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Abstract

Y.G. Kim¹, Y.J. Lee¹, E.D. Lee², S.D. Lee², J.W. Kwon², W.B. Kim² C.-K. Shim¹ and M.G. Lee¹

¹College of Pharmacy, Seoul National University, and ²Research Laboratory, Dong-A Pharmaceutical Company, Yongin, Korea
Aim: A bioequivalence study of the closerin capsules to the dura seromycin capsules was conducted. Patients and methods: Twenty-four healthy male Korean volunteers received each medicine at the cycloserine dose of 250 mg in a 2 × 2 crossover study. There was a one-week washout period between the doses. Plasma concentrations of cycloserine were monitored by a high-performance liquid chromatography for over a period of 72 hours after the administration. AUCinf (the area under the plasma concentration-time curve from time zero to time infinity) was calculated by the linear-log trapezoidal method. Cmax (maximum plasma drug concentration) and Tmax (time to reach Cmax) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUCinf and Cmax, and untransformed Tmax. Results: There were no significant differences between the medications in AUCinf and Cmax. The point estimates and 90% confidence intervals for AUCinf (parametric) and Cmax (parametric) were, in point estimate (90% confidence interval), 0.992 (0.950 ~ 1.037) and 1.051 (0.965 ~ 1.144), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration Guidelines. The corresponding value of Tmax was 0.000 (–0.250 ~ 0.125). Moreover, the modified Pitman-Morgan’s adjusted F test and equal variance test (one-sided) indicated that the 2 medications were comparable in intra- and inter-individual variability in cycloserine bioavailability. Conclusion: Therefore, these results indicate that the 2 medications of cycloserine are bioequivalent and, thus, may be prescribed interchangeably.Correspondence to:
Dr. M.G. Lee; College of Pharmacy, Seoul National University, San 56-1, Shinrim-Dong, Kwanak-Gu, Seoul 151-742, Korea

Abstract

Y.C. Bechtel¹, E. Haffen¹, H. Lelouët¹, M.P. Brientini¹, G. Paintaud³, J.P. Miguet² and P.R. Bechtel¹

¹Pharmacologie Clinique, Faculté de Médecine et de Pharmacie, ²Service d’Hépatologie, Hôpital Universitaire, Besançon, and ³Laboratoire de Pharmacologie et Toxicologie, Hôpital Universitaire, Tours, France
Objectives: To evaluate the polygenic regulated caffeine metabolism in a group of 226 patients with liver alcoholic cirrhosis classified according to the Child score. Methods: Over a 14-year period an hepatic function test, using caffeine as probe drug, has been systematically associated to the usual clinical and biochemical investigations performed in patients with liver alcoholic cirrhosis. “Caffeine test” consisted in a 200 mg caffeine oral intake. Urines were collected over 24 hours: caffeine (137X), 1-7 dimethylxanthine (17X), 1-3 dimethylxanthine (13X), 1-3 dimethylurate (13U), 3-7 dimethylxanthine (37X), 1-7 dimethylurate (17U), 1-methylxanthine (1X), 1-methylurate (1U), 7-methylxanthine (7X), 3-methylxanthine (3X), and 5-acetylamino-6-formylamino-3-methyluracyl (AFMU) were analyzed by high performance liquid chromatography (HPLC). Total and individual metabolite urinary elimination rates were expressed in mmol/24 hours. Enzyme activities were evaluated from the following urinary metabolites ratios: (AFMU+1U+1X)/17U for CYP1A2, 17U/ 17X for CYP2A6, AFMU/(AFMU+ 1U+1X) for NAT-2, 1U/1X for XO. Results: Compared to healthy subjects, whatever the Child score, caffeine metabolism was reduced by half in patients with alcoholic cirrhosis. The main cause was the decreased CYP1A2 activity. On the other hand, XO and CYP2A6 activities were increased and NAT-2 activity remained unchanged in slow acetylators (SA) and decreased in rapid acetylators (RA) Child B and C. Bimodality of NAT-2 distribution was unclear, but a right assignment of RA and SA phenotype in cirrhotic patients, confirmed by comparison with genotype, was obtained, using the antimode value of NAT-2 distribution used in healthy subjects. At last, there was an interindividual variability in caffeine metabolism as great as in the usual laboratory parameters. Conclusion: Metabolism of caffeine is decreased in patients with alcoholic liver cirrhosis. This decrease paralleled the modifications of the usual laboratory tests and does not bring additional information on the severity of the disease. But the equilibrium between the various metabolic pathways of caffeine is impaired. Beyond the changes of a specific enzymatic activity, this must be taken into account particularly for drugs whose metabolism is of the polygenic regulation type.Correspondence to:
Dr. P.R. Bechtel; Pharmacologie Clinique, Faculté de Médecine et de Pharmacie, Place Saint Jacques 25030 Besançon Cedex, France

