Volume 42, No. 7/2004(July)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Abstracts
4th International Symposium on Microdialysis June 18th – 19th, 2004, Vienna, Austria
Abstract
Organizing committee: B. Blöchl-Daum, M. Brunner, C. Joukhadar and M. Müller
Pharmacodynamics
Topical skin penetration of diclofenac after single- and multiple-dose application
Abstract
P. Dehghanyar1, B.X. Mayer1, K. Namiranian1, H. Mascher2, M. Müller1 and M. Brunner1
1Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Vienna Medical University, Vienna, and 2Pharmanalyt GmbH, Baden, Austria
Objective: Transdermal penetration of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to be highly variable. The present study was performed to gain insight into the transdermal penetration process of topically applied diclofenac and to test whether transdermal absorption leads to pharmacologically effective concentrations in dermal tissue layers beneath the application site. Material and method: Six healthy male volunteers participated in this 2-way crossover study and were assigned to 2 treatment groups. In the first group, diclofenac was applied at a therapeutic dose of 60 mg/100 cm2 3 times daily for 4 days with subsequent occlusion with a plastic foil for 4 hours to enhance transdermal drug absorption. After a 1-week wash-out, diclofenac was applied at a single dose of 300 mg/100 cm2 without occlusion. Diclofenac in both groups was applied on a previously shaven area of the thigh. Transdermal penetration was assessed employing in vivo microdialysis. Results: After multiple-dose administration mean diclofenac concentrations of 0.48 ± 0.35 ng × ml–1 were observed in subcutaneous tissue (mean ± SEM). The mean AUCsubcutis/plasma ratio of 0.08 ± 0.02 indicates redistribution of diclofenac from the systemic circulation to the tissue. After single-dose treatment, mean tissue concentrations were 24.26 ± 46.43 ng × ml–1 with a mean AUCsubcutis/plasma ratio of 60.85 ± 57.59, which suggests direct tissue penetration of diclofenac. Conclusions: Transdermal penetration of diclofenac after multiple as well as after single application of the present formulation is highly variable. In addition to other factors influencing the transdermal penetration process, dose and mode of administration are important factors determining whether pharmacologically effective local tissue concentrations are attained.Correspondence to:
Dr. M. Brunner
Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics Währinger Gürtel 18-20
A-1090 Vienna, Austria
Email: martin.brunner@meduniwien.ac.at
Therapeutics
Urinary tract infection in men
Abstract
E. Hummers-Pradier, A.M. Ohse, M. Koch, W.R. Heizmann and M.M. Kochen
1Department of General Practice/Family Medicine, University of Göttingen, 2Medical Partnership Wagner, Stibbe, Kast, Bispink and Partner, Göttingen, and 3Institute for Microbiology and Infectiology, Berlin, Germany
Objective: To explore the prevalence and microbiology of urinary tract infection (UTI) in symptomatic men in a primary care setting and to determine the appropriateness of patient management of these conditions by the general practitioners. Methods: A cross-sectional survey was carried out matching documentation of symptoms and management with urine culture and results of susceptibility tests. All patients presenting with symptoms typical for a UTI in 36 teaching general practices in the area of Göttingen, Germany, were eligible for enrolment in the study. 15% (n = 90) of all patients were adult men. General practitioners (GPs) were instructed to manage patients as usual. Patient characteristics, dipstick tests and treatment were matched with results of urine cultures and susceptibility testing. Results: Men presenting with symptoms indicative of UTI were predominantly elderly (median age 61 years) and 41% had additional risk factors. Antibiotics were prescribed for 36%, but these were not well-targeted. Urine culture revealed UTI in 60%, of which half had low colony counts (23% of all patients) or multiple bacterial growth (7%); 40% had sterile urine. Dipstick tests proved unhelpful: leukocytes and nitrite had sensitivities of 54% and 38%, specificities of 55% and 84%, positive predictive values of 65% and 78% and negative predictive values of 44% and 46%, respectively. Resistance levels were 53% for amoxicillin and cefaclor, 28% for cefixim, 22% for ciprofloxacin, 34% for both trimethoprim as individual substance and the combination with sulfamethoxazole (cotrimoxazole) and 25% for nitrofurantoin. Conclusion: Men with symptoms indicative of a UTI should not be treated empirically. A urine culture and antibiogram should be obtained before a treatment decision is made. A low-count UTI was common and should not be considered normal.Correspondence to:
