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Abstract

M.-W. Lo¹, J.B. McCrea², C.R. Shadle², M. Hesney³, R. Chiou¹, D. Cylc¹, A.S. Yuan¹ and M.R. Goldberg²

¹Drug Metabolism, ²Clinical Pharmacology, and ³Clinical Biostatistics, Merck Research Laboratories, West Point, PA, USA
Background: Enalapril in RAPIDISC* (wafer), a new easy-to-administer formulation of enalapril, may improve the convenience of enalapril therapy, thereby helping patients adhere to antihypertensive treatment. Subjects and methods: To determine whether 20 mg enalapril wafer is bioequivalent to the conventional 20 mg enalapril tablet, an open-label, two-period crossover study was performed in 16 healthy male volunteers. Cumulative urinary recovery of free enalaprilat (active metabolite of enalapril) and the serum maximum concentration of free enalaprilat (Cmax) were the primary pharmacokinetic parameters used to determine bioequivalence in this study. Bioequivalence was defined as the geometric mean ratio (wafer : tablet) falling within the equivalence limits of 0.80 to 1.25 for both parameters. Results: Cumulative urinary recovery of free enalaprilat (0 – 72 hours) was similar between the wafer and conventional tablet formulations (arithmetic mean 5.13 vs. 5.03 mg, about 36% of dose). The geometric mean ratio of the urinary recovery of free enalaprilat (wafer : tablet) was 1.03 (90% CI: 0.93, 1.15). Cmax of serum enalaprilat was also similar between the wafer and conventional tablet formulations (arithmetic mean 85.7 vs. 76.3 ng/ml). The geometric mean Cmax ratio (wafer : tablet) was 1.10 (90% CI: 1.00, 1.22). Both enalapril formulations were well tolerated. Conclusion: This study demonstrates that 20 mg enalapril in RAPIDISC is bioequivalent to 20 mg enalapril conventional tablet.Correspondence to:
Dr. M.-W. Lo; Clinical Drug Metabolism, Merck Research Laboratories, WP75-100, P.O. Box 4, West Point, PA 19486-0004, USA

Abstract

S. Tatsunami¹, A. Ito², K. Kawata², R. Kuwabara¹, K. Fukutake³ and K. Yamada⁴

¹Radioisotope Research Institute, St. Marianna University School of Medicine, Kawasaki, ²Division of Clinical Laboratory Medicine, Yokohama City University Hospital, School of Medicine, Yokohama, ³Department of Clinical Pathology, Tokyo Medical University Hospital, Tokyo, and ⁴Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Japan
Objective: The typical regimen for lamivudine is 150 mg bis in die (bid). However, pharmacokinetic values of lamivudine will differ among individual patients. In addition, few studies regarding the pharmacokinetics of lamivudine in the Japanese people have so far been reported. Therefore, we have aimed to examine the variation in the pharmacokinetic values of lamiduvine present in six Japanese patients with HIV-1 infection. Patients and methods: Lamivudine concentrations were measured in three hemophiliacs (HIV-1-asymptomatic carrier, AC) and three non-hemophiliacs (2 of these patients were AC and one had AIDS-related complex, ARC). In order to simulate the lamivudine plasma concentrations found in chronic oral administration, we added an absorption compartment to the two-compartment model. Results: The mean ± SD of Tmax, Cmax, AUC0-¥, and t1/2b were 1.2 ± 0.5 (hours), 1280 ± 267 (ng/ml), 6778 ± 2763 (ng×h/ml), and 10.3 ± 4.7 (hours), respectively. Although these values were comparable on average to those previously reported, there were noticeable differences with respect to the various time courses of drug plasma concentration among each patient. Conclusion: Computations speculated that the trough and peak plasma concentrations as well as the AUC at steady-state change significantly depending on each patient. It suggests that individual pharmacokinetic values of lamivudine should be determined before deciding the optimal administration dose for specific patients.Correspondence to:
Dr. S. Tatsunami; Radioisotope Research Institute, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Japan 216-8511

Abstract

F.D. Suyatna, R. Setiabudy, E. Herwana and O. Tjandra

Department of Pharmacology, Medical Faculty, University of Indonesia, Jakarta, Indonesia
Objective: This study was designed to investigate the butyrylcholinesterase (BChE) and C5+ variant phenotypes in a Javanese ethnic group in Indonesia. Blood-donors, materials and methods: Random blood samples from a Javanese ethnic group were obtained from the Indonesian Red Cross Service. The donors were 40.09 ± 9.53 years old, consisting of 358 (89.45%) males and 42 females (10.55%). The plasma content of BChE was determined spectrophotometrically using benzoylcholine as substrate, and phenotyping of BChE was performed using the inhibitors 10 mM dibucaine and 50 mM sodium fluoride. Phenotyping of the C5+ variant was carried out by means of polyacrylamide gel electrophoresis using a 7.5% (w/v) acrylamide slab gel and a 3% (w/v) acrylamide stacking gel, and stained with fast red azo dye. Results: The results show that of 398 samples studied, the average activities of BChE are 1.00 ± 0.22 U/ml. 377 individuals (94.72%) show normal activities, whereas 21 individuals (5.78%) are below normal (< 0.690 U/ml). The mean ± SD of dibucaine number (DN) is 83 ± 5 and the fluoride number (FN) is 66 ± 6. From this population we identified one individual with UA phenotype (total activity: 0.310 U/ml, DN: 62, and FN: 50). The frequency of C5+ variant in the population as detected by acrylamide electrophoresis is 21%. Conclusion: Our data indicate that the atypical allele of BChE is rare and that the C5+ variant is detected in high frequency in the ethnic Javanese of Indonesia.Correspondence to:
Dr. F.D. Suyatna; Department of Pharmacology, Medical Faculty, University of Indonesia, Salemba 6, Jakarta 10430, Indonesia

