Volume 49, No. 5/2011(May)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Editorial
Are statins really useless in “primary prevention”? Recent Cochrane meta-analysis revisited
T.B. Grammer and W. Maerz
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 5/2011 (293-296)
Are statins really useless in “primary prevention”? Recent Cochrane meta-analysis revisited
T.B. Grammer and W. Maerz
Original Research
Clarithromycin-induced hypersomnia in children
W.J. Baranowski
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 5/2011 (297-299)
Clarithromycin-induced hypersomnia in children
W.J. Baranowski
Higher Vocational School of LKO, Lodz, Poland
Two cases of hypersomnia in children caused by therapeutic doses of oral clarithromycin are presented. Clarithromycin-induced hypersomnia in children has not been reported before. A 4-year-old girl and 13-year-old boy received clarithromycin as monotherapy. The girl fell into a deep sleep after every dose of the antibiotic. The boy reported daytime sleepiness and prolongation of night-time sleep during the antibiotic therapy. In both cases the hypersomnia receded after cessation of clarithromycin therapy. The onset of hypersomnia after clarithromycin intake, its remission once the drug was stopped, and the absence of other possible causative factors favored the diagnosis of clarithromycin-induced hypersomnia, further supported by the scores on Naranjo’s Adverse Drug Reaction Probability Scale in both cases. Clinicians evaluating children receiving clarithromycin and exhibiting suddenly changed behavior should keep in mind that the antibiotic can produce uncommon adverse reactions.Correspondence to:
W.J. Baranowski
Higher Vocational School of LKO in Lodz
ul. Wolczanska 93, 90515 Lodz, Poland
Email: wszlko@op.pl
Original Research
Effect of linagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers
E.U. Graefe-Mody, T. Brand, A. Ring, B. Withopf, J. Stangier, M. Iovino and H.-J. Woerle
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 5/2011 (300-310)
Effect of linagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers
E.U. Graefe-Mody1, T. Brand2, A. Ring3, B. Withopf4, J. Stangier4, M. Iovino2 and H.-J. Woerle1
1Therapeutic Area Metabolism, 2Department of Clinical Research, 3Medical Data Services, and 4Department of Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Objective: To investigate the effect of the estimated highest therapeutic dose of linagliptin (5 mg) on the pharmacokinetics and pharmacodynamics of warfarin, a CYP2C9 substrate. Subjects and methods: This open-label, 2-period, fixed-sequence trial enrolled 18 healthy male volunteers, 17 of whom were homozygous for CYP2C9*1/*1. Subjects received a single oral dose of warfarin (10 mg) followed by a washout period of at least 14 days. Subjects then received oral linagliptin 5 mg once daily for 12 days (i.e. steady state) with a single dose of warfarin (10 mg) on Day 6. R(+) warfarin, S(-) warfarin, prothrombin time (PT) and international normalized ratio (INR) were assayed pre-dose and up to 168 h post-dose. Results: The geometric mean ratios (GMRs) (90% confidence interval (CI)) of AUC0–∞ and Cmax for (linagliptin + warfarin)/warfarin were 98.5 (95.7 – 101.5) and 99.7 (94.7 – 104.9), respectively, for R-warfarin; 103.0 (99.1 – 107.0) and 100.9 (93.7 – 108.6), respectively, for S-warfarin. Concomitant administration of linagliptin and warfarin had o clinically relevant effect on the AUC0–168 for INR or PT. The GMRs (90% CI) of INR nd PT AUC0–168 for (linagliptin + warfarin)/ warfarin were 93.4 (86.2 – 101.1) and 103.2 (95.4 – 111.6), respectively. The corresponding Eax values for both INR and PT were slightly increased after co-administration of linagliptin and warfarin compared with warfarin alone, being 104.3 (85.2 – 127.6) and 15.1 (94.3 –140.6), respectively, reflecting the higher variability of these endpoints. Co-administration of linagliptin and warfarin was well tolerated. Conclusions: Coadministration of linagliptin did not alter the pharmacokinetics or pharmacodynamics of R- or S-warfarin, indicating that no dosage adjustment for warfarin is necessary when co-administered with linagliptin.Correspondence to:
Dr. U. Graefe-Mody
Therapeutic Area Metabolism
Boehringer Ingelheim GmbH
Binger Str. 173
55216 Ingelheim, Germany
Email: Ulrike.Graefe-Mody@boehringer-ingelheim.com
Original Research
Cyclosporine A area-under-time-concentration-curve in rheumatologic patients after the first dose. Which of the sparse sampling strategies will predict the best?
