Volume 45, No. 12/2007(December)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Therapeutics
Insulin glargine added to therapy with oral antidiabetic agents improves glycemic control and reduces long-term complications in patients with type 2 diabetes – a simulation with the Diabetes Mellitus Model (DMM)
H.U. Janka, F. Hessel, S. Walzer and E. Müller
Abstract
H.U. Janka, F. Hessel, S. Walzer and E. Müller
1Klinikum Bremen Nord, Bremen, 2Sanofi-Aventis Pharma GmbH, Berlin, and 3Analytica International, Loerrach, Germany
Objective: The purpose of this study was to compare the effect of two insulin therapies with respect to long-term complications in type 2 diabetes patients using the Diabetes Mellitus Model (DMM). The therapies under investigation were insulin glargine combined with the oral antidiabetic agents, glimepiride and metformin, (BOT = basal supported oral treatment) and premixed insulin (CT = conventional therapy). Methods: The DMM predicts complications over a 10-year period using data from published studies. Particular interest is placed on the influence of HbA1c levels related to time. The simulations are based on 10,000 virtual patients taking BOT and CT and the clinical data are based on the results of the LAPTOP study (Lantus® + Amaryl® + metformin versus premixed insulin in patients with type 2 diabetes mellitus after failing oral treatment pathways) comparing BOT and CT for 24 weeks. The simulations were performed in patients aged 60 ± 9 years with type 2 diabetes in which the duration of disease had a baseline of 9 ± 7 years. Sensitivity analyses were carried out by changing the response rate of those on BOT, the age of patients and duration of diabetes. Results: The overall relative risk reductions obtained with BOT versus CT for the base case are, 11% for the nervous and vascular systems, 7% for the renal system, 5% for ophthalmic disorders, 3% for the cardiovascular system and mortality and 6% for any kind of event after 10 years. The advantages of BOT were robust to all the changes in the sensitivity analyses. When compared with the base case, the best therapeutic effects were obtained in younger patients who had been diabetic for a shorter period. Conclusions: Using the DMM data from the LAPTOP study, simulations based on both therapies showed that the BOT regimen provides better glycemic control and reduction in HbA1c thereby leading to a reduction in the long-term complications of diabetes and mortality.
Correspondence to:
F. Hessel, Sanofi-Aventis Deutschland GmbH, Potsdamer Strasse 8, 10785 Berlin, Germany
Therapeutics
Effectiveness and safety of olanzapine in the treatment of Asian outpatients with schizophrenia
M.H. Habil, H. Gondoyoewono, H.R. Chaudhry, U. Samanwongthai, A.R.A. Hamid, I.T. Hashmi, R. Budiman, A.G. Knowles and R. Buenaventura
Abstract
M.H. Habil, H. Gondoyoewono, H.R. Chaudhry, U. Samanwongthai, A.R.A. Hamid, I.T. Hashmi, R. Budiman, A.G. Knowles and R. Buenaventura
1Department of Psychological Medicine, University of Malaya, Kuala Lumpur, Malaysia, 2Department of Psychiatry, Trisakti University, Jakarta, Indonesia, 3Department of Psychiatry, Fatima Jinnah Medical College & Sir Ganga Ram Hospital, Lahore, Pakistan, 4Srithanya Psychiatric Hospital, Nonthaburi, Thailand, 5Department of Psychiatry, Universiti Kebangsaan Malaysia, Bangi, Malaysia, 6Department of Psychiatry, Shalimar Hospital, Lahore, Pakistan, 7Department of Psychiatry, University of Indonesia, Depok and Jakarta, Indonesia, 8Clinical Outcomes Research Institute, Eli Lilly Australia Pty Ltd., West Ryde, NSW, Australia, and 9Eli Lilly (Philippines), Inc., Quezon City, Philippines
