Volume 44, No. 11/2006(November)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Therapeutics
Application of data mining to predict the dosage of vancomycin as an outcome variable in a teaching hospital population
A.L.F. Chan, J.-X. Chen and H.-Y. Wang
Abstract
A.L.F. Chan1, J.-X. Chen2 and H.-Y. Wang1
1Department of Pharmacy, Chi Mei Medical Center, and 2Institute of Information Management, National Sun Yat-sen University, Yung Kang City, Tainan, Taiwan
Objective: Data mining is a process used to extract potentially valuable information hidden in large volumes of raw data. The aim of this study was to explore the possibility of using easy to implement and effective supervised learning techniques to predict the dosage of vancomycin. Methods: To reach this goal, we considered the prediction of the dosage of vancomycin as a classification problem. We chose the C4.5 decision tree technique for the dosage prediction process and supplied it with a boosting technique to enhance its performance. Results: The potential predictor variables were collected from 833 patients with methicillin-resistant Staphylococcus aureus, or penicillin intolerance who were being treated with vancomycin and undergoing therapeutic drug monitoring (TDM) after attainment of steady state blood concentrations. Attributes tested as potential predictors included age, sex, weight, serum creatinine concentration, dosing interval, and variables from 1-compartment model kinetics such as Kd, Vd, and t1/2. Conclusions: The results showed that the proposed method can utilize a variety of parameters to predict the dosage of vancomycin in the population used and that it performs well over a range of patient ages and renal function. The method may offer an alternative to existing methods used to support decision-making in clinical practice.Correspondence to:
Dr. A.L.F. Chan
Department of Pharmacy
Chi Mei Medical Center
901, Chung Hwa Road, Yung Kang City, Tainan, 710, Taiwan
Email: cmh5500@mail.chimei.org.tw
Drug Safety
Multiple drug prescribing by general practitioners in a German region: implications for drug interactions and patient safety
R. Fux, D. Greiner, M. Geldmacher, K. Mörike and C.H. Gleiter
Abstract
R. Fux1, D. Greiner1, M. Geldmacher2, K. Mörike1 and C.H. Gleiter1
1Department of Clinical Pharmacology, Institute of Pharmacology and Toxicology, University Hospital Tübingen, Tübingen, and 2Health Insurance Medical Service (MDK) Baden-Württemberg, Lahr/Schwarzwald, Germany
Objective: An increased number of drugs used by patients enhances the risk of potentially hazardous drug interactions. So far, no representative data are available about how common this problem is in German general practices. Methods: We performed a retrospective analysis using a prescription database for a German region. The 50 general practitioners (out of 1,457) who wrote the most prescriptions during January to March 2003 were included. Data on 4,153 patients who were prescribed at least 10 drugs were analyzed for 92 predefined Drug Combinations Prone to Interact (DCPI) to a clinically relevant extent and possible contraindications. Results: From 92 DCPIs, 71 occurred in the analyzed population between 1 and 275 times. The total number of DCPI cases was 1,295, which included 10% (n = 129) of contraindicated combinations. Among 4,153 analyzed patients, 822 patients (19.8%) were affected by at least 1 DCPI. In 268 patients (6.5%), multiple DCPIs occurred. The most frequently found drug pairs were digitalis/diuretics, digitalis/calcium channel blockers, and theophylline/quinolones. Among contraindicated combinations, tricyclic antidepressants, St. John’s wort and antiarrhythmic drugs were most frequently involved. In about 1/3 of patients treated for chronic heart failure, pharmacotherapy appeared not to be guideline-adherent. Conclusion: Drug interactions, especially in polypharmacotherapy, represent a potential hazard which must be taken into account by the prescribing physician. Our study is the first to use a prescription database for the evaluation of drug prescriptions within a German region.Correspondence to:
C.H. Gleiter, MD
Department of Clinical Pharmacology
Institute of Pharmacology and Toxicology
University Hospital Tübingen
Otfried-Müller-Straße 45
72076 Tübingen, Germany
Email: christoph.gleiter@med.uni-tuebingen.de
Drug Safety
Safety profile of proton pump inhibitors according to the spontaneous reports of suspected adverse reactions
E. Salgueiro, T. Rubio, A. Hidalgo and G. Manso
Abstract
E. Salgueiro, T. Rubio, A. Hidalgo and G. Manso
Pharmacovigilance Center of Asturias, Faculty of Medicine, University of Oviedo, Spain