B. Koristkova, M. Grundmann, D. Suchy, I. Perinova, H. Brozmanova and O. Mayer
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 5/2011 (311-320)
Cyclosporine A area-under-time-concentration-curve in rheumatologic patients after the first dose. Which of the sparse sampling strategies will predict the best?
B. Koristkova1, M. Grundmann1, D. Suchy2, I. Perinova1, H. Brozmanova1 and O. Mayer2
1Department of Clinical Pharmacology, Ostrava University Hospital and Medical Faculty, University of Ostrava, Ostrava, and 2Department of Internal Medicine, University Hospital, Plzen, Czech Republic
Objective: The aim of the present study was to validate the limited sampling strategies (LSS:s) for prediction of AUC of cyclosporine A (CsA) after the first dose in rheumatologic patients. Methods: 22 patients suffering from rheumathoid arthritis, systemic lupus erythematodus, ankylosing spondylitis dermato(poly)myositis or seronegative spondylarthritis were treated with Neoral® (female/male: 11/3, mean ± SD: age 49 ± 14 y, body weight 75 ± 12 kg, height 166 ± 7 cm, dose 71 ± 25 mg, dose per kg 1.0 ± 0.3 mg/kg), or Consupren® (7/1, 78 ± 36, 175 ± 8, 82 ± 22, 1.1 ± 0.3). Two patients whose C12h were missing were excluded from the AUC0–12 calculation. Whole blood levels of CsA were analyzed with HPLC. Blood samples were collected at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after taking the first dose. Altogether 115 LSS:s obtained from the literature were validated. A linear trapezoidal rule was used as a reference method. Mean percentage prediction error (%PE) < ± 15% and maximal one value of absolute %PE > 30% were considered to be acceptable. The root mean squared error (RMSE) was evaluated for equations that passed the criteria. Results: The best performance with all values of the absolute %PE < 30% was found in three LSS:s for AUC0–12 and two for AUC0–8: AUC0–12 = 123.792 + 1.165 × C1h + 3.021 × C3h + 7.33 × C8h; 97.6 + 1.27 × C1h + 3.14 × C3h + 4.06 × C6h; or 124.3 + 1.34 × C1h – 0.16 × C2h + 3.27 × C3h + 3.96 × C6h; AUC0–8 = –19.8 + 1.99 × C2h + 2.38 × C4h + 3.15 × C6h or –22.4 + 2.51 × C2h + 5.49 × C6h. Validation criteria were further fulfilled in AUC0–12 = 24 + 3.66 × C0h + 2.11 × C1.5h + 4.54 × C4h or 0.2 + 2 × C2h + 10.2 × C6h; AUC0–8 = 55.37 + 2.89 × C0h + 1.08 × C1 + 0.9 × C2h + 2.23 × C3h; and AUC0–4 = –41 + 1.17 × C1h + 1.85 × C2h. Only one equation proposed for AUC0–6 did not pass the validation criteria. Conclusions: Equations validated for prediction of AUC0–12, AUC0–8 and AUC0–4 might be used for LSS:s of CsA independently of the length of treatment, indication, dosage or galenic formulation.Correspondence to:
B. Koristkova, PhD
Department of Clinical Pharmacology
Ostrava University Hospital and Medical Faculty
University of Ostrava
17. listopadu 1790
708 52 Ostrava, Czech Republic
Email: blanka.koristkova@seznam.cz
Original Research
Effect of multiple doses of fimasartan, an angiotensin II receptor antagonist, on the steady-state pharmacokinetics of digoxin in healthy volunteers
S. Yi, J.W. Kim, T.-E. Kim, J.Kim, Y.K. Jun, J. Choi, S.H. Yoon, J.-Y. Cho, S.H. Song, S.-G. Shin, I.-J. Jang and K.-S. Yu
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 5/2011 (321-327)
Effect of multiple doses of fimasartan, an angiotensin II receptor antagonist, on the steady-state pharmacokinetics of digoxin in healthy volunteers
S. Yi1, J.W. Kim1, T.-E. Kim1, J.Kim1, Y.K. Jun2, J. Choi3, S.H. Yoon1, J.-Y. Cho1, S.H. Song4, S.-G. Shin1, I.-J. Jang1 and K.-S. Yu1
1Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, 2R&D Center, 3Clinical Research Team, Boryung Pharm. Co., and 4Department of Laboratory Medicine, Seoul National
University Hospital, Seoul, Republic of Korea
Fimasartan (BR-A-657) is an angiotensin II receptor antagonist, recently approved as an antihypertensive agent. Objective: This study aimed to investigate whether administration of fimasartan has an effect on the steady-state pharmacokinetics of digoxin. Methods: An open-label, two-period, two-treatment, single-sequence, crossover study was conducted in 14 healthy male volunteers. On the first day of each 7-day treatment period, subjects received a loading dose of digoxin 0.5 mg, either alone or together with fimasartan 240 mg in the morning, followed by an additional dose of digoxin 0.25 mg after 6 h. On the subsequent 6 days, digoxin 0.25 mg, either alone or with fimasartan 240 mg was administered once daily. Serial blood samples for pharmacokinetics were collected up to 24 h after the last administration in each period. Results: The geometric mean ratio and 90% confidence intervals (CI) for the Cmax,ss and AUCτ,ss of digoxin (with/without fimasartan) were 1.307 (1.123 – 1.520) and 1.087 (1.015 – 1.165), respectively. Study medications were well-tolerated without serious adverse events or clinically meaningful changes. Conclusions: Coadministration of fimasartan with digoxin does not result in clinically significant changes of digoxin pharmacokinetics at steady-state in healthy subjects.Correspondence to:
K.-S. Yu, MD, PhD
Department of Pharmacology and Clinical
Pharmacology
Seoul National University
College of Medicine and Hospital, 2306
Clinical Research Institute
Seoul National University Hospital
101 Daehangno, Jongno-gu
Seoul 110-744, Republic of Korea
Email: ksyu@snu.ac.kr
Original Research
Coagulation status in patients with coronary artery disease taking 100 mg aspirin and healthy volunteers using PFA-100® and ROTEM®
M. Feuring, M. Wehling, A. Ruf, H. Burkhardt and A. Schultz
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 5/2011 (328-335)
Coagulation status in patients with coronary artery disease taking 100 mg aspirin and healthy volunteers using PFA-100® and ROTEM®
M. Feuring, M. Wehling, A. Ruf, H. Burkhardt and A. Schultz
1Institute of Experimental and Clinical Pharmacology and Toxicology, Medical
Faculty Mannheim, University of Heidelberg, Heidelberg, 2Center for Laboratory
Medicine, Microbiology and Transfusion Medicine, Klinikum Karlsruhe, Karlsruhe,
and 3IV. Medical Clinic, Medical Faculty Mannheim, University of Heidelberg,
Heidelberg, Germany
Previous investigation revealed that age is a major risk factor for thomboembolic events. Earlier studies with thrombelastography have demonstrated procoagulant activity in elderly patients with coronary artery disease. The aim of the present study was to investigate age-related differences in the coagulation status of patients with documented coronary artery disease, healthy elderly and healthy young volunteers with the rotation thrombelastography (ROTEM®) and PFA-100®. Measured with ROTEM®, mean clot formation time (CFT (EXTEM)) in healthy young volunteers (120.8 ± 73.5 s) was significantly longer than
in healthy elderly (78.3 ± 36.7 s, p < 0.05) and in patients with coronary artery disease
(74.3 ± 59.1 s, p < 0.05). No difference was found between healthy elderly and patients