Objective: The objective of this study was to assess the effectiveness and safety of olanzapine in the treatment of schizophrenia among Asian patients in an outpatient setting. Methods: This was an open-label, prospective, observational study involving 339 patients from Indonesia, Pakistan, Malaysia, Thailand, and Singapore. Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression Severity scale (CGI-S), and safety parameters were assessed. Results: 62% of patients responded to olanzapine treatment, defined a priori as a reduction in BPRS of > 40% from baseline. Following the 8-week treatment period, the BPRS total, BPRS positive, BPRS negative, and CGI-S scores decreased by 18.7 (95% CI: 17.4, 20.2), 6.1 (5.6, 6.6), 2.9 (2.6, 3.2), and 1.5 points (median 1.0), respectively (p < 0.0001). In total, 31 of the 339 patients (9.1%) failed to complete the study according to the study description. Loss to follow-up and personal conflict were the most common reasons for discontinuation. There were 30 treatment-emergent adverse events with six serious cases, assessed as unrelated to study drug, reported. Conclusion: This study further demonstrates the effectiveness and safety of olanzapine in actual clinical practice settings, in reducing the severity of psychopathological symptoms in Asian patients with schizophrenia.Correspondence to:
M.H. Habil, MBBS, MpsychMed, Jabatan Perubatan Psikologi, Fakulti Perubatan, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
Email: hussain_habil@um.edu.my
Drug-Drug Interactions
Trends in polypharmacy and potential drug-drug interactions across educational groups in elderly patients in Sweden for the period 1992 – 2002
S.I. Haider, K. Johnell, M. Thorslund and J. Fastbom
Abstract
S.I. Haider, K. Johnell, M. Thorslund and J. Fastbom
1Aging Research Center, Karolinska Institutet, and 2Department of Social Work, Stockholm University, Stockholm, Sweden
Objective: This study investigates the changes in drug use, polypharmacy and potential drug-drug interactions (DDIs) between educational groups of Swedish elderly over a 10-year period from 1992 – 2002. Methods: We used data from SWEOLD I (n = 512) from 1992 and SWEOLD II from 2002 (n = 561), which are nationally representative surveys of the elderly population in Sweden aged 77 years and older. Both community-based and institutionalized persons were included. Information on drug use was based on personal interviews and all drugs used in the two weeks prior to the studies were recorded. The three outcomes under study were drug use, polypharmacy (concurrent use of five or more drugs), and potential DDIs. Results: In the SWEOLD data from 1992 – 2002, the mean number of drugs used per person increased from 2.5 – 4.4. Overall, 81% of the study participants were drug users in 1992 as compared to 88% in 2002. The prevalence of polypharmacy increased 3-fold (from 18% in 1992 to 42% in 2002) after controlling for age and gender. In both SWEOLD surveys, the less educated reported polypharmacy more often (19% in 1992 and 46% in 2002) than the higher educated (12% in 1992 and 36% in 2002). Potential DDIs also increased, both among the less educated (14% in 1992 to 26% in 2002) and the higher educated (18% in 1992 to 24% in 2002). The most pronounced changes in the consumption of specific drug groups were observed in antithrombotic agents, b-blocking agents, ACE inhibitors, and vitamin B12 and folic acid. In general, the use of most therapeutic classes increased more among the well educated compared to less educated men between 1992 and 2002, whereas the opposite relationship prevailed among women. Conclusion: This study indicates that the use of drugs, polypharmacy and potential DDIs have increased during 1992 to 2002 among the elderly. These changes were most prominent among the less educated women. Polypharmacy and potential DDIs represent potential health hazards for the elderly. Therefore, the trends of increasing polypharmacy and drug-drug interactions deserve attention and the mechanisms behind should be investigated further.Correspondence to:
S.I. Haider, MScPharm, MScPH, Aging Research Center, Karolinska Institutet, Gävlegatan 16, 113 30 Stockholm, Sweden
Email: Imran.Haider@ki.se
Pharmacoeconomics
Clinical and economic analyses of antimicrobial therapy in fever wards of a Hong Kong teaching hospital
C.-F. Mak, D.K.M. Choi, R.S.M. Wong and J.H.S. You
Abstract
C.-F. Mak, D.K.M. Choi, R.S.M. Wong and J.H.S. You