Objective: To evaluate similarities and differences in safety among proton pump inhibitors (PPIs) under the usual conditions of prescription. Methods: A search of spontaneous reports on adverse reactions associated with these drugs and registered between January 1, 2004 and December 31, 2004 was undertaken in the Spanish Pharmacovigilance System Database. We compared the frequency of reports with the consumption of PPIs, and analyzed the organ and system distribution for each PPI. Of the organ and system groups more commonly affected, diarrhea, myalgia, abnormal vision and hepatitis were selected for further analysis. Results: Nearly 8 times more reports for omeprazole compared to other drugs were found but a similar difference was observed in their consumption. Skin and appendage disorders were more frequently reported for omeprazole and rabeprazole, the urinary, female reproductive and endocrine systems for lansoprazole, musculoskeletal for omeprazole and esomeprazole, vision for pantoprazole, rabeprazole and esomeprazole, gastro-intestinal tract for omeprazole and lansoprazole and liver and biliary systems for omeprazole, lansoprazole and pantoprazole. Myalgia appears more often in younger patients than diarrhea, abnormal vision or hepatitis and shows longer periods of latency and recovery. The four adverse reactions analyzed were mainly reversible. Conclusion: A direct relationship was found between consumption and the number of reports. Some organ and system groups were affected by more than one PPI and this showed a specific pattern of group toxicity to these pharmacological agents. Some reports involved only lansoprazole and these require further analysis.
Correspondence to:
Dr. G. Manso
Pharmacovigilance Center of Asturias
Department of Medicine, Pharmacology
Faculty of Medicine
C/Julián Clavería 6, 33006 Oviedo, Spain
Email: gmanso@uniovi.es
Pharmacokinetics
Mass balance study of [14C] rabeprazole following oral administration in healthy subjects
T. Setoyama, W.J. Drijfhout, N.C. van de Merbel, T.J. Humphries and J. Hasegawa
Abstract
T. Setoyama1, W.J. Drijfhout2, N.C. van de Merbel2, T.J. Humphries3 and J. Hasegawa4
1Preclinical Development, Eisai Research Institute of Boston, Inc., Andover, MA, USA, 2Pharma Bio-Research, Zuidlaren, The Netherlands, 3Berlex, Wayne, NJ, USA, and 4Eisai Company, Ltd., Tokyo, Japan
The study was designed to determine the excretion balance of radiolabeled rabeprazole in urine and feces and to examine the metabolite profile in plasma, urine and feces after a single oral dose of [14C] rabeprazole, preceded by once daily dose of rabeprazole for 7 days. Six healthy subjects were enrolled in this study. The study was a single-center, open-label, multiple-dose, mass-balance study. Each subject received a single 20 mg dose of rabeprazole tablet for 7 days followed by the administration of 20 mg of [14C] rabeprazole as an oral solution after an overnight fast on Day 8. After oral dosing of [14C] rabeprazole, the mean Cmax of total radioactivity was 1,080 ± 215 ng equivalent/ml with 0.33 ± 0.13 hours of the mean tmax. The apparent elimination half-life of total [14C] radioactivity was 12.6 ± 3.4 hours. The total [14C] recovery in urine and feces was 99.8 ± 0.7% by 168 hours after oral administration of [14C] rabeprazole, and mean cumulative [14C] radioactivity excreted in urine was 90.0 ± 1.7% by 168 hours and 79.8 ± 2.5% of the radioactivity was excreted in urine within 24 hours. Excretion via feces added to the total by 9.8%. The major radioactive component in the early plasma samples was rabeprazole, however the thioether and thioether carboxylic acid metabolites were the main radioactive components in the later plasma sample. These results support the previous finding that the substantial contribution of the non-enzymatic thioether pathway minimizes the effect of CYP2C19 polymorphism on the inter-individual variation of plasma clearance of rabeprazole compared with other PPIs. Low levels of the sulfone metabolite were detected only in early plasma samples. No rabeprazole was detected in any urine and feces samples. The main radioactive components in urine were thioether carboxylic acid and mercapturic acid conjugate metabolites, and in the feces, the thioether carboxylic acid metabolite. The administration of [14C] rabeprazole was safe as evidenced by the lack of serious adverse events and the fact that all observed events were mild in intensity. [14C] rabeprazole was rapidly absorbed after oral administration and mostly excreted in urine.Correspondence to:
T. Setoyama
Preclinical Development
Eisai Research Institute of Boston, Inc.
