Volume 49, No. 10/2011(October)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Original Research
Adverse drug reactions (ADRs) associated with hospital admissions – elderly female patients are at highest risk
C. Hofer-Dueckelmann, E. Prinz, W. Beindl, J. Szymanski, G. Fellhofer, M. Pichler and J. Schuler
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 10/2011 (577-586)
Adverse drug reactions (ADRs) associated with hospital admissions – elderly female patients are at highest risk
C. Hofer-Dueckelmann1, E. Prinz2, W. Beindl1, J. Szymanski3, G. Fellhofer1, M. Pichler2 and J. Schuler2
1Pharmacy Department, Landesapotheke Salzburg, 2Department of Cardiology, Landeskrankenhaus Salzburg, Private Paracelsus Medical University, Salzburg, Austria, and 3Helios Klinikum Wuppertal, Universität Witten/Herdecke, Department of Clinical Pharmacology, Wuppertal, Germany
Background: ADRs represent a significant problem in drug utilisation. The prevalence of admissions caused by ADRs varies depending on the observational site, studied population, data collection method and the used definitions. Women seem to be more frequently affected than men. Objective: To assess the incidence and quality of ADRs related to hospital admissions, to identify the drugs most commonly involved and to define risk factors and preventive strategies for those ADRs. Material and methods: 3,190 medical records of all newly admitted internal ward patients were assessed in a prospective observational study in an internal hospital over 6 months. Potential ADRs at hospital admission were identified following a list of suspicious symptoms and laboratory results. Cases were evaluated by means of a computer tool and data-base specialized on detecting causality and severity of ADRs. Results: 304 ADRs were identified in 242 patients (7.6%), with 60% directly leading to admission. More women than men encountered an ADR (10 vs. 6%, p < 0.005). Analyzed separately by age groups, this gender difference became significant at an age of ≥ 81 years. The most common ADRs were electrolyte imbalances and over-anticoagulation. Diuretics and vitamin K antagonists were significantly correlated with ADRs. 62% of all ADRs were severe or life-threatening. Conclusion: ADRs leading or related to hospital admission are highly prevalent. Older age and female gender are significantly associated with ADR related hospital admissons. Causative drugs are the ones prescribed most frequently. Multidisciplinary preventive strategies and surveillance methods are necessary to ensure better care and patient safety especially for elderly women.Correspondence to:
C. Hofer-Dueckelmann
Pharmacy Department
Landesapotheke Salzburg
Müllner Hauptstr. 50
5020 Salzburg, Austria
Email: c.dueckelmann@salk.at
Original Research
Imaging patterns and prognosis of patients with gefitinib-related interstitial lung disease
M.-K. Yuan, C.-Y. Chang, S.- C. Chang, S.-J. Chang, G.- J. Tang, Y.-F. Wei, Y.-C. Liu, C.-Y. Chen and C.-J. Yu
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 10/2011 (587-593)
Imaging patterns and prognosis of patients with gefitinib-related interstitial lung disease
M.-K. Yuan1, C.-Y. Chang2, S.-C. Chang3, S.-J. Chang4, G.-J. Tang3, Y.-F. Wei5, Y.-C. Liu3, C.-Y. Chen3 and C.-J. Yu6
1Department of Radiology, National Yang-Ming University Hospital, Yilan, 2Department of Chest Medicine, Far Eastern Memorial Hospital, Taipei, 3Department of Internal Medicine, National Yang-Ming University Hospital, Yilan, 4Department of Industrial Management and Enterprise Information, Aletheia University, Taipei, 5E-DA Hospital/I-Shou University, Kaohsiung County, and 6Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
