Volume 42, No. 2/2004(February)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Review
Ginkgo biloba special extract EGb 761 in the treatment of peripheral arterial occlusive disease (PAOD) – a review based on randomized, controlled studies
Abstract
S. Horsch and C. Walther
1Surgical Department, Hospital Porz/Rhein, Köln, and 2Clinical Research Department, Dr. Willmar Schwabe GmbH and Co. KG, Karlsruhe, Germany
Objective: The present review gives an overview and evaluation of clinical studies proving the efficacy of EGb 761 in patients with PAOD. Methods: Relevant original papers and reports on this topic were identified by means of a literature search. Only randomized, double-blind, placebo-controlled clinical trials in patients with the indication peripheral arterial occlusive disease in stage II according to Fontaine were included (only treatment with the oral form of EGb 761). For the selected studies the ratio q of the walking distance between EGb 761 and placebo was calculated and a test for relevant superiority of EGb 761 was performed (according to the guidelines of the Deutsche Gesellschaft für Angiologie (German Society of Angiology) [Heidrich et al. 1996]). Furthermore, a pooled estimation of the ratio was carried out. Results: Nine studies complied with the criteria. The methodological quality and design of the trials were heterogeneous. In the majority of the studies, there was an advantage of EGb 761 in the increase of pain-free walking distance compared to placebo. For 7 studies, the advantage was found to be statistically significant. Testing the relevant superiority showed a significant result in 6 of the selected studies. The pooled estimator of the ratio amounts to q = 1.23 (95% CI: 1.16, 1.31) and demonstrates the efficacy of EGb 761 over placebo as well. Conclusions: This review confirms the efficacy of Ginkgo biloba special extract EGb 761. It demonstrates not only the statistical significance of the difference with respect to placebo but also the clinical relevance for the treatment of patients with PAOD.
Pharmacogenetics
Glucuronidation of acetaminophen is independent of UGT1A1 promotor genotype
Abstract
S.K. Rauchschwalbe1,2, M.T. Zühlsdorf2, G. Wensing2 and J. Kuhlmann2
1Julius-Maximilians University of Würzburg, and 2Institute of Clinical Pharmacology, Bayer AG, Wuppertal, Germany
The metabolism of acetaminophen (paracetamol) is thought to be altered in patients with Gilbert’s syndrome (GS), a chronic unconjugated hyperbilirubinemia. The underlying cause of GS is a polymorphism in the promotor region of the uridine diphosphate glucuronosyltransferase isoform 1A1 gene (UGT1A1*28), its encoded enzyme being responsible for the glucuronidation of bilirubin and presumably acetaminophen. Decreased enzyme activity results in elevated bilirubin levels and may activate various metabolic pathways leading to higher amounts of potentially hepatotoxic acetaminophen metabolites. Patients with GS might be more susceptible to unexpected side effects while taking acetaminophen and other drugs which are substrates of UGT1A1. The possibility of a correlation between glucuronidation capacity with respect to acetaminophen, UGT1A1 promotor polymorphism and the bilirubin serum level were investigated in 23 healthy male volunteers selected for UGT1A1 genotype (6 wildtypes, 9 mutants and 8 heterozygotes). One gram acetaminophen was administered p.o. and urine was collected over 2 4-hour periods. Unchanged acetaminophen and its glucuronide metabolite were determined using HPLC. The metabolic ratios unchanged acetaminophen/acetaminophen glucuronide in UGT1A1-wildtypes, heterozygotes and mutants showed no statistically significant differences. An association between metabolic ratio and serum bilirubin level could not be detected in any of the urine collection periods. These data confirm that there is no correlation between the capacity to glucuronidate acetaminophen, the UGT1A1 genotype and the bilirubin serum level. Acetaminophen is likely to be substrate of a UGT isoform other than the UGT1A1.