1 Corporate Drive
Andover, MA 01810, USA
Email: tsutomu_setoyama@eisai.com
Pharmacoeconomics
Consumption costs of inappropriate medicines estimated from bulk purchase data: the example of NSAIDs in Guatemala
A. Figueras, J.M. del Valle and J.C. Valdés
Abstract
A. Figueras1, J.M. del Valle2 and J.C. Valdés3
1Fundació Institut Català de Farmacologia, Hospital Vall d’Hebron, Universitat Autònoma de Barcelona, Spain, 2National Pharmacovigilance Program, Ministerio de Salud Pública y Asistencia Social, 3Medicines Advisor, Ministerio de Salud Pública y Asistencia Social de Guatemala, Guatemala
Objective: In contexts where access to medicines is limited or troublesome, it may be important to identify the cases in which there exists access to medicines, but where this access is “inefficient” because it results in non-healing, avoidable toxicity or excessive cost in conditions of similar efficacy. Despite obvious limitations, bulk medicines purchase data of public institutions used to be the only available approximation on what is consumed in some countries. The aim of this study was to describe the results of a qualitative analysis of bulk consumption data, focusing on nonsteroidal anti-inflammatory drugs (NSAIDs) as an example. Method: The list of all drugs purchased by the Health Ministry of Guatemala in 2004 was quantitatively and qualitatively analyzed both according to the number of units and value. All NSAIDs bought during that period were analyzed in order to find potential intervention areas which could be addressed to improve drug selection. Results: The studied list included 693 products with a value of 102 million US$. Among the top-20 purchased medicines by defined daily doses (DDDs) were several NSAIDs (including aceclofenac, meloxicam and piroxicam). Ranitidine, ciprofibrate and dimethicone were also among these top-20 drugs. In addition, aceclofenac was among the top-20 drugs according to value. The cost of “second-line” NSAIDs was several times higher than the “first-line” diclofenac or ibuprofen. Providing equal efficacy and similar toxicity exists, a theoretical switch from second- to first-line NSAIDs could save up to 2,377 million US$/year. Conclusions: Although it is an old and well-known method, the analysis of bulk consumption data continues to provide information that may help to identify areas of potential improvement in settings without many resources. In the present theoretical example, educative interventions addressed to rational selection of NSAIDs could save more than 2% of the annual drug expenditure of the country. Co-ordinated actions addressed to other drugs could decrease inefficient drug expenditure and improve the quality of health-care.Correspondence to:
A. Figueras, MD
Fundació Institut Català de Farmacologia
Hospital Vall d’Hebron
Passeig de la Vall d’Hebron 119-129
08035 Barcelona, Spain
Email: afs@icf.uab.es
Drug Interactions
Roflumilast, a once-daily oral phosphodiesterase 4 inhibitor, lacks relevant pharmacokinetic interactions with inhaled salbutamol when co-administered in healthy subjects
T.D. Bethke, T. Giessmann, K. Westphal, A. Weinbrenner, B. Hauns, D. Hauschke, M. David, G. Lahu, K. Zech, R. Hermann and W. Siegmund
Abstract
T.D. Bethke, T. Giessmann, K. Westphal, A. Weinbrenner, B. Hauns, D. Hauschke, M. David, G. Lahu, K. Zech, R. Hermann and W. Siegmund
1ALTANA Pharma AG, Konstanz, and 2Department of Clinical Pharmacology, Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, University of Greifswald, Germany
Objective: Roflumilast is an oral, once-daily phosphodiesterase 4 inhibitor under investigation for the treatment of chronic obstructive pulmonary disease and asthma. In clinical practice, the drug is likely to be co-administered with inhaled bronchodilating b2-adrenoceptor agonists. Therefore, this study investigated the pharmacokinetic characteristics of roflumilast and its pharmacodynamically active metabolite roflumilast N-oxide when co-administered with orally inhaled salbutamol in healthy subjects. Methods: In this open, randomized clinical study, 12 healthy male subjects received repeated doses of oral roflumilast 500 µg once daily, orally