Purpose: We aimed to summarize the imaging findings of 25 patients with gefitinib-related interstitial lung disease (ILD), and identify the factors related to prognosis of gefitinib-related ILD in patients with non-small-cell-lung cancer. Materials and methods: Diagnosis of gefitinib-induced ILD by at least two chest radiologists was based on a review and analysis of the chest radiography and CT findings plus clinical data in the medical records. All patients were diagnosed with Stage III – IV non-small-cell carcinoma (adenocarcinoma (n = 24), bronchioalveolar cell carcinoma (n = 1)) and essential clinical data such as gefitinib as first-line use and survival status were recorded and analyzed to determine whether these were prognosis predictors. The imaging findings were classified into four patterns according to the previous largest study in Japan. Results: The 25 chest radiographs were classified as Pattern A (n = 8), Pattern B (n = 3), Pattern C (n = 6), and pattern D (n = 8). Likewise the 23 CT images were classified as pattern A (n = 8; 34.8%), B (n = 3; 13%), C (n = 5; 21.7%), and D (n = 7; 30.4%). The mortality rate was significantly higher in patients with pattern D than in patients with the other patterns. Pattern D imaging findings were also significantly correlated with non first-line use of gefitinib (p = 0.007). Conclusions: We found an increase in mortality rate in patients with gefitinib associated ILD/pattern D compared to other radiological patterns. Familiarity with these imaging patterns can facilitate early and accurate diagnosis and help physicians gauge clinical prognosis of gefitinib-related ILD.Correspondence to:
Dr. S.-C. Chang
Department of Internal Medicine
National Yang-Ming University Hospital
No.152, Xin-Min Road
Yilan City 260, Taiwan
Email: dtsurga9@yahoo.com.tw
Original Research
A thorough QT study to evaluate the effects of singledose exenatide 10 μg on cardiac repolarization in healthy subjects
H. Linnebjerg, M. Seger, P.A. Kothare, T. Hunt, A.M. Wolka and M.I. Mitchell
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 10/2011 (594-604)
A thorough QT study to evaluate the effects of singledose exenatide 10 μg on cardiac repolarization in healthy subjects
H. Linnebjerg1, M. Seger2, P.A. Kothare2, T. Hunt1, A.M. Wolka2 and M.I. Mitchell1
1Lilly Research Centre, Eli Lilly and Company Limited, Erl Wood Manor, Windlesham, Surrey, UK, and 2Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
Objective: This was a singledose, randomized, positive- and placebocontrolled, double-dummy, double-blinded, 3-period crossover thorough QT study of exenatide, a glucagon-like peptide-1 receptor agonist for the treatment of Type 2 diabetes that enhances insulin secretion in a glucose- dependent fashion. Methods: Healthy subjects (n = 70) underwent an initial tolerability screening, receiving subcutaneous exenatide 10 μg daily for 3 consecutive days. Subjects who passed tolerability screening (n = 62) received exenatide 10 μg, placebo, and moxifloxacin (400 mg orally; positive control) separated by washout periods of approximately 5 days. Twelve-lead electrocardiograms and blood samples for plasma exenatide, glucose, and insulin were collected. QT intervals were heart rate-corrected using Fridericia’s correction (QTcF) and an individual correction (QTcI) and were analyzed as change from predose (ΔQTcF, or ΔQTcI). The relationships between the QTc interval and plasma exenatide, glucose, and insulin concentrations were also explored. Results: Based on ΔQTcF and ΔQTcI assessments, exenatide 10 μg did not show a clinically significant prolongation of QT compared with placebo; the upper bound of the 2-sided 90% confidence interval (CI) for the largest mean difference from placebo was < 10 msec with both corrections. A positive slope was observed between plasma exenatide and ΔΔQTcF (0.02 (95% CI 0.01, 0.03), p < 0.001); no significant slope was observed between plasma exenatide concentrations and ΔΔQTcI (0.01 (95% CI 0.00, 0.02), p = 0.064). The plasma exenatide versus QTc analyses may be confounded by exenatide’s glucose-lowering effect. A negative slope was observed between plasma glucose and [delta]QTcF (–1.5 (95% CI –2.2, –0.7), p < 0.001) and between plasma glucose and ΔQTcI (–1.6 (95% CI –2.3, –0.9), p < 0.0001). Plasma insulin and ΔQTcF were not correlated. Conclusion: This study demonstrated that single-dose exenatide 10 μg was not associated with clinically meaningful prolongation of the QTc interval.Correspondence to:
H. Linnebjerg, MSc, PhD
Lilly Research Centre
Eli Lilly and Company Limited
Erl Wood Manor