Pharmacogenetics
CYP1A1 alleles in women with focal nodular hyperplasia of the liver (FNH)
Abstract
A. Lazar1, H. Menzel1,2, I. Cascorbi5, G. Kümel1, M. Sachs3, S. Rietbrock1,2, I. Roots4 and U. Fuhr1,2
1Department of Pharmacology, University Hospital, University of Cologne, Clinical Pharmacology, 2Pharmazentrum Frankfurt, Klinikum der Johann-Wolfgang-Goethe-Universität, 3Clinic of General Surgery, Klinikum der Johann-Wolfgang-Goethe-Universität, Frankfurt am Main, 4Institute of Clinical Pharmacology, University Medical Center Charité, Humboldt University of Berlin, and 5Institute of Pharmacology, Ernst Moritz Arndt University, Greifswald, Germany
Objective: Disorders of steroid hormone metabolism might be related to the etiology of focal nodular hyperplasia of the liver (FNH), a benign tumor, especially prevalent in women. The cytochrome P450 1A1 (CYP1A1) enzyme is implicated in the bioactivation of multiple precarcinogens as well as in the metabolism of steroids. Genetic polymorphisms of CYP1A1 have been associated with altered catalytic activity in the hydroxylation of sex hormones and this may account for interindividual variability in exposure to hormone-mediated cell proliferation signals and reactive steroid metabolites. In the study at hand, we aimed to evaluate a possible association between CYP1A1*1, *2A, *2B, and *4 alleles and FNH. Method: Genotyping of 26 affected female patients of Caucasian origin was carried out using PCR/RFLP. Results: Allele frequencies for the CYP1A1 variants *2A, *2B and *4 in 26 female patients with FNH were 0.058, 0.019 and 0.058, respectively. Crude odds ratios for the individual alleles were 0.75 (95% CI 0.23 – 2.44), 0.72 (95% CI 0.10 – 5.34) and 1.96 (95% CI 0.59 – 6.50), respectively. There were no significant differences between these values and corresponding allele frequencies obtained in a large German sample of unaffected Caucasian women. Conclusion: The present data do not suggest a relevant association between CYP1A1 polymorphisms and focal nodular hyperplasia of the liver in female Caucasians.
Nicotine replacement therapy
Changes in hemorheological and biochemical parameters following short-term and long-term smoking cessation induced by nicotine replacement therapy (NRT)
Abstract
K.-O. Haustein, J. Krause, H. Haustein, T. Rasmussen and N. Cort
1Fritz-Lickint-Institute for Nicotine Research and Smoking Cessation, Erfurt, Germany, and 2Pharmacia Consumer Healthcare, Helsingborg, Sweden
Objectives: Cigarette smoking causes cardiovascular (CV) disease, but the relative roles of nicotine and other components of tobacco smoke remain unclear. We investigated the effect of stopping smoking by using nicotine replacement therapy (NRT) on hemorheology parameters, on the cotinine and thiocyanate plasma concentrations and the exhaled carbon monoxide (CO). Design: Open, parallel-group trial (intervention group and control smokers). Subjects: 197 males, aged 25 – 45 years, smoking > 20 cigarettes per day (cpd). Interventions: 164 subjects were instructed to stop smoking and received NRT for 12 weeks and 33 acted as controls. After 12 weeks, NRT was discontinued and all subjects were followed-up at 26 weeks. Beginning with week 4, the treated subjects were divided into abstainers (self-reported, verified by exhaled CO < 10 ppm) and nonabstainers, not able to stay abstinent since baseline. The group of the nonabstainers was stratified in 2 subgroups, the reducers (smoked < 50% of baseline number of cpd) and relapsers (smoked 50 – 100% of baseline cpd). Main outcome measures: Plasma viscosity, erythrocyte deformability, fibrinogen, transcutaneous partial oxygen tension (tcpO2), hematocrit, white blood cells, cotinine and thiocyanate plasma concentrations and exhaled CO, all assessed at 4, 8, 12 and 26 weeks. Results: After 6 months, plasma fibrinogen (228.2 vs. 275.4 mg/dl at baseline, p < 0.001), tcpO2 (50.4 vs. 34.9 mm mercury at baseline, p < 0.0001) were significantly improved in abstainers, but changes in plasma viscosity and erythrocyte deformability were inconclusive. Cotinine and thiocyanate (abstainers: 6.2 ng/ml at week 26 vs. 10.4 ng/ml at baseline, p < 0.0001) and expired CO (abstainers: 30.4 vs. 4.2 ppm, control vs. week 26, p < 0.0001) accurately followed the changes in smoking and/or NRT use in all of the groups. Other CV risk factors such as hematocrit and white blood cell count decreased to a greater extent in abstainers than in reducers and relapsers. Not only abstainers but also reducers did benefit of the temporarily stop smoking. Conclusions: Smoking cessation improved CV parameters despite the measured cotinine and thiocyanate plasma levels, and use of nicotine medications did not negate these improvements. A smoking cessation for a short time and smoking of reduced cpd also improved these parameters temporarily.
