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Abstract

T.J. Cleophas

European College of Pharmaceutical Medicine, President American College of Angiology, c/o Albert Schweitzer Hospital, Dordrecht, Netherlands

Abstract

G. Micieli¹, A. Cavallini¹, S. Marcheselli¹, F. Mailland², L. Ambrosoli² and G. Nappi¹

¹Headache Center, Department of Neurology, “C. Mondino” Institute, University of Pavia, Italy, and ²Scientific Department, Poli Group, Lugano, Switzerland
Objective: A double-blind, crossover study was carried out to compare the efficacy of a-dihydroergocryptine mesylate (10 mg twice daily) vs propranolol (40 mg twice daily) in the prophylaxis of migraine without aura, and to identify possible predictors of therapeutic response by evaluating the symptomatological profile of individual migraine attacks and the autonomic cardiovascular response to noradrenergic and dopaminergic (cold pressor, bromocriptine) tests. Patients and methods: Forty migraineurs (10 males, 30 females) were randomized according to a two-period (3-month), two-treatment, crossover design. Efficacy was assessed using quantitative data recorded in the patient’s headache diary. Data were evaluated using the Wallenstein’s method. Results: Both drugs showed a significant reduction in all the efficacy variables (headache attacks, days with headache, analgesic consumption) with no difference between treatments. Neither a bromocriptine test, nor a cold pressor test nor the symptomatological profile of individual migraine attacks differed between the two groups of migraine patients. Ten patients experienced at least one adverse drug reaction during the first period of the crossover design, 5 being treated with a-dihydroergocryptine and 5 with propranolol. Conclusions: It is concluded that a-dihydroergocryptine is an effective medication for migraine prophylaxis. The biochemical tests and the type of psychological profile cannot be used to predict drug response.Correspondence to:
Dr. G. Micieli; Headache Center, Department of Neurology, “C. Mondino” Institute, University of Pavia, Italy
Email: micieli@mondino.it

Abstract

B. Szelies, R. Mielke, J. Kessler and W.-D. Heiss

Neurologische Universitätsklinik, Köln, Germany
Objective: Electroencephalographic and clinical effects of piracetam in post-stroke aphasia were evaluated in a prospective, randomized, double-blind, placebo-controlled trial. Methods: In 24 patients with mild to moderate aphasia after ischemic stroke, quantitative topographic EEG at rest was studied before and after a 6-week treatment period. Results: In the active treatment group, a significant shift in the alpha-rhythm from frontal to occipital regions was observed which may be due to a restitution of corticothalamic circuits involved in the generation of alpha-activity. Conclusion: Neuropsychological scores improved significantly and markedly in various domains of speech during piracetam treatment, whereas improvements were less marked and restricted to a few categories in the placebo group.Correspondence to:
Prof. Dr. B. Szelies; Neurologische Universitätsklinik, Joseph-Stelzmann-Straße 9, D-50931 Köln, Germany
Email: b.szelies@pet.mpin-koeln.mpg.de

Abstract

M. Tsadkin¹,², G. Holcberg¹, O. Sapir¹, M. Hallak¹, M. Huleihel¹, M. Katz¹, H. Polachek², M. Mazor¹ and Z. Ben-Zvi²

¹Department of Obstetrics and Gynecology, Soroka University Medical Center and ²Department of Clinical Pharmacology, Faculty of Health Science, Ben-Gurion University, Beer-Sheva, Israel
Objective: To determine the effects of albumin (BSA) concentration in perfusion medium on digoxin transfer in isolated perfused human placental cotyledon. Study design: Isolated placental cotyledons from 13 normal human placentas were dually perfused after cannulating artery and vein of the chorionic plate and piercing 4 catheters through the corresponding basal plate with M199 medium enriched with BSA and glucose. Flow rates were 12 and 6 ml/min in the maternal and fetal circuits, respectively. Digoxin was added to the maternal reservoir at a final concentration of 5.51 ± 1.00 ng/ml. BSA in maternal and fetal perfusate was kept at 3 concentrations: 1, 3 and 5 mg/ml (Groups I, II, III). Transplacental passage of digoxin was calculated from repeated fetal and maternal perfusate samples collected over 3 hours in the 3 groups. Digoxin levels were measured by FPIA (TDx, Abbott). Results: There was no transfer of digoxin from the maternal to fetal compartment when the concentration of BSA was 1 mg/ml. Increasing the concentration of BSA led to a substantial increase in the transfer of digoxin to the fetal compartment. Steady state levels of digoxin in the fetal compartment were 0.61 ± 0.19 ng/ml at 3 mg/ml of BSA. Conclusion: Maternal and fetal serum concentration of BSA affect digoxin transfer in isolated perfused human placentas. Three mg/ml are considered to be the optimal albumin concentration.Correspondence to:
Dr. G. Holcberg; Department of Obstetric and Gynecology, Soroka University Medical Center, Faculty of Health Science, Ben-Gurion University, P.O. Box 151, Beer-Sheva, 84101, Israel
Email: holcberg@bgumail.bgu.ac.il