Abstract

I. Soria, P. Myhre, V. Horton, P. Ellefson, S. McCarville, K. Schmitt and M. Owens

³M Pharmaceuticals, St. Paul, MN, USA
Objectives: The present study, the first clinical pharmacokinetic report of the immune response modifier imiquimod, was conducted to assess the effect of food on the oral absorption of imiquimod, to characterize its pharmacokinetics, and to estimate its oral bioavailability. Subjects and methods: Sixteen healthy male volunteers completed this open-label, randomized, three-period crossover study. Subjects received a 100 mg oral dose of imiquimod after fasting in one period, after a standarized, high fat meal in another, and a 30 mg subcutaneous dose in the third period. Results: The oral bioavailability of imiquimod was on average 47%, and independent of whether imiquimod was administered with or without food. Oral imiquimod was absorbed in both fasted and non-fasted states with an absorption half-life of approximately 1 hour. However, there seemed to be a delay in the initiation of the absorption process when food was administered, which translated in to a Tmax of approximately 2.6 hours while fasting and one hour later in the non-fasted state. Imiquimod was rapidly eliminated with a half-life of approximately 2.5 hours and a total body clearance of approximately 970 ml/h×kg. Although equivalence could not be established due to the large intersubject variability, no significant differences in rate (Cmax) and extent (AUC) of oral absorption were observed between the fasted and non-fasted states. In addition, the Cmax, AUC and bioavailability values for individual subjects were consistent between both oral treatments. Conclusion: This study suggests that food does not have a major effect on the rate, extent of absorption or bioavailability of oral imiquimod, and thus, it is suitable to administer imiquimod orally in either the fasted or non-fasted states.Correspondence to:
Dr. I. Soria; Department of Pharmacokinetics and Drug Metabolism, 3M Pharmaceuticals, 3M Center, Building 270-3S-05, St. Paul, MN 55144-1000, USA

Abstract

H.Y. Lane¹,³, H.C. Liu⁴, C.M. VanDenBerg², M.H. Su³,⁵, M.W. Jann² and W.H. Chang¹

¹Department of Psychiatry, Tzu-Chi General Hospital and Tzu-Chi University, Hualien, Taiwan ²Mercer University, Southern School of Pharmacy, Atlanta, GA, USA, ³The Graduate Institute of Life Sciences, National Defense Medical Center, ⁴Hung-Tzu Psychiatric Hospital, and ⁵The School of Pharmacy, National Defense Medical Center, Taipei, Taiwan
The disposition of olanzapine was evaluated in 21 male chronic schizophrenic patients. A single 10 mg dose of olanzapine was administered and blood sampling performed over the following 120 hours. The mean (± SD) oral clearance and elimination half-life of olanzapine were 51.5 ± 61.6 l/h and 30.9 ± 4.3 hours, respectively. A wide interpatient variability was found. Compared to the population norms, no significant differences were observed between different populations and Chinese patients in olanzapine disposition.Correspondence to:
Dr. W.H. Chang; Department of Psychiatry, Tzu-Chi General Hospital, 707, Section 3, Chung-Yan Road, Hualien City, Taiwan 970