Therapeutics
Predicting the glomerular filtration rate from serum creatinine, serum cystatin C and the Cockcroft and Gault formula with regard to drug dosage adjustment
Abstract
O. Schück, V. Teplan, J. Sibová and M. Štollová
Institute for Clinical and Experimental Medicine, Prague, Czech Republic
Objectives: To compare the accuracy of the classification of the degree of decrease in glomerular filtration rate (GFR), measured exactly (as inulin clearance) on the basis of serum concentrations of creatinine (Scr), cystatin C (Scyst) and creatinine clearance predicted according to Cockcroft and Gault (CG), and to establish whether any of the above methods is more accurate than the other 2. Subjects: The study was conducted in 126 patients (52 men, 74 women) aged 18 to 64 years with various chronic renal diseases (predominantly various forms of glomerulonephritis and tubulointerstitial nephritis). The study subjects were divided into 3 subgroups according to GFR levels. Subgroup A (n = 41) included individuals with GFR > 50 ml/min/1.73 m2, subgroup B (n = 56) was made up by individuals with GFR of 20 – 50 ml/min/1.73 m2, while subgroup C (n = 29) comprised individuals with GFR < 20 ml/ min/1.73 m2. Methods: GFR was determined on the basis of renal inulin clearance (Cin) under conditions of stable plasma levels and water loading. Each individual had his/her Scr, Scyst values measured and CG was calculated. Results were evaluated using discrimination analysis. Results: Mean values and SD of the monitored markers in the subgroups were as follows. Subgroup A: Scr 102.4 (38.3) mmol/l, Scyst 1.46 (0.42) mg/l, CG 80.0 (19.2) ml/ min/1.73 m2. Subgroup B: Scr 161.2 (45.6) mmol/l, Scyst 2.01 (0.55) mg/l, CG 46.1 (16.7) ml/min/1.73 m2. Subgroup C: Scr 314.9 (58.3) mmol/l, Scyst 3.41 (0.96) mg/l , CG 24.8 (7.6) ml/min/1.73 m2. The percent of correct classifications and the respective confidence intervals (95%) for the methods used were as follows. Subgroup A: Scr 79.3 (64.6, 94.0), Scyst 75.9 (60.3, 91.5), CG 86.2 (73.6, 98.8). Subgroup B: Scr 51.8 (35.5, 68.1), Scyst 57.1 (41.5, 72.7), CG 64.3 (48.6, 80.0). Subgroup C: Scr 90.2 (81.0, 99.2), Scyst 80.5 (68.1, 92.9), CG 87.8 (77.8, 97.8). The percent of correct classifications established on the basis of Scr, Scyst and CG in subgroup B is significantly lower than that of correct classifications in subgroups A and C (p < 0.05 – 0.001). The percent of correct classifications using Scr, Scyst and CG, estimated separately for each subgroup (A, B, C) does not differ significantly. Conclusions: The findings support the assumption that estimation of the decrease in GFR using Scr, Scyst and CG is, as regards their utilization in everyday practice, suitable for individuals with severely decreased GFR (< 20 ml/min/1.73 m2) and for individuals with a decrease in GFR to levels > 50 ml/min/1.73 m2. Estimation of the decrease in GFR using the above subgroups did not demonstrate significant differences among Scr, Scyst and CG. Using the above markers, estimation of the decrease in GFR is the least reliable with GFR values in the range of 20 – 50 ml/min/1.73 m2.
Therapeutics
Safety of AT-1015, a novel 5-HT2A antagonist, in combination with high-dose aspirin: an open-label study
Abstract
D. Anderson, N. Kato, K. Onomichi, H. Uchida, S. Shelley, D. Engert and J. Ilgenfritz
1Ajinomoto Pharmaceuticals Europe Limited, Redhill, UK, 2Ajinomoto Incorporation, Tokyo, Japan, 3GCP Management Services Limited, Romsey, UK, 4LCG Bioscience, Bourn Hall Clinic, Bourn, Cambridge, UK, and 5BioCor LLC, Yardley, Philadelphia, USA
Objective: To assess the safety of AT-1015 in combination with high-dose aspirin (300 mg daily). Study subjects were 17 healthy male volunteers. Methods: This was an open-label, single-center study. Subjects received aspirin 300 mg once daily, alone on days 1 – 4, and together with AT-1015 40 mg twice daily on days 5 – 11. A follow-up assessment was performed on day 18. The primary outcome measure was bleeding time; secondary outcome measures were vital signs, adverse events, physical examinations, 12-lead electrocardiograms (ECG) and laboratory safety tests. Results: There was a significant increase in bleeding time between screening and the end of the aspirin-only period (mean bleeding time 4.8 vs 7.6 min, p = 0.01), but there were no further significant increases during the combination treatment period. The most common adverse events were dry mouth, epistaxis, gingival bleeding and abdominal pain. All treatment-related adverse events were mild in severity and no major bleeding episodes occurred. There were no clinically significant changes in vital signs, physical examinations, 12-lead ECGs or laboratory safety tests. Conclusions: AT-1015 was safe and well-tolerated in healthy male volunteers when taken in combination with high-dose aspirin, and did not significantly prolong bleeding time compared with aspirin alone.
