Volume 45, No. 10/2007(October)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Pharmacokinetics
Pharmacokinetics of ceftazidime and cefepime in burn patients: the importance of age and creatinine clearance
J.M. Conil, B. Georges, M. Lavit, T. Seguin, I. Tack, K. Samii, G. Chabanon, G. Houin and S. Saivin
Abstract
J.M. Conil, B. Georges, M. Lavit, T. Seguin, I. Tack, K. Samii, G. Chabanon, G. Houin and S. Saivin
1Service d’Anesthésie-Réanimation, Hôpital de Rangueil, Toulouse, 2Laboratoire de Pharmacocinétique et Toxicologie Clinique, Institut Fédératif de Biologie, Toulouse, 3Laboratoire de Cinétique des Xénobiotiques, UMR 181 Physiopathologie et Toxicologie Expérimentale (UPTE INRA-ENVT), Faculté des Sciences Pharmaceutiques, Toulouse, 4Laboratoire d’Explorations Fonctionnelles Physiologiques, Hôpital de Rangueil, Toulouse, and 5Laboratoire de Bactériologie-Hygiène, Institut Fédératif de Biologie, Toulouse, France
Aim: The standard dosage recommendations for β-lactam antibiotics can result in very low drug levels in intensive care (IC) patients and burn patients in the absence of renal dysfunction. We studied the pharmacokinetic parameters and serum concentrations of ceftazidime (CF) and cefepime (CE) in burn patients and analyzed the modifications according to clinical and biological parameters and in particular age and creatinine clearance. Material and methods: Two pharmacokinetic studies were carried out with daily doses of 1 g × 6 for CF (n = 17) and 2 g × 3 for CE (n = 13). Creatinine clearance (CLCR) was both estimated and measured. Blood was sampled at steady state after an initial and a subsequent antibiotic dose. Cmax (maximal) and Cmin (minimal) concentrations were measured by HPLC. The influence of clinical and biological data was analyzed using ANOVA, ANCOVA and stepwise multiple linear regression. Results: The ratio of Cmin to the low MIC break point (4 mg/l) was lower than 4 in 52% of subjects receiving CF and in 80% of subjects receiving CE. The Cmin of CF was correlated with measured CLCR and was higher in mechanically ventilated patients than in non-ventilated patients. The clearance of CF was correlated with age. The Cmin of CE was correlated with age and drug clearance with measured CLCR. Therefore dosage adjustment of these drugs in burn patients needs to take into account age, measured creatinine clearance and the danger of low concentrations occurring when the creatinine clearance is greater than 120 ml.min–1. Conclusion: In burn patients, the pharmacokinetic disposition of CF and CE was much more variable than in healthy subjects. Age and CLCR were predictors of the disposition of these antibiotics. Shortening the dosage interval or using continuous infusions will prevent low serum levels and keep trough levels above the MIC for longer periods of time. In view of the lack of a bedside measurement technique for ceftazidime and cefepime levels, we suggest a more frequent use of measured CLCR in order to attain efficacious clinical concentrations.Correspondence to:
Dr. S. Saivin, Laboratoire de Pharmacocinétique et Toxicologie Clinique, Institut Fédératif de Biologie, 330 Avenue de Grande Bretagne TSA 40031, 31059 Toulouse Cedex 9, France
Email: saivin.s@chu-toulouse.fr
Pharmacokinetics
Effect of food on the pharmacokinetics of lonafarnib (SCH 66336) following single and multiple doses
Y. Zhu, P. Statkevich and D.L. Cutler
Abstract
Y. Zhu, P. Statkevich and D.L. Cutler
Schering-Plough Research Institute, Kenilworth, NJ, USA