1School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong and 2Department of Medicine and Therapeutics, Faculty of Medicine, The Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
Objective: The aims of this study were to evaluate the use of antimicrobial agents in the fever wards of a Hong Kong teaching hospital and to identify those factors associated with treatment failure and having an influence on the total direct medical costs of antimicrobial therapy. Methods: This was a retrospective observational study. Demographic and clinical data were collected on 123 patients admitted to the fever wards in a local teaching hospital between July 2004 and August 2004. Multivariate analyses were performed to identify factors associated with treatment failure and the total direct medical treatment cost. Results: The rate of treatment failure was 30.1% (37 out of 123 patients). The mean total direct medical cost was HK$ 26,442 ± 17,153 (US$ 1 = HK$ 7.8). The empirical therapy in 90 (73.2%) patients complied with the institutional guidelines. 25 (20.3%) patients were eligible for renal dosage adjustment and in 7 (28%) of these patients the dosage of antimicrobial agents was renally adjusted. Of the 27 patients in whom pathogens were identified, 9 (33.3%) patients were eligible for antimicrobial streamlining (changing to an antibiotic with a narrower spectrum) but streamlining was only done in 2 (22.2%) patients. Multivariate analysis showed that the history of malignant diseases (RR = 5.07; 95% CI = 1.06 – 24.22) and non-compliance with the institutional treatment guidelines for selection of empirical antimicrobial therapy (RR = 3.58; 95% CI = 1.35 – 9.54) were risk factors associated with treatment failure. Duration of intravenous antimicrobial therapy was associated with the total cost of treatment (RR = 1.60; 95% CI = 1.35 – 2.10). Conclusion: Non-compliance with treatment guidelines in empirical antimicrobial treatment and the duration of intravenous antimicrobial therapy were modifiable risk factors for treatment failure and total treatment cost, respectively.Correspondence to:
J.H.S. You, Associate Professor, Center for Pharmacoeconomics Research, School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong
Email: joyceyou@cuhk.edu.hk
Letter to the Editor
Psoriasis aggravation and metoprolol treatment – a prospective observational case study
R. Fux, K. Mörike, A.M.T. Pröhmer, U. Delabar, E. Schaeffeler, C.H. Gleiter and M. Schwab
Abstract
R. Fux, K. Mörike, A.M.T. Pröhmer, U. Delabar, E. Schaeffeler, C.H. Gleiter and M. Schwab
1Department of Clinical Pharmacology, Institute of Pharmacology and Toxicology, University Hospital Tübingen, Tübingen, Germany
2Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Stuttgart, Germany
Correspondence to:
Prof. Dr. C.H. Gleiter, Universitätsklinikum Tübingen, Institut für Pharmakologie und Toxikologie, Abteilung Klinische Pharmakologie Otfried-Müller-Str. 45, D-72076 Tübingen, Germany
Email: christoph.gleiter@med.uni-tuebingen.de
Bioavailability Section
Similar bioavailability of dexmethylphenidate extended (bimodal) release, dexmethyl-phenidate immediate release and racemic methylphenidate extended (bimodal) release formulations in man
D. Tuerck, Y. Wang, M. Maboudian, Y. Wang, G. Sedek, F. Pommier and S. Appel-Dingemanse
Abstract
D. Tuerck, Y. Wang, M. Maboudian, Y. Wang, G. Sedek, F. Pommier and S. Appel-Dingemanse
1Exploratory Development, Drug Metabolism and Pharmacokinetics, Novartis Pharma Basel, Switzerland, 2Exploratory Clinical Pharmacology, Oncology, 3Exploratory Clinical Development, 4Biostatistics and Reporting, Novartis Pharmaceuticals Inc., East Hanover, NJ, USA and 5Drug Metabolism and Pharmacokinetics, Novartis Pharma, Rueil-Malmaison Cedex, France