Abstract

L. Tothfalusi¹ and L. Endrenyi²

¹Department of Pharmacodynamics, Semmelweis University of Budapest, Budapest, Hungary, and ²Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
Background: One of the claimed benefits of the individual bioequivalence (IBE) approach has been that the aggregate regulatory model rewards a test formulation when it has a within-subject variation smaller than the reference product. Hauck et al. [1996] demonstrated that, in the absence of random variations, this property of IBE was due to the tradeoff between the difference of the means and the deviation between the intrasubject variances of the two formulations. The tradeoff was a consequence of the aggregate regulatory model. However, calculations of Endrenyi and Hao [1998] showed that, in the presence of random variations, not only rewards but also penalties can arise due to chance alone. Methods: A data set of 55 investigations made public by the FDA in 1999 and containing replicate crossover designs was analyzed. Two parameters, AUC and Cmax, were determined in each investigation. Results: The analyses of the FDA data indicate that: rewards and penalties occur at similar frequencies, large rewards and penalties are recorded quite often, and the aggregate IBE model is rather insensitive to the difference between the estimated means and is compatible with the frequent occurrence of large deviations. Conclusion: Rewards and penalties, apparently arising from random variations, can affect regulatory decisions on the acceptance of IBE and can lead to incorrect conclusions.Correspondence to:
Dr. L. Endrenyi; University of Toronto, Department of Pharmacology, Toronto, ON M5S 1A8, Canada
Email: l.endrenyi@utoronto.ca

Abstract

C.H. Oliveira, E. Abib, Y.B. Vannuchi, M. Sucupira, J. Ilha and G. De Nucci

Cartesius Analytical Unit, Department of Pharmacology, São Paulo, Brazil
Objective: To compare the bioavailability of two amoxicillin oral suspension (250 mg/5 ml) formulations and two amoxicillin capsule (500 mg) formulations (Amoxicilina from Medley S/A Indústria Farmaceûtica, Brazil, as test formulations and Amoxil from SmithKline Beecham Laboratórios Ltda., Brazil, as reference formulations) in 48 volunteers of both sexes. Material and methods: The study was conducted open with a randomized two-period crossover design and a one-week washout period. Plasma samples were obtained over a 12-hour interval. Amoxicillin concentrations were analyzed by combined reversed phase liquid chromatography and tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using the selected ion monitoring method. From the amoxicillin plasma concentration vs. time curves the following pharmacokinetic parameters were obtained: AUClast, AUC0-¥ and Cmax. Results: Geometric mean of Amoxicilina/Amoxil 250 mg/5 ml individual percent ratio was 103.70% for AUClast, 103.15% for AUC0- ¥ and 106.79% for Cmax. The 90% confidence intervals were 97.82 – 109.94%, 97.40 to 109.24%, and 96.38 – 118.33%, respectively. Geometric mean of Amoxicilina/Amoxil 500 mg capsule individual percent ratio was 93.26% for AUClast, 93.27% for AUC0-¥ and 90.74% for Cmax. The 90% confidence intervals were 85.0 – 102.33%, 85.12 – 102.31%, and 80.14 – 102.73%, respectively. Conclusion: Since the 90% CI for both Cmax, AUClast and AUC0-¥ were within the 80 – 125% interval proposed by the Food and Drug Administration, it was concluded that Amoxicilina 250 mg/5 ml oral suspension and Amoxicilina 500 mg capsule were bioequivalent to Amoxil 250 mg/5 ml oral suspension and to Amoxil capsule 500 mg, respectively, with regard to both the rate and extent of absorption.Correspondence to:
Dr. C.H. Oliveira; 415 Jesuino Marcondes Machado Ave. 13092-320 Campinas, SP, Brazil

Abstract

B.S.J. van Toor¹, A. Buchwald², E. Stengele², D. Trenk², C. Gercek³ and C.M. de Mey⁴