Abstract

F.E. Lerner¹,², G. Caliendo³, V. Santagada³, G.S.M. Santana⁴, M.E.A. Moraes⁴ and G. De Nucci¹

¹Department of Pharmacology, Cartesius Analytical Unit, Biomedical Sciences Institute, University of São Paulo, ²Department of Pharmacology, Miguel Servet Clinical Pharmacology Unit, State University of Campinas (UNICAMP), Campinas, Brazil, ³Dipartimento de Chimica Farmaceutica e Tossicologica, Università de Napoli “Federico II”, Naples, Italy, and ⁴Department of Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil
Objective: To assess the bioequivalence of two tablet formulations of clarithromycin (Clamicin 500 mg from Medley Indústria Farmacêutica, Brazil, as the test formulation, and Biaxin 500 mg from Abbott Industries, USA, as the reference formulation). Methods: A single 500 mg oral dose of each formulation was administrated in 24 healthy volunteers of both sexes (12 males and 12 females). The study was conducted open, randomized, two-period crossover design with a 7-day interval between doses. The plasma concentrations of clarithromycin were quantified by reversed phase liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reaction monitoring (MRM) method. 14-hydroxyclarithromycin concentration was estimated semiquantitatively as equivalent of clarithromycin/ml. The precision of the method was evaluated using calibration curves and plasma quality control samples. The pharmacokinetic parameters calculated for both compounds included: AUC(0-48h), AUC(0-¥), Cmax, Cmax/AUC(0-48h), Tmax, T1/2 and Ke. Results: Standard curves of clarithromycin in plasma were linear in the range of 0.05 mg×ml–1 to 10 mg×ml–1 (r > 0.999). The limit of quantification was 5 ng/ml. Within- and between-run plasma quality control CV were 5.8% and 15.7%, respectively. Inaccuracy within- and between-runs were 14% and 17%, respectively. 90% CI for clarithromycin geometric mean AUC(0-48h), AUC(0-¥) and Cmax ratios (test/reference) were: 88.7% – 103.1%, 89.4% – 103.7% and 85.4% – 99.6%, respectively, and for hydroxyclarithomycin were 80.3% – 108.6%, 80.1% – 110.1% and 85.4% – 112.6%, respectively. Conclusion: The method described for the quantification of charithomycin and its main metabolite is accurate and sensitive. Clamicin was considered bioequivalent to Biaxin based on the rate and extent of absorption. Since these were no significant differences in the bioequivalence determined using the pharmacokinetic parameters of either clarithromycin or 14-hydroxyclarithromycin, we suggest that future bioequivalence trials of this drug may be performed by quantifying clarithromycin only.Correspondence to:
Dr. G. De Nucci, Av. Jesuino Marcondes Machado 415, Campinas, SP-Brazil, 13092-320

Abstract

M. Manorot, N. Rojanasthien, B. Kumsorn and S. Teekachunhatean

Division of Clinical Pharmacology, Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Thailand
Aim: To determine the bioequivalence of two oral formulations of generic fluconazole in twelve healthy Thai volunteers. Subjects, materials and methods: The test preparation was Flucozole (Siam Bheasach, Thailand) and the reference was Diflucan (Pfizer Inc.). The two products were administered as 200 mg single oral doses in a two-period crossover design with a two-week washout period. After drug administration, serial blood samples were collected over a period of 72 hours. Serum fluconazole concentrations were determined by HPLC, and the pharmacokinetic parameters were analyzed by non-compartmental analysis. Results: The time to reach the maximal concentration (Tmax, hour) of Flucozole (1.18 ± 0.56) was statistically faster than that of Diflucan (1.59 ± 0.54). The 90% confidence intervals of the AUC0-¥ ratio and the Cmax ratio mT/mR for Flucozole/Diflucan were 0.97 – 1.20 and 1.01 – 1.26, respectively. These values were within the acceptable bioequivalence intervals of 0.80 – 1.25 and 0.7 – 1.43 for the ratio of the average AUC0-¥ and Cmax, respectively. Conclusion: Thus, our study demonstrated the bioequivalence of Flucozole and Diflucan with respect to the rate (Cmax) and extent of absorption (AUC0-¥).Correspondence to:
Dr. N. Rojanasthein; Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

Abstract

I. Kraus¹ and D. Vitezic²

¹Department of Gastroenterology, University Hospital Center Rijeka, Rijeka ²Department for Science and Clinical Pharmacology, University Hospital Center Rijeka and Department of Pharmacology, University of Rijeka Medical School, Rijeka, Croatia
This is a report of the alpha interferon-induced acute anosmia in a 37-year old patient with chronic hepatitis C. This exceptionally rare side-effect started in our patient as a smelling problem 2 weeks after the initiation of the therapy, and anosmia is still present 13 months after the discontinuation of the alpha interferon. We presume that neurotoxic mechanism could be responsible for this side-effect.Correspondence to:
Dr. I. Kraus; Department of Gastroenterology, University Hospital Center Rijeka, Kresimirova 42, 51000 Rijeka, Kroatien

Abstract

S. Ozgocmen¹, S.A. Catal¹, O. Ardicoglu² and A. Kamanli²

¹Department of Physical Medicine and Rehabilitation, Ankara State Hospital, Ulucanlar, Ankara, and ²Department of Physical Medicine and Rehabilitation, Division of Rheumatology, Firat University, School of Medicine, Elazig, Turkey

Abstract

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Volume 38, No. 7/2000(July)