Objective: The d-isomer of methylphenidate (d-MPH) is the pharmacologically active part of the racemic mixture of methylphenidate (d,l-MPH), which has been used for decades in the treatment of attention-deficit/hyperactivity disorder (ADHD). A modified release formulation with bimodal release for the pure d-enantiomer (Focalin XR) has been developed to enable a fast onset of action and a sustained activity for once-daily administration. It was intended to achieve a bimodal concentration-time profile as observed after administration of two immediate release Focalin tablets. The pharmacokinetics of this d-MPH bimodal release formulation were compared with a d-MPH immediate release formulation and a similar bimodal release formulation of d,l-MPH in healthy adult volunteers. Materials and methods: 25 volunteers received a single 20 mg dose of d-MPH bimodal release formulation, two 10 mg doses of a d-MPH immediate release formulation given 4 h apart and a single 40 mg dose of d,l-MPH bimodal release formulation (1 : 1 ratio for d : l enantiomers). The washout between treatments in this 3-way crossover study was 7 days. Results: All three formulations were well-tolerated at the doses tested. The d-MPH bimodal release formulation generated two distinct d-MPH plasma concentration peaks and both peak concentrations and the time to peak were similar to those of the d-MPH immediate release formulation given 4 h apart and the d,l-MPH bimodal release formulation. The three formulations had Cmax and AUC0-¥ values of 15.5 ± 4.3 ng/ml and 119 ± 41 ng × h/ml for bimodal release d-MPH, 17.9 ± 5.3 ng/ml and 115 ± 40 ng × h/ml for immediate release d-MPH, and 16.4 ± 4.4 ng/ml and 122 ± 36 ng × h/ml for d,l-MPH bimodal release, respectively. Conclusions: In summary, the 20 mg extended (bimodal) release formulation of d-MPH (Focalin XR) demonstrated a bimodal concentration-time profile and was bioequivalent to two 10 mg doses of immediate release d-MPH (Focalin) and was bioequivalent to 40 mg extended (bimodal) release d,l-MPH (Ritalin LA).Correspondence to:
S. Appel-Dingemanse, PhD, Novartis Pharma AG, Exploratory Development, Drug Metabolism and Pharmacokinetics, Lichtstraße 35, 4002 Basel, Switzerland
Email: silke.appeldingemanse@novartis.com
Bioavailability Section
Comparative bioavailability study of two phenoxymethylpenicillin potassium tablet formulations in healthy volunteers
R.A. Moreno, L. Boldrina, A. Guermani, J. Mazucheli, C. Sverdloff and N.C. Borges
Abstract
R.A. Moreno, L. Boldrina, A. Guermani, J. Mazucheli, C. Sverdloff and N.C. Borges
1Synchrophar Assessoria e Desenvolvimento de Projetos Clínicos and
2Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil
Objective: The aim of this study was to evaluate the performance of 2 phenoxymethylpenicillin 500,000 UI tablet formulations in healthy human volunteers. Material and methods: The study was conducted using an open, randomized crossover design with a 7-day washout interval. A single dose of each formulation was administered to 26 healthy volunteers as assessed by clinical and laboratory test evaluations. The plasma samples were obtained over an 8-h interval and phenoxymethylpenicillin concentrations were quantified by a suitable and validated HPLC-UV method with detection at 220 nm. Systolic and diastolic blood pressure and pulse rate measurement were taken pre dose and at intervals up to 8 h. Results: Tolerance of both products was adequate. The mean of Meracilina/Pen-Ve-Oral 500,000 UI% geometric mean was 99.89% for AUC0-t, 100.86% for AUC0-¥ and 101.11% for Cmax. The 90% confidence intervals were 94.62 – 105.46%, 95.22 – 106.83% and 98.61 – 103.87%, respectively. The mean recovery of phenoxymethylpenicillin was 94.8%, while the retention time observed for phenoxymethylpenicillin and phenytoin (internal standard) was 4 and 10 min, respectively. The limit of quantification was 0.10 mg/l. Conclusion: Since the 90% CI for AUC0-t, AUC0-¥ and Cmax ratios were all within the 80 – 125% interval proposed by the US FDA and accepted by ANVISA, it was concluded that the Meracilina formulation (manufactured by Aché S.A.) is bioequivalent to Pen-Ve-Oral (manufactured by Eurofarma) for both the rate and the extent of bioavailability.Correspondence to:
R.A. Moreno, 38 Dr. Candido Gomide Street, Campinas, SP, Brazil
Email: moreno@synchrophar.com