inhaled salbutamol 200 µg 3 times daily, and a combination of both drugs over 7 days according to a 3-period, changeover design with 14 days washout between treatments. Results: Co-administration of roflumilast and salbutamol did not markedly change roflumilast or roflumilast N-oxide disposition. Point estimates (90% confidence intervals) of area under the curve from 0 – 24 h (AUC0–24) and maximum plasma concentration in steady state (Cmax,ss) for roflumilast with salbutamol versus roflumilast alone were 1.05 (0.94, 1.17) and 0.97 (0.84, 1.10); the respective point estimates (90% confidence intervals) for AUC0–24 and Cmax,ss of roflumilast N-oxide were 0.98 (0.91, 1.06) and 0.98 (0.92, 1.03). Roflumilast co-administration did not alter the pharmacokinetics of steady state salbutamol. The respective point estimates (90% confidence intervals) for AUC0–6 and Cmax,ss of salbutamol with roflumilast versus salbutamol alone were 1.10 (0.99, 1.21), 1.08 (0.91, 1.28). The combination of both drugs was well tolerated. Conclusion: There were no relevant pharmacokinetic interactions between roflumilast and salbutamol at therapeutically effective doses. Correspondence to:
Prof. Dr. W. Siegmund
Department of Clinical Pharmacology
Peter Holtz Research Center of Pharmacology and Experimental Therapeutics
Ernst Moritz Arndt University of Greifswald
Friedrich-Löffler-Straße 23d
17487 Greifswald, Germany
Email: siegmuw@uni-greifswald.de
Clinical Trials
Baseline serum lipids and renal function in chronic kidney disease patients entering the LORD trial
R.G. Fassett, M.J. Ball, I.K. Robertson, D.P. Geraghty and J.S. Coombes
Abstract
R.G. Fassett, M.J. Ball, I.K. Robertson, D.P. Geraghty and J.S. Coombes
1Renal Research Tasmania, Launceston General Hospital, 2School of Human Life Sciences, University of Tasmania, Launceston, Tasmania, 3School of Human Movement Studies, University of Queensland, St. Lucia, Queensland, Australia
Objective: Previous studies investigating associations between serum lipids and renal disease have generally not taken into account dietary intake or physical activity – both known to influence circulating lipids. Furthermore, inclusion of patients on HMG-CoA reductase inhibitors may also have influenced findings due to the pleiotropic effect of this medication. Therefore, the aim of this study is to determine the relationships between serum lipids and renal function in a group of patients not taking lipid-lowering medication and taking into account dietary intake and physical activity. Methods: Data from 100 patients enrolled in the Lipid Lowering and Onset of Renal Disease (LORD) trial were used in this study. Patients were included with serum creatinine > 120 mmol/l, and excluded if they were taking lipid-lowering medication. Unadjusted and adjusted relationships were determined between fasting serum lipid concentrations (total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol/HDL ratio) and measures of renal function (estimated glomerular filtration rate (eGFR), creatinine clearance and serum creatinine) and urinary protein excretion. Results: Significant (p < 0.05) negative unadjusted relationships were found between lipids (total cholesterol, LDL and HDL cholesterol) and serum creatinine. In support of these findings, logarithmically-transformed lipids (total cholesterol, LDL and HDL cholesterol) were significantly associated with eGFR and creatinine clearance although the effects were of a smaller magnitude. Adjustment for dietary saturated fat intake and physical activity did not substantially change these effects. Conclusion: These data do not support the premise that lipids are associated with renal dysfunction in patients with normocholesterolemia. Correspondence to:
J.S. Coombes, PhD
School of Human Movement Studies
Room 535 Connell Building
University of Queensland
St. Lucia, Queensland, Australia
Email: jcoombes@hms.uq.edu.au
Case Report
Beneficial effect of long-acting injectable risperidone on the neurocognitive deficit of a schizophrenic patient: a case report
K.N. Fountoulakis, S. Kantartzis, M. Siamouli, P. Panagiotidis, S.G. Kaprinis, E. Kourila, A. Iacovides and G.S. Kaprinis
