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Abstract

M. Burian, J. Freudenstein, M. Tegtmeier, B. Naser-Hijazi, H.-H. Henneicke-von Zepelin and W. Legrum

¹Department of Pharmacology and Toxicology, Philipps University, Marburg, and ²Schaper and Brümmer, GmbH and Co. KG, Salzgitter, Germany
Objective: Coumarin, used in the treatment of chronic venous diseases, is mainly metabolized to non-toxic 7-hydroxy-coumarin by CYP2A6. At least, 3 variant alleles, CYP2A6*2, CYP2A6*3 and CYP2A6*4A, have been shown to encode catalytically defective proteins. Sporadic elevation of liver enzymes has been reported on the chronic administration of coumarin. We sought to determine if susceptibility to coumarin-associated liver dysfunction is genetically determined by polymorphism in CYP2A6 and impairment of the 7-hydroxylation of coumarin. Additionally, we were interested in the effect of polymorphism on smoking because of the predominant role of CYP2A6 in the metabolism of nicotine. Methods: The investigation was performed prospectively within a randomized double-blind clinical trial of the coumarin-containing drug SB-LOT (90 mg coumarin + 540 mg troxerutin/d) vs. placebo in 231 German patients with chronic venous insufficiency. Monitoring of the hepatic status involved regular measurements of liver function during the 16-week treatment. Genotyping of CYP2A6 was carried out by means of PCR and confirmed by DNA sequencing analysis. Results: The allelic frequencies of the variant CYP2A6*2 and CYP2A6*3 alleles were 0.023 and 0.014, respectively. There was no significant difference in the incidence of liver dysfunction between heterozygotes with CYP2A6*2, CYP2A6*3 and wild-type homozygotes. CYP2A6 polymorphism had no significant effect on smoking behavior. Conclusion: No evidence was obtained that the studied polymorphism in CYP2A6 is a determinant of the coumarin-associated liver dysfunction.

Abstract

H. Seeger, P. Hadji and A.O. Mueck

Section of Endocrinology and Menopause, Women’s University Hospital, Tübingen, Germany
Objectives: Evidence is accumulating that estradiol metabolites are not merely waste products but may play physiologic and pathophysiologic roles. In the present study, effect of estradiol metabolites on the proliferation of human female osteoblasts was investigated for the first time and compared to effect of their parent substance 17b-estradiol. Materials and methods: Osteoblasts from female hipbone were incubated with estradiol and estradiol metabolites at dosages of 10–9, 10–7 and 10–5 M for 7 days. Cell proliferation was measured using a cell counter. Results: Estradiol had no effect on cell proliferation at the tested concentrations. In contrast, the A-ring metabolites 2-hydroxyestrone, 2-hydroxyestradiol, 2-hydroxyestriol, 4-hydroxyestrone and 4-hydroxyestradiol displayed significant increases in cell proliferation, although only at high physiologic or pharmacologic dosages. Methylation of these metabolites completely abolished their proliferating property. For the D-ring metabolites estrone, estriol, estetrol and 16a-hydroxyestrone, no significant changes in cell proliferation were observed. Conclusion: The present results suggest that endogenous estradiol metabolites are capable of stimulating the proliferation of human female osteoblastic cells. None of the estradiol metabolites examined inhibited cell proliferation. Thus, estradiol metabolism may play a decisive role in development and maintenance of bone mass.

Abstract

R. Hawel¹, G. Klein², F. Singer³, F. Mayrhofer⁴ and S.T. Kähler⁵

¹Rehabilitationszentrum für Erkrankungen des rheumatischen Formenkreises, Bad Hofgastein, ²Sonderkrankenanstalt für rheumatische Erkrankungen und Herz-Kreislauf-Krankheiten und Ludwig-Boltzmann-Institut für Rehabilitation interner Erkrankungen, Saalfelden, ³Sonderkrankenanstalt Laab im Walde, Laab im Walde, ⁴Sonderkrankenanstalt Bad Schallerbach, Rehabilitationszentrum für rheumatische, orthopädische und neurologische Erkrankungen, Bad Schallerbach, and ⁵Medical Department Gebro Pharma GmbH, Fieberbrunn, Austria
Context: Osteoarthritis (OA) is often treated with nonsteroidal anti-inflammatory drugs (NSAIDs) or selective inhibitors of cyclooxygenase-2 (COX-2). Objective: This clinical trial aimed to assess directly the relative therapeutic efficacy of the isolated active enantiomer of ibuprofen, named dexibuprofen (S(+)-ibuprofen) in a special crystal form, and the selective COX-2 inhibitor celecoxib in adults with OA of the hip. Moreover, the hypothesis that the tolerability/safety profile of dexibuprofen is comparable to celecoxib is to be tested. Methods: The investigation was a randomized, parallel-group, double-blind, active controlled clinical trial, conducted from January 2001 to February 2002 in 4 rehabilitation centers in Austria. 148 inpatients were randomly assigned to dexibuprofen 800 mg or celecoxib 200 mg daily. The primary criterion was the improvement in the Western Ontario and McMasters osteoarthritis index (WOMAC OA index) after 15 days of therapy. Results: Evaluation of the WOMAC OA index proved that dexibuprofen 400 mg b.i.d. is not inferior to celecoxib 100 mg b.i.d. with the Mann-Whitney estimator equal to 0.5129 and the corresponding lower boundary of the 95% confidence interval equal to 0.4409. The overall incidence of adverse drug reactions was 12.16% in the dexibuprofen group and 13.51% in the celecoxib group. 8.1% of patients on dexibuprofen and 9.5% on celecoxib suffered from gastrointestinal disorders. Conclusion: In the presented clinical trial dexibuprofen has at least equal efficacy and a comparable safety/tolerability profile as celecoxib in adult patients suffering from osteoarthritis of the hip.

