, Croatia

Abstract

B.B. Ceyhan and T. Çelikel

Marmara University School of Medicine, Department of Pulmonary Medicine, Altunizade-Istanbul, Turkey
Objectives: Recent studies have shown that inhaled standard heparin exhibits protection towards various bronchoconstrictor stimuli in asthma including methacholine. Low molecular weight heparins (LMWH) (4000 – 5000 daltons) have higher bioavailability than standard heparins (12,000 – 16,000 daltons). It is possible that the anti-asthmatic activity of heparin may be molecular weight-dependent. The purpose of the present investigation was to study the effect of LMWH on methacholine-induced bronchoconstriction and to compare the effect of LMWH with that of standard heparin. Subjects: Fifteen subjects (7 male, 8 female, mean age: 33 ± 13 years, range: 20 – 65) with mild asthma were studied. Method: Methacholine bronchial provocation tests were performed in a single-blind, crossover, randomized order and repeated 45 minutes after placebo or aerosolized standard heparin (1.000 U/kg) or aerosolized LMWH (Enoksaparin, Clexane, 0.8 mg/kg). Results: There was no significant difference in baseline FEV1 values between study days. The standard heparin and enoksaparin inhibited bronchoconstriction induced by methacholine. The geometric mean log PD20 values after placebo, standard heparin, and enoksaparin were 0.24 ± 0.57 (1.74) mg/ml, 0.79 ± 0.59 (6.17 mg/ml), 0.76 ± 0.57 (5.75mg/ml), respectively (p < 0.0009). Three subjects in standard heparin group and two subjects in enoksaparin group showed increased hyperreactivity, the others showed decreased bronchial hyperreactivity. The degree of protection offered by standard heparin and enoksaparin did not show any statistical difference. Conclusions: These data suggest that both inhaled LMWH and inhaled standard heparin play inhibitory roles in methacholine-induced bronchoconstriction.Correspondence to:
Prof. Dr. B.B. Ceyhan, Marmara University Hospital, Altunizade-Istanbul, Turkey

Abstract

U. Tröger¹, W. Brandt² and W. Röse²

¹Institut für Klinische Pharmakologie, and ²Klinik für Anästhesiologie und Intensivtherapie, Otto-von-Guericke-Universität, Magdeburg, Germany
Objective: This is the report about a very early onset of phenytoin hypersensitivity reaction showing respiratory insufficiency, fever, hepatic and skin reactions in a 68-year-old male patient who was concomitantly treated with high dose dexamethasone/prednisolone because of brain edema. Case report: The patient developed a hypersensitivity reaction one week after starting a phenytoin treatment, 250 mg daily intravenously, because of a focal epileptic seizure after a transsphenoidal resection of a pituitary tumor. The drug hypersensitivity was diagnosed first clinically and was confirmed by an in vitro rechallenge using the lymphocyte transformation test three months later. Phenytoin itself did not stimulate the lymphocytes’ proliferation. The test was performed successfully using human reference sera. Conclusions: The results suggest that protein-bound reactive drug metabolites which are assumed to occur in the sera may be responsible for the reaction. Corticosteroids did not prevent the reaction and even seem to mask laboratory and clinical findings. Dexamethasone might accelerate the accumulation of potential allergotoxic epoxide metabolites. Both phenytoin and dexamethasone should be withdrawn urgently in the case of suspected hypersensitivity syndrome.Correspondence to:
Dr. U. Tröger; Institut für Klinische Pharmakologie, Otto-von-Guericke-Universität, Leipziger Straße 44, D-39120 Magdeburg, Germany

Abstract

J. Borrás-Blasco, J.D. Rosique-Robles, J. Peris-Martí, F.J. Santos-Calle, A. Navarro-Ruiz and M. Gonzalez-Delgado

Hospital General, Universitario de Elche, Elche/Alicante, Spain
Objetive: To report a case of a patient diagnosed as having bronchial asthma treated with intravenous infusion of theophylline, who presented an episode of altered theophylline metabolism with a disproportionately increase in serum concentrations together with tachycardia and symptoms of intoxication. Case summary: A 51-year-old white woman with a history of bronchial asthma was treated with intravenous infusion of theophylline in an Intensive Care Unit. Bayesian pharmacokinetic approach for dose individualization was done and linear kinetics of theophylline were observed. At therapeutic dose, an alteration of theophylline metabolism had happened, that induced a decrease on the theophylline clearance coinciding with an increase of dose. The serum concentration at this dose was 23.9 mg/ml and this was associated with symptoms compatible with intoxication by theophylline. All factors that could change theophylline elimination were analyzed. A possible drug interaction, hypothyroidism and cardiac failure were ruled out. Clinical hepatic insufficiency was not determined, but an increase of hepatic enzymes was observed. Theophylline infusion was suspended during 5 hours, the serum levels returned to therapeutic values and hepatic enzymes returned to their initial values. Discussion: Episodes of anormal theophylline kinetics may occur, even with doses and serum concentrations considered to be therapeutic, especially in critically ill patients or those whose physical condition has deteriorated. This makes it necessary to carry out therapeutic drug monitoring of theophylline in this group of the population.Correspondence to:
Dr. J. Borrás-Blasco; Hospital General, Universitario de Elche, Partida Huertos y Molinos S/N, E-03202 Elche/Alicante, Spain

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Volume 38, No. 9/2000(September)