¹Research, Development and Medicine, Boehringer Ingelheim GmbH, Ingelheim, ²Department of Clinical Pharmacology, Herzzentrum, Bad Krozingen, ³Department of Biostatistics, Boehringer Ingelheim Pharma KG, Ingelheim, and ⁴Applied Clinical Pharmacology Services, Mainz-Kastel, Germany
Aim: This study investigated the bioavailability of single doses of 1.12 and 2.24 mg chlorphenamine maleate applied intranasally (0.4% nasal spray) relative to a single peroral dose of 8 mg chlorphenamine maleate (tablets). Methods: Twenty-four (24) subjects were treated with single nasal doses of 1.12 mg and 2.24 mg chlorphenamine maleate (0.4% nasal spray) and two 4 mg chlorphenamine maleate tablets (Piriton) on 3 separate study days according to a 3-way cross-over design with a 7-day wash-out between periods. Blood was sampled before and at 0.25, 0.50, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12, 16 and 24 hours after drug administration. Additional blood samples were obtained 36, 48 and 72 hours after peroral administration only. All subjects were included in the pharmacokinetic analysis. Results: Nasally applied chlorphenamine maleate was readily absorbed, reaching peak plasma levels after 0.25 to 3.0 hours. The dose-normalized estimated mean Cmax values were 1.24, 1.43 and 1.21 ng/ml for the peroral tablet and the 1.12 mg and 2.24 mg nasal dose, respectively. The dose-normalized estimated mean AUC0-¥ values were 25.91, 26.44 and 25.56 ng×h/ml for the tablet and the 1.12 and 2.24 mg nasal dose, respectively. The estimated treatment ratios (nasal dose to tablet) of the dose-normalized values for the 1.12 mg nasal dose were 1.15 (90% CI: 1.0 – 1.32) and 1.02 (90% CI: 0.88 – 1.18) for Cmax and AUC0-¥, respectively, for the 2.24 mg nasal dose they were 0.98 (90% CI: 0.85 – 1.13) and 0.99 (90% CI: 0.85 – 1.13) for Cmax and AUC0-¥, respectively. The other pharmacokinetic characteristics (tmax, t1/2, lz, AUC(0-tf), MRTtot, CL/f and Vz/f) were comparable across all treatments. These data indicate that the disposition of chlorphenamine maleate was independent of the route and dose of administration. Conclusions: Chlorphenamine maleate is readily absorbed after nasal application using a 0.4% nasal spray. The nasal administration showed that the systemic bioavailability at the two dose levels used was comparable to that for the tablet. Maximum concentrations on the low dose, however, were higher and those on the high dose were comparable to those for the tablet. The nasal application of chlorphenamine maleate does not alter the overall systemic exposure compared to the oral route.Correspondence to:
B.S.J. van Toor; Bayer AG, Pharmaforschungszentrum, Aprather Weg, D-42115 Wuppertal, Germany
Email: bert.vantoor.bt@bayer-ag.de

Abstract

J. Chládek¹, L. Sispera¹, J. Martínková¹, B. Zaludek², P. Sova², S. Mièuda¹, J. Grim¹, J. Cermanová¹, B. Zaludek², P. Sova² and A. Franc²

Department of Pharmacology, Faculty of Medicine, Charles University, Hradec Králové, Czech Republic
Aim: The bioequivalence of two rimantadine tablet formulations was determined. Methods: The study was designed as a randomized, two-period, two-sequence, crossover study. Twenty-four healthy male volunteers received a single 100 mg dose of rimantadine hydrochloride as test (Rimantadin Lachema 100 tbl. obd., produced by Lachema, a.s., Brno, Czech Republic) and reference formulations (Flumadine 100 tbl. obd., produced by Forest Pharmaceuticals, St. Louis, USA). The two administrations were separated by 14 days and were performed in the fasting state. Blood samples were obtained at 15 time points during the interval 0 – 120 h after administration. Rimantadine plasma concentrations were determined by gas chromatography with electron-capture detection. Results: The geometric mean concentration-time profiles of rimantadine after administration of the two formulations were superimposable. The following pharmacokinetic parameters refer to the geometric mean [exp(mean ± SD)] values for the test and reference formulations, respectively: Cmax (ng/ml) 70.5 (60.0 – 82.7) vs. 70.0 (59.9 to 81.7), AUC0-¥ (ng×h/ml) 2872 (2224 to 3707) vs. 2849 (2195 – 3699), AUC0-120h 2744 (2184 – 3448) vs. 2712 (2138 – 3441), t1/2 (h) 25.8 (20.1 – 33.0) vs. 25.7 (20.6 to 32.1). Median (range) tmax (h) values were 4.5 (2.0 – 8.0) and 6.0 (2.0 – 8.0). Parametric 90% confidence intervals for the expected mean percentage ratios (test/reference) of the pharmacokinetic variables were within the range of 97% to 105%. The median (91.1% confidence interval) difference in tmax was –0.3 h (–2.0 – 0.5). The point and interval estimates were identical when truncated AUCs (0 – 96 h, 0 – 72 h, 0 – 48 h and 0 – 24 h) were used in calculations. Conclusion: The two rimantadine formulations were equivalent in both the rate and extent of bioavailability and they were also well tolerated. This study confirms the findings of other studies showing that for immediate release formulations of drugs with long half-lives shortening the duration over which blood samples are collected improves the economics, is more ethical and does not impair the quality of data.Correspondence to:
Dr. J. Chládek; Department of Pharmacology, Faculty of Medicine, Charles University, Simkova 870, CZ-500 01 Hradec Králové, Czech Republic
Email: chladekj@lfhk.cuni.cz

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Volume 39, No. 4/2001(April)