Windlesham, Surrey, GU20 6PH
United Kingdom
Email: linnebjerg_helle@lilly.com
Original Research
Antiplatelet therapy in diabetic ischemic stroke patients: associated factors and outcomes
Y. Hassan, S.W. Al-Jabi, N. Abd Aziz, I. Looi and S.H. Zyoud
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 10/2011 (605-613)
Antiplatelet therapy in diabetic ischemic stroke patients: associated factors and outcomes
Y. Hassan1, S.W. Al-Jabi2,3, N. Abd Aziz1, I. Looi4 and S.H. Zyoud3,5
1Department of Pharmacy Practice, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, Bandar Puncak Alam, Selangor Darul Ehsan, 2Clinical Pharmacy Program, School of Pharmaceutical Sciences, Universiti Sains Malaysia (USM), Penang, Malaysia, 3Faculty of pharmacy, An-Najah National University, Nablus, Palestine, 4Clinical Research Center, Hospital Pulau Pinang, and 5National Poison Center, Universiti Sains Malaysia (USM), Penang, Malaysia
Background: Patients with diabetes mellitus (DM) are more prone to develop atherosclerotic complications including stroke. Moreover, as a primary and secondary prevention of stroke, antiplatelet therapy is recommended by clinical guidelines for patients with DM. Aims: This study aimed to determine the prevalence of antiplatelet therapy use prior to current stroke in diabetic ischemic stroke patients, to examine the factors associated with the use of this important therapy and to assess the impact of the previous use of antiplatelet therapy on ischemic stroke outcomes. Methods: An observational study of diabetic acute ischemic stroke patients attending a Malaysian hospital during a 1-year period was carried out. Demographic information, risk factors, previous antiplatelet use and variables used to assess stroke outcomes were collected from medical records. Results: Overall, 295 diabetic stroke patients were analyzed. The prevalence of previous antiplatelet use among diabetic patients was 38.3%. The independent variables associated with the previous use of antiplatelet medication were previous stroke attack (p < 0.001) and ischemic heart disease (p < 0.001). Better outcomes as measured by a minor Glasgow Coma Scale at admission (p = 0.032), and a higher Modified Barthel index at discharge (p = 0.027) were observed among patients on previous antiplatelet therapy. Conclusion: Our data suggest that antiplatelet therapy is under prescribed among such diabetic stroke patients, particularly in primary prevention. Effective methods to increase antiplatelet use and to enhance the adherence of clinical practice guidelines should be considered at the national and community level.Correspondence to:
Y. Hassan PharmD
Professor of Clinical Pharmacy
Department of Pharmacy Practice
Faculty of Pharmacy
Universiti Teknologi MARA (UiTM)
Puncak Alam Campus
Bandar Puncak Alam 42300,
Selangor Darul Ehsan, Malaysia
Email: dryahaya2909@puncakalam.uitm.edu.my
Original Research
The efficacy of nebulized procaterol versus nebulized salbutamol for the treatment of moderate acute asthma: a randomized, double-blind, parallel group study
H. Mangunnegoro, F. Novariska, W.H. Wiyono, A. Setiawati and M. Louisa
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 10/2011 (614-621)
The efficacy of nebulized procaterol versus nebulized salbutamol for the treatment of moderate acute asthma: a randomized, double-blind, parallel group study
H. Mangunnegoro1, F. Novariska1, W.H. Wiyono1, A. Setiawati2 and M. Louisa2
1Department of Pulmonology and Respiratory Medicine, Faculty of Medicine University of Indonesia/Persahabatan Hospital, and 2Department of Pharmacology and Therapeutics, Faculty of Medicine University of Indonesia, Jakarta, Indonesia