Abstract

E. Gyr¹, R. Brenneisen¹, D. Bourquin¹, T. Lehmann¹, D. Vonlanthen¹ and I. Hug²

¹Department of Clinical Research, University of Bern, Bern, Switzerland, and ²Janus Project, Basel, Switzerland
Objective: The pharmacokinetics and pharmacodynamics of high-dose intravenous (i.v.), oral and rectal diacetylmorphine (diamorphine, heroin, DAM) preparations were compared. Method: Two heroin-dependent patients participating in a heroin-assisted treatment program received single or repeated doses of 200 – 690 mg DAM i.v., orally (capsules, controlled-release tablets) and rectally. Plasma and urine profiles of DAM and metabolites were monitored by high-performance liquid chromatography and gas chromatography mass spectrometry, flash and high effects by visual analog scaling (VAS). Results: DAM was only detectable in plasma after i.v. administration. With a t1/2b of 1.3 – 2.2 min it was rapidly desacetylated to 6-acetylmorphine which was further metabolized to morphine and its 3- and 6-O-glucuronide. Morphine-3-glucuronide was the dominating metabolite in plasma and urine independent of the administration route. Oral and rectal doses and dosage intervals were adequate to produce flash and high effects without any cardiovascular and respiratory side-effects nor withdrawal symptoms. Conclusions: Oral and rectal DAM should further be tested and validated on a wider patient group for the non-invasive, long-term application of high-dose DAM within heroin-assisted treatment programs as alternative to the harmful i.v. application.Correspondence to:
Prof. Dr. R. Brenneisen; Department of Clinical Research, University of Bern, Murtenstraße 35, CH-3010 Bern, Switzerland

Abstract

J.C. Rodriguez¹, D. Buckner², S. Schoenike¹, O. Gomez-Marin³, C. Oiticica² and W.R. Thompson²

¹Department of Pediatric Pharmacy Services, Jackson Children’s Hospital, ²Division of Pediatric Surgery, and ³Departments of Epidemiology and Public Health and Pediatrics, University of Miami, Florida, USA
Background and purpose: An increased incidence of post-surgical infectious complications in children admitted with a diagnosis of perforated appendicitis led to development of a disease-specific antibiogram and modification of our post-operative antibiotic regimen. Methods: A historical control group comprised of 32 pediatric patients receiving ampicillin, gentamicin, and clindamycin (group AGC) was compared to a cohort of 32 children receiving ticarcillin/ clavulanate plus gentamicin (group TG). The surgical procedure, peri-operative management, and inclusion, exclusion and discharge criteria were the same for each group. Outcome measures including length of stay, time to defervesce, incidence of infectious complications, and clinical failures to the antibiotic regimen were compared. Results: The groups were similar with respect to gender, age, weight, surgical time, pre-operative leukocytes, and number of intra-operative bacterial isolates cultured per patient. Length of stay was 10.1 days in group TG and 12.5 days for group AGC (p = 0.0197). The number of clinical failures was reduced from 9 (28.1%) to 2 (6.3%) in group TG (p = 0.02). The time to defervesce was decreased by 1.4 days, and the number of infectious complications was reduced to 2.5-fold in group TG patients. Conclusions: Ticarcillin/clavulanate plus gentamicin was clinically more effective than ampicillin, gentamicin, and clindamycin combination therapy in the management of perforated appendicitis in our pediatric population.Correspondence to:
Dr. J.C. Rodriguez; Jackson Memorial Hospital, Department of Pharmacy, 1611 NW 12th Avenue, Miami, Florida 33136, USA

Abstract

I. Mai¹, H. Krüger¹, K. Budde², A. Johne¹, J. Brockmöller¹, H.-H. Neumayer² and I. Roots¹

¹Institute of Clinical Pharmacology and ²Department of Nephrology, Charité University Medical Center, Humboldt University of Berlin, Germany
Contrary to common belief, over-the-counter herbal remedies may cause clinically relevant drug interactions. With the enclosed report we would like to alert other physicians that herbal extracts of Saint John’s wort (Hypericum perforatum) may cause a sudden remarkable decrease of cyclosporin trough concentrations. A kidney transplantation patient treated with 75 mg bid doses of cyclosporin for many years experienced a sudden drop in her cyclosporin trough concentrations. This change was in temporal relationship to hypericum extract comedication, and a re-challenge gave similar results. The mean dose-normalized cyclosporin concentration during this comedication (90% confidence interval) was 0.48 (0.43 to 0.54) ng/(ml × mg) and was constantly below the respective concentration without the herbal remedy (0.84 (0.79 to 0.89) ng/(ml × mg)). This difference in the pharmacokinetics of cyclosporin indicates a relevant influence of St John’s wort extract. The potential clinical consequence of this pharmacokinetic herb-drug interaction is apparent, since low cyclosporin levels are associated with an increased risk of rejection after organ transplantation and are usually not suspected upon intake of plant products. In view of the permanently increasing use of St John’s wort preparations for various indications and the clinical relevance of this interaction, our report may contribute to the ongoing debate on the prescription status and safety of hypericum extracts.Correspondence to:
Dr. I. Mai; Institute of Clinical Pharmacology, Charité University Medical Center, Humboldt University of Berlin, D-10098 Berlin, Germany

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Volume 38, No. 10/2000(October)