Dr. E. Hummers-Pradier
Department of General Practice and Family Medicine
University of Göttingen
Humboldtallee 38
D-37073 Göttingen, Germany
Email: ehummer@gwdg.de
Bioavailability section
Bioequivalence evaluation of 2 brands of cefuroxime axetil 250 mg tablets in healthy human volunteers
Abstract
C. Pistos, S. Michalea, M. Kalovidouris, G. Kontopoulos and M. Georgarakis
1Integrated Laboratory Services, Athens, 2Cardiologist, Thessaloniki, and 3Laboratory of Pharmaceutics and Drug Control, Department of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greece
Objective: To assess the bioequivalence of 2 oral cefuroxime axetil (250 mg) tablets formulation. The reference preparation was Zinadol/Glaxo Wellcome, England, while the test preparation was cefuroxime axetil/Pharmathen, Athens, Greece. Subjects, material and methods: The study was an open, randomized, 2-period, 2-sequence, 2-treatment crossover, involving 24 healthy male and female volunteers. All volunteers completed the study. Cefuroxime axetil plasma concentrations were measured utilizing a sensitive, reproducible and accurate HPLC method. Care was taken through the collection and analysis of the samples due to instability of cefuroxime axetil in light. Pharmacokinetic parameters used to assess bioequivalence were AUC0-last, AUC0-inf for the extent of absorption and Cmax and tmax for the rate of absorption. Statistical evaluation of Cmax, AUC0-last, and AUC0-inf was done using 2-way analysis of variance (ANOVA) after semilogarithmic transformation. Tmax values were tested using the distribution-free Hodges-Lehman interval. Results: The parametric 90% confidence intervals for ratio T/R ranged from 98.91 – 111.65% (point estimate 105.09%) for AUC0-last, 99.41 – 111.78% (point estimate 105.41%) for AUC0-inf and 87.61 – 102.89% (point estimate 94.95%) for Cmax, respectively. Based on the results of tmax, Kel and t1/2 there were no statistically significant differences. Conclusion: The 2 cefuroxime axetil preparations, examined in accordance with the European Union bioequivalence requirements, are equivalent with respect to rate and extent of absorption.
Correspondence to:
Dr. C. Pistos
1 K. Paxinou and Epaminonda Str.
GR-15343 Aghia Paraskevi, Greece
Email: cpistos@ilsgr.com
Bioavailability section
Comparative bioavailability study of doxycycline hyclate (equivalent to 100 mg doxycycline) capsules (doxycin vs vibramycin) for bioequivalence evaluation in healthy adult volunteers
Abstract
I.A. Alsarra, M.S. Al-Said, K.I. Al-Khamis, E.M. Niazy, Y.M. El-Sayed, K.A. Al-Rashood, M.J. Al-Yamani and S.A. Al-Balla
1College of Pharmacy, and 2Department of Medicine, King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia
This investigation was carried out to evaluate the bioavailability of a new capsule formulation of doxycycline (100 mg), doxycin, relative to the reference product, vibramycin (100 mg) capsules. The bioavailability was carried out in 24 healthy male volunteers who received a single dose (100 mg) of the test (A) and the reference (B) products after an overnight fast of at least 10 hours on 2 treatment days. The treatment periods were separated by a 2-week washout period. A randomized, balanced 2-way crossover design was used. After dosing, serial blood samples were collected for a period of 48 hours. Plasma concentrations of doxycycline were analyzed by a sensitive and validated high-performance liquid chromatography assay. The pharmacokinetic parameters for doxycycline were determined using standard noncompartmental methods. The parameters AUC0-t, AUC0-¥, Cmax, Kel, t1/2 and Cmax/AUC0-¥ were analyzed statistically using log-transformed data. The time to maximum concentration (tmax) was analyzed using raw data. The parametric 90% confidence intervals of the mean values of the pharmacokinetic parameters: AUC0-t, AUC0-¥, Cmax and Cmax/AUC0-¥ were within the range 80 – 125% which is acceptable for bioequivalence (using log-transformed data). The calculated 90% confidence intervals based on the ANOVA analysis of the mean test/reference ratios of AUC0-t, AUC0-¥, Cmax and Cmax/AUC0-¥ were 95.98 – 109.56%, 92.21 to 107.66%, 93.90 – 112.56%, and 96.0 to 106.91% respectively. The test formulation was found bioequivalent to the reference formulation with regard to AUC0-t, AUC0-¥, Cmax and Cmax/AUC0-¥ by the Schuirmann’s two 1-sided t-tests. Therefore, the 2 formulations were considered to be bioequivalent.Correspondence to:
Dr. I.A. Alsarra
Department of Pharmaceutics
College of Pharmacy, King Saud University
P.O. Box 2457
Riyadh 11451, Saudi Arabia
Email: ialsarra@ksu.edu.sa