Objective: β2 agonists have been used widely as relievers in asthma management. Procaterol is a selective β2 agonist, claimed to be more selective than salbutamol. The present study aimed to compare the efficacy of nebulized procaterol with nebulized salbutamol in the treatment of moderate acute asthma. Methods: This was a randomized, double-blind, parallel group study in 140 patients with moderate acute asthma according to modified GINA 1998 who visited emergency department of Persahabatan Hospital, Jakarta. Patients were randomly assigned to receive three doses of either nebulized procaterol or salbutamol. The primary efficacy variable was the improvement in predicted peak expiratory flow rate (PEFR), while the secondary efficacy variable was the improvement in asthma score and the incidence and severity of adverse events. This study is registered at Current Controlled Trials, number ISCTRN25669625. Results: Baseline characteristics were similar in both groups. After treatment, there were significant improvement of % PEFR (p < 0.001) and asthma score (p < 0.001) in procaterol (n = 68) and salbutamol (n = 69) groups. It was shown that procaterol and salbutamol produced similar efficacy in improving % predicted PEFR and decreasing asthma score. Both treatments were well tolerated. Palpitation and sinus tachycardia were found as adverse events with low incidence. Conclusion: In moderate acute asthma, nebulized procaterol and nebulized salbutamol were both effective in improving PEFR and decreasing asthma score. Both treatments were well tolerated, adverse reactions were rare.Correspondence to:
F. Novariska
Clinical Study Unit
Departemen Farmakologi dan Terapeutik
Fakultas Kedokteran
Universitas Indonesia
Jl. Salemba 6
Jakarta Pusat, Jakarta, 10430, Indonesia
Email: riskapulmo@yahoo.co.id
Case Report
Glucocorticoid-resistant Evans’ syndrome successfully controlled with low-dose cyclosporine
D. Janić, L. Krivokapić- Dokmanović, N. Jovanović, J. Lazić, P. Rodić and S. Janković
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 10/2011 (622-625)
Glucocorticoid-resistant Evans’ syndrome successfully controlled with low-dose cyclosporine
D. Janić1,2, L. Krivokapić-Dokmanović1,2, N. Jovanović1,2, J. Lazić2, P. Rodić2 and S. Janković2
1School of Medicine, University of Belgrade and 2University Children’s Hospital, Belgrade, Republic of Serbia
Objective: To present a patient suffering from Evans’ syndrome (ES), whose bouts of severe cytopenia were prevented by low-dose cyclosporine maintenance therapy. Case summary: A boy suffering from frequent mild respiratory infections, first time evaluated in a tertiary care pediatric center at age 4, was found to have lymphadenopathy and mild splenomegaly. The thrombocytopenia was first noted at age 6. He was diagnosed to have ES at the age of 8, during another bout of thrombocytopenia, this time associated with Coombs-positive hemolytic anemia. Immunoglobulin concentration in the plasma was measured repeatedly, and was in the normal range, or even increased. Lymphocyte subpopulation numbers were in the normal range, with decreased CD4+/ CD8+ ratio (0.6). Autoimmune lymphoproliferative syndrome was excluded by the absence of CD4-CD8- T lymphocytes. Since the patient failed to respond to standard therapy with prednisolon 2 mg/kg, high dose intravenous methylprednisolone (10 mg/ kg/d for 3 days) and high dose intravenous immunoglobulin (1 g/kg/d for 2 days), cyclosporine treatment was initiated (6 mg/ kg/d) and resulted in normalization of platelet count and resolution of hemolysis. Two attempts to withdraw cyclosporine therapy resulted in life-threatening hemolytic crisis with severe thrombocytopenia, requiring the re-institution of cyclosporine. The dose of cyclosporine was eventually tapered to the present 0.5 mg/kg, corresponding to drug serum levels of 5 – 8 mg/ml. The patient is now free of manifestations of Evans’ syndrome but, after 20 years of cyclosporine treatment, has slightly impaired kidney function. Conclusion: Low-dose cyclosporine therapy given to our patient appears to have subdued the autoimmune process thought to underlie the manifestations of ES, albeit at the cost of some toxicity to the kidneys.Correspondence to:
D. Janić, MD, PhD
Department of Hematology and Oncology (Head)
University Children’s Hospital
Tiršova 10
11000 Belgrade, Serbia
Email: dragana.janic@mfub.bg.ac.rs
Short Report
Lepirudin dose-dependently increases thrombelastography parameters at therapeutic plasma concentrations as measured with ROTEM® – a pilot study
M. Feuring, M. Wehling and A. Schultz
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 10/2011 (626-628)