Therapeutics
Drug changes at the interface between primary and secondary care
Abstract
W. Himmel, M.M. Kochen, U. Sorns and E. Hummers-Pradier
Department of General Practice, University of Göttingen, Göttingen, Germany
Objective: To analyze the frequency and factors associated with drug change in a sample of patients referred to hospital by their general practitioner. Methods: This observational study is based on a chart review of 100 consecutively recruited patients with a chronic disease who were referred to the general internal medicine wards in each of 3 district general hospitals in Germany (total 300 patients). The frequency of drug cancellation, replacement, dosage alteration, change in manufacturer and of commencing treatment with a new drug were recorded. Results: Half of the drugs used in chronic treatment (644/1,330) and prescribed by general practitioners were continued during hospitalization. The fraction canceled was 36%. In the rest of the drugs in this group, there were some minor changes carried out by the hospital. On the day of the drug survey, a total of 1,572 drugs were being taken by the patients and 724 of these drugs were newly prescribed by hospital. Only 13 patients experienced no change to their drug regimen during their stay in hospital. In more than 60% of patients (184/300), there were 3 or more changes made in their drug regimen. The rate of drug cancellation for antihypertensive and cardiac drugs in patients referred to hospital for cardiovascular and non-cardiovascular problems did not differ. Conclusion: During hospitalization, nearly every patient is confronted with some form of drug change. Of major concern is the high rate of drug change affecting drugs being taken for diseases other than that associated with the hospitalization. Hospital drug policy should encourage clinicians to continue drug regimens in newly admitted patients whenever medically appropriate and caution clinicians against making unnecessary changes to drug regimens prescribed by general practitioners.
Therapeutics
Alternative versus conventional treatment strategy in uncomplicated acute otitis media in children: a prospective, open, controlled parallel-group comparison
Abstract
T.P.U. Wustrow for the Otovowen Study Group
ENT Associates, Munich, Germany
Objectives: Evidence from clinical trials questions the benefit-risk ratio of first-line antibiotic treatment for uncomplicated acute otitis media in childhood. Alternative treatment strategies are very popular but have not been the subject of larger controlled clinical trials. This trial compares an alternative with a conventional treatment strategy for acute otitis media. Methods and patients: 390 children aged 1 – 10 years presenting with uncomplicated acute otitis media participated in a prospective, open, non-randomized, controlled, parallel-group study. According to self-assignment of investigators, children were treated either conventionally (free combinations of decongestant nose drops, mucolytics, analgesics and antibiotics) or alternatively with Otovowen® (fixed combination of plant-based tinctures and homeopathic potencies), supplemented by conventional medications when considered necessary. Results: Alternatively treated patients (n = 192) had significantly less severe otoscopic findings and clinical symptom ratings at baseline than children treated in conventional centers (n = 193). Patients cared for by conventional therapists took more antibiotics (80.5% vs. 14.4%; c2-test, p < 0.001) and analgesics (66.8% vs. 53.2%; c2-test, p = 0.007). Times to recovery were 5.3 ± 2.4 and 5.1 ± 2.2 days for alternative and conventional treatment, respectively. Odds ratios (OR) with a lower limit of 1-sided 97.5% confidence interval (CI) were 0.98 (0.76), 0.95 (0.73) and 0.88 (0.69) for results adjusted to baseline otoscopy, pain and symptom score, respectively (Cox-Mantel test). Absence from school or preschool nursery was 1.7 days in both groups; ORs (CI) were 1.00 (0.76), 0.96 (0.73) and 1.04 (0.80). Noninferiority of alternative treatment (CI limit of OR above 0.696) was not proven for pain resolution (–5.2 vs. –5.8 score points); OR (CI) were 0.87 (0.68), 1.15 (0.87) and 0.74 (0.58). Alternative treatment was judged both by doctors (Mann-Whitney estimator with 2-sided 95% CI 0.41 (0.35 – 0.47)) and parents (0.42 (0.36 – 0.48)), to be significantly better tolerated than conventional treatment. Conclusions: In primary care management of uncomplicated acute otitis media in childhood, an alternative treatment strategy based on the natural medicine, Otovowen may substantially reduce the use of antibiotics without disadvantage to the clinical outcome.