Abstract
K.N. Fountoulakis, S. Kantartzis, M. Siamouli, P. Panagiotidis, S.G. Kaprinis, E. Kourila, A. Iacovides and G.S. Kaprinis
3rd Department of Psychiatry, Aristotle University of Thessaloniki, Greece
We report the case of a 37-year-old female patient suffering from schizophrenia, disorganized type. Adherence to treatment was always a major problem. During the last 2 years the patient was disorganized and was refusing treatment. Since the patient was already receiving a very high (double) dose per os, it was decided to administer two 50 ml ampoules of long-acting, injectable risperidone plus 5 mg of haloperidol per os daily. After 80 days of treatment, all positive, negative and even neurocognitive symptoms improved markedly. Extrapyramidal side effects did not appear at any stage of treatment. The most impressive neurocognitive improvement concerned the clock drawing test, which was in parallel with her improvement in both the positive and negative symptoms of the PANSS.Correspondence to:
K.N. Fountoulakis MD, PhD
1st Parodos Ampelonon Street
55535 Pylaia Thessaloniki, Greece
Email: kfount@panafonet.gr
Bioavailability Section
Bioequivalence study of two fluoxetine capsule formulations in healthy Middle Eastern volunteers
A.-N. Zaid, A. Bowirrat, J.J. Kort and M. Oscar-Berman
Abstract
A.-N. Zaid1, A. Bowirrat1,2, J.J. Kort3 and M. Oscar-Berman4
1Faculty of Pharmacy, An-Najah National University, Nablus, Palestine, 2The Regional Research and Development Center, The Galilee Society, Shefa-Amr, Israel, 3R and D Manager, Pharmacare PLC Company, Ramallah, Palestine, 4Departments of Psychiatry, Neurology and Anatomy and Neurobiology, BostonUniversity School of Medicine and Boston VA Healthcare System, Boston, MA, USA
Objective: To assess the bioequivalence of two fluoxetine hydrochloride capsule (20 mg) formulations (Fluoxicare capsule from Pharmacare Ltd., Chemicals and Cosmetics, Ramallah, Palestine, as test formulation, and Prozac from Eli Lilly Ltd., Basingstoke, UK, as reference formulation). Design and methods: The study was conducted open with a randomized 2-period crossover design and a 6-week washout period. Participants were 24 healthy male volunteers aged 18 – 28 years, divided into 2 groups of 12 subjects. One group was given the originator drug (reference formulation), and the other was given the test formulation. Blood samples were obtained at baseline and at 14 time points during the interval 0 – 96 hours after drug administration. The concentrations of the samples were assayed spectrophotometrically at 220 nm using a Shimadzu 160 A UV-visible spectrometer. We calculated the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax), and time of maximum plasma concentration (tmax) for each subject. Logarithmic transformation of the AUC and Cmax was used for the statistical analyses and to assess the bioavailability of the two formulations, using analyses of variance (ANOVA) and Satherwait t-tests for unequal variances. The ANOVA performed of tmax in Cmax, and in AUC provided the appropriate intra-subject variance estimates to evaluate the 90% confidence intervals for the differences between study variables after administration of the test and reference formulations. Statistical analyses were conducted on AUC0-4 as the extrapolated part of the AUC, a truncated area approach was adapted. Results: The mean pharmacokinetic parameters for both of the drugs under study were as follows: Cmax = 61.24 (± 12.96) ng/ml for the test formulation, and for the reference formulation Cmax = 61.39 (± 14.1) ng/ml, the effects were statistically equivalent. The tmax for the test formulation was 8.25 (± 1.7) and 7.33 (± 0.96) for the reference formulation. The area under the curve to infinity (AUC0-¥ (ng, day/ml)) for the test formulation and for the reference formulation were 293.02 (± 52.69) and 296.15 (± 61.69), respectively. Conclusions: The two formulations had equivalent pharmacokinetic parameters, were well-tolerated, and their relative bioavailability was 98.94%. Correspondence to:
M. Oscar-Berman, PhD
Boston University School of Medicine
L815 715 Albany Street
Boston, MA 02118, USA
Email: oscar@bu.edu
