Volume 40, No. 1/2002(January)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Editorial
On Excellence in Scientific Publishing
B.G. Woodcock
Alcoholic cirrhosis
Effects of silymarin MZ-80 on oxidative stress in patients with alcoholic cirrhosis
M.I. Lucena, R.J. Andrade, J.P. de la Cruz, M. Rodriguez-Mendizabal, E. Blanco, F. Sánchez de la Cuesta
Abstract
M.I. Lucena1, R.J. Andrade2, J.P. de la Cruz1, M. Rodriguez-Mendizabal1, E. Blanco1, F. Sánchez de la Cuesta1
1Clinical Pharmacology Service and 2Liver Unit, Gastroenterology Service, University Hospital, School of Medicine, Málaga, Spain
Background: The role of silymarin in the treatment of liver cirrhosis is controversial. Aim: Clinical outcome, biochemical profile and the antiperoxidative effects of silymarin MZ-80 during 6 months treatment were investigated in patients with alcoholic liver cirrhosis. Methods: Sixty consecutive patients with alcoholic liver cirrhosis were randomized to receive either silymarin MZ-80 (S) (150 mg t.i.d. per day) or placebo (P) for periods of 6 months. Erythrocyte total glutathione (GSH) content, platelet malondialdehyde (MDA) and serum aminoterminal propeptide of procollagen Type III (PIIINP) were determined at baseline and at the end of treatment. Results: Forty-nine patients completed the study (24 S and 25 P). The 2 groups were well-matched for demographic as well as baseline clinical and laboratory parameters. Silymarin increased total GSH at 6 months (4.5 ± 3.4 to 5.8 ± 4.0 mmol/g Hb) whereas, in the placebo group, GSH remained unchanged (4.1 ± 3.9 to 4.4 ± 4.1 mmol/gHb) (p < 0.001), and platelet-derived non-induced MDA decreased by 33% (p < 0.015). A parallel decrease in PIIINP values was seen with silymarin (1.82 ± 1.03 to 1.36 ± 0.5 U/ml, p < 0.033) but not with placebo (1.31 ± 0.4 to 1.27 ± 0.6 U/ml). There were no concurrent changes on laboratory indices of the pathology. Conclusions: Silymarin is well-tolerated and produces a small increase in glutathione and a decrease in lipid peroxidation in peripheral blood cells in patients with alcoholic liver cirrhosis. Despite these effects no changes in routine liver tests were observed during the course of therapy.Correspondence to:
M.I. Lucena; Department of Pharmacology, School of Medicine, E-29071 Málaga, Spain
Email: lucena@uma.es
ACE-inhibitors
Moexipril shows a long duration of action related to an extended pharmacokinetic half-life and prolonged ACE inhibition
W. Cawello, H. Boekens, J. Waitzinger and U. Miller
Abstract
W. Cawello1, H. Boekens2, J. Waitzinger3 and U. Miller2
1Clinical Development, 2Bioanalytics, Schwarz Pharma AG, Monheim, and 3AAI Deutschland GmbH, Neu-Ulm, Germany
Objective: To characterize the lipophilic ACE inhibitor moexipril and its active metabolite moexiprilat regarding the duration of action, the susceptibility of the pharmacokinetics and pharmacodynamics to food intake and the concentration-dependent effect. Methods: Three independent, open, randomized studies were performed in healthy subjects using crossover or parallel-group designs. In the first study, pharmacokinetics (AUC, Cmax, tmax, t1/2) and ACE inhibition (up to 72 h) were investigated following single oral doses of 15 mg moexipril administered in the fasting and postprandial state (n = 24). The individual ACE inhibition data and plasma concentration data were fitted to an Emax model. In the second study, carried out in 52 volunteers, the pharmacokinetics were followed over 36 h following administration of 2 single oral doses of 15 mg moexipril. In the third study, the pharmacokinetics after multiple dosing of 15 mg moexipril once daily for 5 days were investigated in 12 young and 12 elderly subjects. Results: Moexiprilat tmax was 1.5 – 2 h with only minor differences between single and multiple dosing. Compared to fasting, the postprandial moexiprilat Cmax and AUC (ratio fed/fasted 58.0%; 90% CI 52.2 – 64.5%) were distinctly reduced (ANOVA p = 0.0001). Moexiprilat showed a biphasic elimination phase with an average t1/2b of 29 – 30 h. In contrast to the a-phase, the