Objective: The objective was to determine whether food affects the pharmacokinetics and safety of lonafarnib, an orally bioavailable farnesyl transferase inhibitor that is under clinical evaluation for the treatment of various hematologic malignancies and solid tumors. Methods: Two Phase 1 studies were conducted in separate patient populations. A single-dose study was performed in 12 healthy subjects who received lonafarnib 100 mg under fasted and fed conditions. Additionally, a multiple-dose study was performed in 19 patients with advanced cancer who received lonafarnib 200 mg Q 12 H for 28 days under fasted and fed conditions. Nine of the 19 patients completed both treatment cycles and were used for pharmacokinetic assessment. A 2-week washout period separated treatments in each study. Single-dose pharmacokinetics were assessed at various time points up to 48 hours postdose and multiple-dose pharmacokinetics were assessed at Day 15 for 24 hours postdose. Results: The pharmacokinetics of lonafarnib were affected by food during single-dose but not multiple-dose administration. Relative oral bioavailabilities (fed vs. fasted) based on log-transformed maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) were 48% and 77%, respectively, following single-dose administration, and 87% and 96%, respectively, following multiple-dose administration. Intrasubject variability in the pharmacokinetic parameters was less pronounced after multiple dosing (17%) than that after single dosing (33%) of lonafarnib. Intersubject variability was unaffected by food in either study. In the single-dose study, 7 of the 12 subjects (58%) reported treatment emergent adverse events, the most common being headache. No clinically significant differences in adverse events were seen between fasting and fed states after a single dose administration. Thus, single dose 100 mg lonafarnib was safe and generally well tolerated. In the multiple-dose study, all 19 subjects reported at least one treatment-emergent adverse event. General disorders including fatigue and anorexia, and gastrointestinal disorders including diarrhea, vomiting and nausea, were the most commonly reported adverse events after multiple doses. While gastrointestinal adverse events were reported with equal frequency under both fasting (82%, 14/17) and fed states (83%, 15/18), the incidence of severe gastrointestinal adverse events was higher in fasted (47%, 8/17) vs. fed subjects (22%, 4/18) after multiple-dose administration. Conclusion: The administration of food does not affect the pharmacokinetics of lonafarnib following multiple-dose administration. We recommend that multiple-dose lonafarnib should be administered with food to enhance tolerability.Correspondence to:
Y. Zhu, MS, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Email: yali.zhu@spcorp.com
Meta-analysis
A meta-analysis to evaluate the efficacy of statins in children with familial hypercholesterolemia
N. Shafiq, B. Bhasin, S. Pattanaik, P. Pandhi, S.P. Venkateshan, M. Singh and S. Malhotra
Abstract
N. Shafiq, B. Bhasin, S. Pattanaik, P. Pandhi, S.P. Venkateshan, M. Singh and S. Malhotra
1Department of Pharmacology, 2Department of Pediatrics, PGIMER, Chandigarh, India
This meta-analysis was conducted to evaluate the effect of statins on the lipid profile in pediatric and adolescent patients with familial hypercholesterolemia (FH). Randomized, double-blind, controlled trials comparing statins with placebo were identified through electronic and manual search; percent reductions from baseline were calculated for various lipid parameters. Standardized mean differences (effect size) with 95% confidence interval (CI) were calculated for each study and pooled effect size was calculated. A total of 6 studies were included in the meta-analysis. As compared to placebo, statins caused a significant decrease in total cholesterol (TC) [–3.11% (95% CI –3.46 to –2.99)], low-density lipoprotein (LDL) [–4.01% (95% CI –4.27 to –3.81)], triglyceride (TG) [–1.41 (95% CI –1.66 to –1.26)] and a significant increase in high-density lipoprotein (HDL) [1.12 (95% CI 0.73 – 1.13)]. In conclusion, statins were shown to have good efficacy for the treatment of FH in children.