Lepirudin dose-dependently increases thrombelastography parameters at therapeutic plasma concentrations as measured with ROTEM® – a pilot study
M. Feuring, M. Wehling and A. Schultz
Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Germany
Background: The aim of this in-vitro pilot study was to assess the usefulness of the thrombelastograph ROTEM® for determining the anticoagulant activity of lepirudin. Methods: The ROTEM® parameters, clotting-time, clot formation time and maximum clot firmness were measured in the presence of increasing concentrations of lepirudin (10–4 μg/ml – 10 μg/ml). Citrated blood was obtained from 16 healthy male subjects. Results: Clotting-time increased from 79.1 ± 53.4 s at baseline to 194.1 ± 151.9 s at a drug concentration of 1μg/ml as measured with EXTEM (p < 0.0001). Borderline significance was found for the difference between maximum clot firmness at baseline (60.2 ± 4.3 mm) and after drug application (55.5 ± 6.5 mm). Conclusions: This pilot investigation shows that the ROTEM® device may be suitable for monitoring lepirudin at low concentrations but the results should be confirmed in a larger study and the ROTEM® device validated against standard methods.Correspondence to:
Prof. Dr. M. Wehling
Institute of Experimental and Clinical Pharmacology and Toxicology
Medical Faculty Mannheim
University of Heidelberg
Maybachstrasse 14
68169 Mannheim, Germany
Email: martin.wehling@medma.uni-heidelberg.de
Bioavailability Section
Bioequivalence assessment of metformin hydrochloride using a limited sampling strategy
L.F. Chen, J.J. Jiao, C.L. Zhang, J.S. Lou and C.X. Liu
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 10/2011 (629-636)
Bioequivalence assessment of metformin hydrochloride using a limited sampling strategy
L.F. Chen1,2, J.J. Jiao2, C.L. Zhang2, J.S. Lou2 and C.X. Liu3
1Department of Pharmacy, Tianjin Haihe Hospital, 2Department of Pharmacology, Pharmacology Teaching and Research Group, Tianjin Medical University, and 3Tianjin State Key Laboratory of Pharmacokinetics and Pharmacodynamics, Tianjin Institute of Pharmaceutical Research, Tianjin, China
Objective: The aim of this study was to develop a limited sampling strategy (LSS) that can be used to assess the bioequivalence of two metformin hydrochloride preparations. Methods: Healthy subjects (n = 20) enrolled in the bioequivalence study received a single oral tablet of 1,000 mg metformin reference formulation or test formulation. The plasma concentration of metformin was determined using a validated HPLC method. A multiple linear regression analysis of the observed metformin Cmax and AUC0–24 versus the concentration of reference formulation was performed to develop LSS models for estimating these parameters. The models were internally validated by the Jackknife method. The best models were employed to assess the bioequivalence of the two metformin formulations. Results: The linear relationship between pharmacokinetic parameters and a single concentration point was poor. Several models for the estimation of these parameters met the predefined criteria (r2 > 0.9). The Jackknife validation procedure revealed that LSS models based on two sampling times – C1.5 and C2 for Cmax; C4.0 and C10.0 for AUC0–24 – were accurate predictor of Cmax and AUC0–24. Prediction errors (PE) were less than 2%, and absolute prediction errors (AE) were less than 10%. PEs beyond 15% occurred in less than 5% of total samples. The bioequivalence assessment of the two metformin formulations, based on the best LSS models, provided results similar to those obtained using all the observed concentration-time data points, and indicated that the two metformin formulations were bioequivalent. Conclusion: A LSS method for assessing the bioequivalence of metformin formulations was established and proved to be applicable and accurate. This LSS method could be considered appropriate for a metformin bioequivalence study, providing an inexpensive cost of sampling acquisition and analysis.Correspondence to:
J.S. Lou
Deparment of Pharmacology
Tianjin Medical University
Tijanjin, 300070 China
Email: jianshilou@163.com