plasma concentrations during the terminal elimination phase were not affected by food. A relationship between ACE inhibition and plasma concentration was not observed. The average ACE inhibition over 72 h was 71% in the fasting state and 74% in the postprandial state. ACE inhibition increased to about 80% after 24 h and decreased to about 60% at 72 h. The S-shaped concentration-effect curve indicated that a moexiprilat level of 1.3 ng/ml was sufficient to produce 50% inhibition of ACE. With repeated dosing there were no signs of drug accumulation and day-to-day drug levels were relatively constant. The trough concentrations at 24 h did not fall below the limit of 1 – 2 ng/ml, i.e. a 50% ACE inhibition. Conclusion: Moexiprilat showed an extended duration of action owing to a long terminal pharmacokinetic half-life and produced a persistent ACE inhibition. Although the pharmacokinetics were partly influenced by food intake, ACE inhibition was not affected. This might be explained by a second compartment directly related to the ACE which is less prone to food effects and the reaching of a ceiling in the sigmoidal concentration-effect curve even with the lower Cmax concentrations associated with the postprandial state.Correspondence to:
Dr. W. Cawello; Clinical Development Schwarz Biosciences GmbH, Alfred-Nobel-Straße 10, D-40789 Monheim, Germany
Email: Willi.Cawello@SchwarzPharma.com
Case reports
Phenytoin toxicity with mandibular tremor secondary to intravenous administration
D. Türkdogan, F. Onat, U. Türe and N. Pamir
Abstract
D. Türkdogan1, F. Onat2, U. Türe1 and N. Pamir1
1Institute of Neurological Sciences, University of Marmara, Maltepe, Istanbul, and 2School of Medicine, Department of Pharmacology and Clinical Pharmacology, University of Marmara, Haydarpasa, Istanbul, Turkey
The parenteral form of phenytoin is the most commonly used antiepileptic agent during the perioperative period in neurosurgery clinics. We report observations in a 52-year-old male patient with hypoalbuminemia and phenytoin intoxicity following 1 day preoperative administration and a 7-day postoperative intravenous administration of the drug with no modification of the oral dose. This report emphasizes the need for careful surveillance of phenytoin-induced toxicity during parenteral therapy, especially in debilitated patients.Correspondence to:
Prof. F. Onat, School of Medicine, Department of Pharmacology and Clinical Pharmacology, University of Marmara, Haydarpasa, 81326 Istanbul, Turkey
Email: fonat@escortnet.com
Case report
Hallucinations with therapeutic doses of clarithromycin
I. Jiménez-Pulido, A. Navarro-Ruiz, P. Sendra, M. Martínez-Ramírez, C. García-Motos and A. Montesinos-Ros
Abstract
I. Jiménez-Pulido1, A. Navarro-Ruiz1, P. Sendra2, M. Martínez-Ramírez1, C. García-Motos1 and A. Montesinos-Ros1
1Pharmacy Service and 2Emergency Service, Hospital General Universitario de Elche, Elche/Alicante, Spain
Objective: Hallucinations caused by adverse reactions to medication are not uncommon and a wide variety of drugs may be involved. We present a case of hallucinations caused by therapeutic doses of oral clarithromycin (500 mg b.i.d). Case report: A 32-year-old woman attended the Emergency Department of the hospital with severe visual hallucinations together with marked anxiety and nervousness following the second dose of clarithromycin, which was the only medication she was taking. The antibiotic was identified as the possible cause of the clinical manifestations and was stopped immediately. The patient did not require hospitalization and was discharged a few hours later with no signs of neurological disturbances. Clarithromycin was substituted by amoxycillin-clavulanic acid (500/125 mg) t.i.d. Conclusions: The temporal relationship between commencement of antibiotic therapy and the appearance of hallucinations, together with the fact that the symptoms disappeared once the antibiotic was suspended, support a causal relationship between clarithromycin and the hallucinations. Further support for a causal relationship was obtained by application of Naranjo’s algorithm which gave a likelihood level for causality of PROBABLE.Correspondence to:
Dr. A. Navarro-Ruiz; Hospital General Universitario de Elche, Pharmacy Service, Camí de l´Almazara, 11, E-03203 Elche/Alicante, Spain
Email: anavarror@sefh.es or navarro_and@gva.es
Pharmacokinetics
PK-PD curve-fitting problems with the Hill equation? Try one of the 1-exp functions derived from Hodgkin, Douglas or Gompertz
F. Keller, M. Giehl, D. Czock and D. Zellner
Abstract
F. Keller1, M. Giehl2, D. Czock1 and D. Zellner1
1Nephrology, University Ulm, and 2Department of Radiology, University Hospital Benjamin Franklin, Berlin
Non-linear phenomena are observed with enzyme kinetics, protein binding, pharmacokinetics or pharmacodynamics. The Hill equation, the Michaelis-Menten equation extended by a power coefficient, is traditionally used for sigmoid curve fitting. Sigmoid saturation phenomena can also be described by exponential functions (1-exp), extended by a power coefficient such as those derived by Hodgkin, Douglas or Gompertz. Comparing the 4 equations, the sigmoid 1-exp function in the form of Hodgkin and Huxley comes closest to the principle of simplicity and succinctness with regard to definition, slope and flexibility of the inflection point. To compare the applicability, a standardized sample of 250 curves was generated by each 1 of the 4 equations and mutually fitted with the remaining 3. The Hill equation gives the closest fit with the data generated by the other functions. The Douglas variant exhibits the highest rate of convergence. The Gompertz function provides the basic feature of a baseline effect. Conclusion: The sigmoid functions investigated (Hill, Hodgkin, Douglas, Gompertz) have differing characteristics and can be used interchangeably for solving specific problems in non-linear modeling.Correspondence to:
Dr. F. Keller; Nephrology, University Hospital, Robert-Koch-Straße 8, D-89070 Ulm, Germany
Email: frieder.keller@medizin.uni-ulm.de
Pharmacokinetics
Anthropometric data and acetylsalicylic acid pharmacokinetics
H.J. Koch and C. Raschka
Abstract
H.J. Koch1 and C. Raschka2
1Psychiatric University Clinic, Regensburg, and 2Institute of Sports Sciences, University of Frankfurt, Germany
The relationship between anthropometric data and pharmacokinetic characteristics of acetylsalicylic acid (ASA) after administration of a single oral dose of 500 mg ASA, an oral and intravenous dose of 500 mg D,L-lysine-mono-acetylsalicylate (Lys-ASA) and an oral dose of 1,000 mg Lys-ASA were evaluated. Individual data from an open, randomized crossover trial in 13 healthy volunteers (age 18 – 50 years, 6 female, 7 male, height 158 – 189 cm, weight 45 – 118 kg) were re-analyzed using a non-compartmental approach. The influence of body weight, height, body surface area and age on pharmacokinetic characteristics (Cmax, Tmax, AUClast, MRTlast, t1/2, Cl, Vd) was assessed using the multiple regression method and pairwise multiple correlations were calculated. Multiple regression analysis showed significant multiple correlation coefficients of approximately 0.86 for Cmax (500 mg Lys-ASA i.v., 1,000 mg Lys-ASA per os and 500 mg ASA per os), Cl and AUClast (1,000 mg Lys-ASA per os). Standardized regression values (b) reflected a major contribution for height, weight and body surface area, but age was not a relevant factor. Pairwise comparisons confirmed negative correlations between anthropometric characteristics and Cmax, AUClast and MRTlast and positive correlations between anthropometric data, Cl and Vd. In conclusion, apart from Tmax and t1/2, all pharmacokinetic characteristics were influenced by body weight, height and body surface area. Whereas repeated administration of high doses in patients with low body weights may give rise to toxic effects, acute single dose administration would not lead to significant under-dosing in tall or stout patients.Correspondence to:
Dr. Dr. H.J. Koch; Department of Gerontopsychiatry, Psychiatric University Clinic, Universitätsstraße 84, D-93053 Regensburg, Germany