Therapeutic drug monitoring
Therapeutic drug monitoring of trazodone: are there pharmacokinetic interactions involving citalopram and fluoxetine?
Abstract
M. Prapotnik1, R. Waschgler2, P. König1, W. Moll2 and A. Conca1
1Department of Psychiatry I, Regional Hospital of Rankweil, and
2Medical Central Laboratory, Feldkirch, Austria
Objective: Therapeutic drug monitoring (TDM) of the new generation antidepressants is subject of controversial discussion. Nonetheless, TDM may safeguard against drug-drug interactions, can be used to control compliance and is valuable in the investigation of overdose. Method: The aim of this prospective study was to investigate serum levels of trazodone when prescribed as monotherapy or when used in combination with the selective serotonin reuptake inhibitors citalopram and fluoxetine in a simultaneous assay using high-performance liquid chromatography (HPLC). Over a 1-year period, we studied 97 patients (63 females) with depressive syndrome who were subdivided into 3 main diagnostic groups. Fifty-two patients were smokers, the mean age was 39.9 years and the mean weight was 72.4 kg; 40 patients were taking trazodone alone, 41 trazodone in combination with citalopram and 16 patients trazodone in combination with fluoxetine. Results: The use of citalopram and fluoxetine in combination with trazodone had no significant impact on trazodone serum levels, and the same was true for differences in body weight and smoking behavior. On the other hand, age and sex had a significant influence on the pharmacokinetic pattern of trazodone, causing higher concentrations in females and in older patients. Since the polypharmacy investigated did not change the serum levels of trazodone, we assume that there is no metabolic interaction between trazodone and citalopram and trazodone and fluoxetine. We observed none of the adverse effects which might have been expected, including dizziness, severe headache, daytime sedation, fatigue or the serotonin syndrome even in a mild form. Conclusion: A “double-tracked” antidepressive treatment using trazodone and the SSRIs citalopram and fluoxetine is associated with a wide safety margin.
Bioavailability section
Cyclosporine bioequivalence study: quantification using
fluorescence polarization immunoassay (FPIA) and radioimmunoassay (RIA)
Abstract
G.D. Mendes, C.H. de Oliveira, M. Sucupira, J.L. Donato, R.A. Moreno and G. De Nucci
1Department of Pharmacology, State University of Campinas, UNICAMP, 2Cartesius Analytical Unit, Department of Pharmacology ICB-USP, and 3Department of Physiology, Faculty of Americana, Campinas, Brazil
Objective: The aim of study was to compare the bioavailability of 2 cyclosporine capsule formulations (100 mg; Sigmasporin Microoral from Novaquímica Divisão Nature’s Plus Farmacêutica Ltd., Brazil, as test formulation and Sandimmune Neoral from Novartis Biociências S.A., Brazil, as reference formulation) in 24 healthy male volunteers. Methods: The study was open, randomized, with a 2-period crossover, a 1-week washout interval between doses. Blood samples were obtained over a 12-hour interval after each oral administration of cyclosporine (2 capsules of 100 mg of each formulation). Cyclosporine blood concentrations were quantified using a fluorescence polarization immunoassay (FPIA) method provided by Abbott Axsym System and Cyclo-Trac SP. Whole-blood radioimmuoassay (RIA) kit was provided by DiaSorin. These assays provided concentration-time curves for cyclosporine in blood concentration from which the following pharmacokinetic parameters were obtained: AUClast, AUCinf, Cmax. Results: Geometric mean and 90% confidence intervals (CI) of Microoral/Neoral as percent ratios were 94.5% (90.8 – 98.4%) for AUClast, 93.8% (89.7 – 98.1%) for AUCinf, and 98.1% (94.5 – 101.8%) for Cmax when cyclosporine was determined using FPIA and 96.1% (91.9 to 100.6%) for AUClast, 95.2% (90.2 – 100.5%) for AUCinf, and 99.4% (96.4 – 102.4%) for Cmax using RIA. Conclusion: Since the 90% CI for Cmax, AUClast and AUCinf ratio were within the 80 – 125% interval proposed by US-FDA, it is concluded that Sigmasporin Microoral 100 mg capsule formulation is bioequivalent to Sandimmune Neoral 100 mg capsule formulation with regard to both rate and the extent of absorption.