Abstract

A. Vallano, J. Llinares, J.M. Arnau, M. Martorell, L. Girona and J.-R. Laporte

¹Fundació Institut Català de Farmacologia, Servei de Farmacologia Clinica, Hospital Universitari Vall d’Hebron, Departament de Farmacologia, Terapèutica i Toxicologia, Universitat Autònoma de Barcelona, WHO Collaborating Centre for Research and Training in Pharmacoepidemiology, and ²Servei de Farmàcia, Hospital de Traumatologia i Rehabilitació, Hospital Universitari Vall d’Hebron, Barcelona, Spain
Objective: Postoperative pain is inadequately treated in many surgical settings. The present study evaluates the impact of analgesic drug-use guidelines in the management of postoperative pain. Patients and methods: A prospective drug utilization study was carried out in 3 stages in a traumatology, orthopedic and rehabilitation tertiary hospital. The first stage, aimed at describing the patterns of use of analgesic strategies in the management of postoperative pain, identified habits, practices and misconceptions regarding this therapeutic area. After this, an ad hoc representative institutional working group agreed on analgesic drug-use guidelines for the management of postoperative pain. These were then published, presented and discussed with surgeons and nurses. After the guidelines had been implemented, their impact was evaluated in terms of the analgesics used, their dosage and their administration schedule. Results: 101 patients were studied before the implementation of the guidelines and 108 patients after. Patients receiving opiate analgesics during the immediate postoperative period increased from 70 – 94% (p < 0.05). First-choice analgesics used according to the guidelines increased from 40 – 89% of choices after the implementation of the guidelines (p < 0.05). Administration of analgesics at regular predetermined intervals increased from 45 – 58% of medical orders, but this increase was not statistically significant (p = 0.07). Prescription of analgesics at adequate doses increased from 67 – 87% (p < 0.05). Conclusion: Education on the treatment of postoperative pain is made up of several messages including the drug of choice and dose regimen. Prescribers seemed more receptive to a change in drug rather than issues related to the correct dose regimen. More research is needed to assess how educational activities can improve the management of postoperative pain.

Abstract

D. Schneider¹, B. Kießling¹, M. Wieczorek¹, I. Bognar-Steinberg², L. Schneider¹ and C.-F. Claussen¹

¹Department of Neurootology, ENT Clinic, University of Würzburg, and
²Department of Clinical Research, Hennig Arzneimittel, Flörsheim am Main, Germany
In the present randomized, comparative, double-blind, 3-way crossover study, possible effects of 3 antivertiginous medications on vigilance were investigated. 30 healthy volunteers received single doses of a fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg (Arlevert®, ARL), dimenhydrinate 50 mg, or betahistine dimesylate 12 mg, in randomized order at 1-week intervals. Spontaneous brain electrical activity (EEG), acoustic late evoked potentials (ALEP) with P300, and reaction time were measured before and 90 (t90) and 180 minutes (t180) after drug intake. All 3 medications led to a delay of P300 (primary criterion) and a decrease of its amplitude. The maximum delay at t180 was found for dimenhydrinate (16.42 ms) and the lowest for betahistine (6.33 ms). Differences ARL vs dimenhydrinate and ARL vs betahistine were not statistically significant (p > 0.05). Spectral analysis of spontaneous EEG showed slight and similar decreases in the power in the a-band under dimenhydrinate and ARL (p = 0.07 and p = 0.03 with respect to baseline, respectively), but basically no change under betahistine. There was no effect on reaction time by either medication. None of the subjects reported drowsiness or any other adverse event. The findings confirm the reported suitability of P300 latency for measurement of drug effects on brain activity, but provide no indication of concomitant impairment of performance capacity by the tested drugs. Global assessment of the results suggests that the fixed combination cinnarizine 20 mg/dimenhydrinate 40 mg exerts only a minor effect on vigilance, not significantly different from betahistine, which is commonly regarded as a non-sedating antivertiginous drug.

Abstract

T. Elmas, O. Mavioglu, S.Oztekin, Z. Elar and H. Guven

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Volume 41, No. 4/2003(April)