Email: horst.koch@bkr-regensburg.de
Bioequivalence
Bioequivalence study of a valsartan tablet and a capsule formulation after single dosing in healthy volunteers using a replicated crossover design
R. Séchaud, P. Graf, H. Bigler, E. Gruendl, M. Letzkus and M. Merz
Abstract
R. Séchaud1, P. Graf1, H. Bigler1, E. Gruendl2, M. Letzkus1 and M. Merz1
1Novartis Pharma AG, Basel, and 2SUVA, Luzern, Switzerland
Aim: Two formulations of valsartan (Diovan), 320 mg tablets and marketed 160 mg capsules, were evaluated for bioequivalence after single dosing. Methods: The study was designed as a single-center, open-label, 2-treatment, 3-period, repeated-measure (replicated), randomized crossover comparison in 40 healthy volunteers, all of whom completed the study successfully. Valsartan was determined in plasma by HPLC with fluorescence detection after solid-phase extraction. Results: Comparing the new 320 mg tablet with 2 × 160 mg of the marketed valsartan capsules taken at the same time, the ratios of the least square means for AUC0-t, AUCall, AUC0-¥ and Cmax were 1.11, 1.10, 1.10 and 1.09, respectively. The 90% confidence intervals of the AUC and Cmax parameters were within the range of 0.80 – 1.25. Conclusions: Bioequivalence of the new 320 mg tablet with 2 marketed 160 mg capsules was demonstrated.Correspondence to:
Dr. R. Séchaud; Novartis Pharma AG, CH-4002 Basel, Switzerland
Email: romain.sechaud@pharma.novartis.com
Industrial medicine
Development and evaluation of an HPLC urinalysis screening test for occupational exposure to 3,4- and 3,5-dichloroanilines
L. El Marbouh, C. Arellano, C. Philibert, P. Evrard, J. Poey and G. Houin
Abstract
L. El Marbouh1, C. Arellano1, C. Philibert1, P. Evrard2, J. Poey1 and G. Houin1,3
1Laboratoire de Cinétique des Xénobiotiques, Faculté des Sciences Pharmaceutiques, 2Service Médical Inter-Entreprise, and 3Service de Pharmacocinétique et Toxicologie Clinique, Centre Hospitalier Universitaire de Rangueil, Toulouse, France
Objective: In order to develop a screening test to detect human occupational exposure to aromatic amines such as 3,4-dichloroaniline (3,4-DCA) and 3,5-dichloroaniline (3,5-DCA), we first investigated the urinary excretion of these highly toxic compounds in the rat. The study was performed after both oral and dermal application, even though contact with the skin is the major route of contamination in the workplace. The aim of this study was to develop a rapid screening test for risk assessment in the workplace. Methods: An initial group of 3 rats was treated with 40 ml of 3,4-DCA solution (30% in methanol), applied topically to the shaved dorsal skin. A second group of 3 rats were administered the same dose of the amine orally by gavage before urine sampling. The same procedure was performed with 3,5-DCA (2 other groups of 3 rats). The urine samples were collected for a period of 24 hours after treatment and the excretion of 3,4-DCA, 3,5-DCA was studied using a GC-MS and an HPLC method after urine extraction. The urine of 2 workers potentially exposed to the amines for a period of 161 and 147 days, respectively, was analyzed by the same methods with urine collection before and at the end of the work shift. Results: The study of excretion in the rat showed that unchanged dichloroanilines and some metabolites were excreted 24 hours after administration of the amines. Based on these results, we propose an HPLC method for the screening of risk assessment in the workplace. The presence of 3,4-DCA and 3,5-DCA in the urine of workers showed that they were absorbing amines during the workshift. Conclusions: These results successfully allowed us to detect contamination due to 3,4-DCA and 3,5-DCA in exposed workers. The HPLC method described provides a satisfactory and sensitive procedure for urine screening in the assessment and monitoring of the occupational exposure to dichloroanilines.Correspondence to:
Dr. G. Houin; Service de Pharmacocinétique et Toxicologie Clinique, Centre Hospitalier Universitaire de Rangueil, F-31062 Toulouse, France
Email: houin.g@chu-toulouse.fr