Correspondence to:
Dr. S. Malhotra, Department of Pharmacology, PGIMER, Chandigarh, 160012, India
Email: samirmalhotra345@yahoo.com
Pharmacodynamics
Plasma and salivary amoxicillin concentrations and effect against oral microorganisms
S. Baglie, A.P. Del Bortolo Ruenis, R.H. Lopes Motta, R.C. Catelli Baglie, G.C. Nobre Franco, L.M. Franco, P.L. Rosalen, P. Silva and F.C. Groppo
Abstract
S. Baglie, A.P. Del Bortolo Ruenis, R.H. Lopes Motta, R.C. Catelli Baglie, G.C. Nobre Franco, L.M. Franco, P.L. Rosalen, P. Silva and F.C. Groppo
1Department of Pharmaceutical Sciences, Ponta Grossa State University, Ponta Grossa, PR, 2Piracicaba Dental School, State University of Campinas, Area of Pharmacology, Anesthesiology and Therapeutics, Piracicaba, SP, 3Department of Pharmacology, Anesthesiology and Therapeutics, Sao Leopoldo Dentistry School, Campinas, SP, 4Faculty of Health Sciences, Methodist University of Piracicaba, UNIMEP, Piracicaba, SP, and 5Bioagri Laboratories Ltda, Piracicaba, SP, Brazil
Plasma and salivary amoxicillin (AMO) concentrations were quantified following a single oral dose (875 mg) of two formulations of AMO (Amoxicillin-EMS Sigma Pharma and Amoxil BD 875 mg). In addition, the effect of amoxicillin against oral microorganisms was accessed. The open, randomized, two-period crossover study was carried out in 20 volunteers. Saliva and blood samples were collected at 0, 0.5, 1, 2, 4, 8 and 12 h after drug administration, and quantified using HPLC-ESI-MS and HPLC, respectively. Streptococci counts, anaerobe counts and total microorganism counts were obtained. No differences were observed between formulations (p > 0.05) in the plasma and salivary AMO concentrations and the pharmacokinetic parameters (Cmax, tmax, AUC0–8, and AUC0–¥) also showed no statistically significant differences between formulations (p > 0.05). Microorganism counts for the two formulations at all sampling times did not differ (p > 0.05) but all microorganism counts at 60 min post-dose showed a significant decrease (p < 0.05). Amoxicillin was effective in reducing oral microorganism levels up to 12 h post-dose.Correspondence to:
Prof. F.C. Groppo, Piracicaba Dental School, State University of Campinas, Area of Pharmacology, Anesthesiology and Therapeutics,
Av. Limeira, 901, Bairro Areiao, 13414-903 Piracicaba, SP, Brazil
Email: fcgroppo@fop.unicamp.br
Pharmacodynamics
Influence of insulin therapy on expression of chemokine receptor CCR5 and selected inflammatory markers in patients with type 2 diabetes mellitus
P. Bogdanski, D. Pupek-Musialik, J. Dytfeld, P.P. Jagodzinski, A. Jablecka, A. Kujawa and K. Musialik
Abstract
P. Bogdanski, D. Pupek-Musialik, J. Dytfeld, P.P. Jagodzinski, A. Jablecka, A. Kujawa and K. Musialik
1Department of Internal Medicine, Metabolic Disorders and Hypertension, 2Department of Biochemistry and Molecular Biology, Collegium Anatomicum, 3Department of Clinical Pharmacology, Karol Marcinkowski University of Medical Sciences, Poznan, Poland
Objective: Leukocyte migration to the subendothelial space is considered crucial in the initiation of atherosclerosis. There is increasing evidence that overexpression of chemokine receptors contribute to this process. CCR5 is one of the receptors present on peripheral T lymphocytes, monocytes and macrophages. We decided to evaluate the expression of CCR5 on monocytes and macrophages in peripheral blood and selected inflammatory markers in patients with type 2 diabetes mellitus before and after the initiation of insulin therapy. Material and methods: A total of 10 patients with newly diagnosed type 2 diabetes and 6 healthy control subjects were studied. Assessment of CCR5 expression on the surface of monocytes and macrophages in peripheral blood was performed using flow cytometry before the initiation of insulin therapy and after 5-week treatment. Serum concentrations of RANTES, TNF-α, IL-6 and hsCRP were assessed. Results: When compared to control subjects, we observed higher densities of CCR5 on the surface of peripheral blood monocytes and macrophages and higher concentrations of RANTES, TNF-α, IL-6 and hsCRP before insulin therapy. After 5-week insulin therapy, there was a significant decrease in the expression of CCR5 on the surface of these cells and a significant fall in serum levels of RANTES, IL-6, TNF-α and hsCRP. Conclusions: Type 2 diabetes leads to an increase in the inflammatory process, and insulin therapy inhibits the early stages of this process.Correspondence to:
Dr. P. Bogdanski, Department of Internal Medicine, Metabolic Disorders and Hypertension, Szamarzewskiego 84, 61-847 Poznan, Poland
Email: pawelbogdanski@wp.pl
Drug Utilization
Differences in antibiotic prescribing in three university hospitals in the Baltic region revealed by a simple protocol for quality assessment of therapeutic indications
U. Dumpis, J. Gulbinovic, J. Struwe, Å. Lagergren, L. Griskevicius and U. Bergman
Abstract
U. Dumpis, J. Gulbinovic, J. Struwe, Å. Lagergren, L. Griskevicius and U. Bergman
1Department of Epidemiology, Stradins University Hospital, Riga, Latvia, 2Department of Pathology, Forensic Medicine and Pharmacology, Vilnius University, Vilnius, Lithuania, 3Department of Clinical Bacteriology and Infection Control, Karolinska Institute, Karolinska University Hospital, Huddinge, Sweden, 4Department of Infectious Diseases, Karolinska Institute, Karolinska University Hospital, Huddinge, Sweden, 5Medical Products Agency, Uppsala, Sweden, 6Center of Hematology, Oncology and Transfusion Medicine, Vilnius University Hospital, Vilnius University, Vilnius, Lithuania, and 7Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institute, WHO Collaborating Center for Drug Utilization Research and Clinical Pharmacological Services, Karolinska University Hospital, Huddinge, Sweden
Objective: To identify inexpensive and simple quality parameters for the surveillance of antibiotic use in hospital settings. Methods: A modified point-prevalence study was conducted in three university hospitals in Huddinge, Sweden, Riga, Latvia, and Vilnius, Lithuania. Each ward was visited once during May in the year 2002. All patients receiving antibiotics were identified and their medical records were reviewed by the authors according to the same protocol. Only data from corresponding departments were evaluated and compared. Results: The prevalence of antibiotic use was 35%, 25% and 24% in Huddinge, Riga and Vilnius, respectively. Almost 2/3 of antibiotics were prescribed for treatment and 1/3 for either surgical or medical prophylaxis. Parenteral administration was significantly more common in Riga and Vilnius than in Huddinge. The most commonly prescribed antibiotics were cephalosporins and fluoroquinolones. Prescription of antibiotics for different diagnoses showed large variation between and within hospitals. The first or second generation cephalosporins were prescribed in most cases of surgical prophylaxis. The duration of surgical prophylaxis exceeded one day in 57%, 63% and 87% of cases in Huddinge, Riga and Vilnius, respectively. All antibiotics in Huddinge, and all except five in Riga were supplied by the hospital pharmacy. Antibiotics bought by patients and donated made up 41% of prescribed antibiotics in Vilnius. Conclusion: This point-prevalence survey using a simple and inexpensive method for benchmarking demonstrated quantitative and qualitative differences in the use of antibiotics between three university hospitals in the Baltic region, differences that now calls for explanations to their rationality. We suggest that the choice of an antibiotic, rates of intravenously administered treatment and duration of surgical prophylaxis are examples of suitable indicators of rational antibiotic use within a hospital but that comparison of such rates between hospitals is less meaningful.
Correspondence to:
U. Dumpis, Department of Epidemiology, Stradins University Hospital, Pilsonu 13, 1002 Riga, Latvia
Email: ugadumpis@stradini.lv