with coronary artery disease. The lowest value for mean maximum clot formation (MCF (EXTEM)) was seen in healthy young volunteers (57.0 ± 6.1 mm) which was significantly different to healthy elderly (61.9 ± 4.8 mm, p < 0.05) and patients with coronary artery disease (65.3 ± 8.4 mm, p < 0.05). No difference could be found between healthy elderly and patients with coronary artery disease, although a trend to higher mean MCF (EXTEM) and lower mean CFT (EXTEM)in patients with coronary artery disease was found. Measured with the collagen/epinephrine cartridge of the PFA-100®, healthy young volunteers (166.4 ± 59.5 s) had numerical but insignificantly longer mean closure times compared to healthy elderly (138.5 ± 53.3 s). These findings point to agerelated differences in thrombelastographic parameters. The ROTEM® analysis indicates an increased coagulability in patients with coronary artery disease and healthy elderly compared to healthy young volunteers.Correspondence to:
Prof. Dr. med. 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
Case Report
Fatal lithium toxicity with therapeutic levels – a case report
P.N. Venkatarathnamma, A.R. Patil and N. Nanjundaiah
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 5/2011 (336-338)
Fatal lithium toxicity with therapeutic levels – a case report
P.N. Venkatarathnamma, A.R. Patil and N. Nanjundaiah
Sri Devaraj Urs Medical College, Karnataka, India
For nearly five decades now, lithium has been used as a drug for treatment of bipolar affective disorder [1]. Adverse effects of lithium have been reported, but still lithium continues to be an effective prophylactic agent for bipolar disorder. Serious and fatal toxicity can occur with levels of lithium considered to be in the therapeutic range [2, 3, 4, 5, 6]. We are reporting a patient who was on lithium for bipolar disorder and was admitted with a history of sudden collapse following vomiting, and sinus bradycardia with ST-T changes. The patient expired with levels of lithium being within therapeutic range.Correspondence to:
Dr. P.N. Venkatarathnamma
Sri Devaraj Urs Medical College
Kolar.PIN CODE: 563101, Karnataka, India
Email: drpnvr@rediffmail.com
Case Report
The persistence of drug-induced fever by teicoplanin – a case report
H. Ochi, K. Wada, H. Okada, N. Kohara, T. Fujita, K. Toda, M. Sakamoto, O. Seguchi, Y. Murata, M. Yanase and T. Nakatani
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 5/2011 (339-343)
The persistence of drug-induced fever by teicoplanin – a case report
H. Ochi1, K. Wada1, H. Okada1, N. Kohara1, T. Fujita2, K. Toda2, M. Sakamoto3, O. Seguchi3, Y. Murata3, M. Yanase3 and T. Nakatani3
Departments of 1Pharmacy, 2Cardiovascular Surgery and 3Organ Transplantation, National Cardiovascular Center, Osaka, Japan
Objective: It was reported that the drug-induced fever of teicoplanin tended to persist after cessation of treatment. It is considered that the long half-life of teicoplanin causes the phenomenon. However there was no detailed report regarding plasma concentration of teicoplanin during onset of drug induced-fever. Therefore we investigated the relation between persistence of drug-induced fever and plasma concentration of teicoplanin. Case: A 38-year-old male patient on the Left Ventricular Assist System (LVAS) was treated with teicoplanin for methicillin-resistant Staphylococcus aureus (MRSA) and he experienced drug-induced fever. Plasma concentrations of teicoplanin were measured not only during the treatment with the drug but also after it was discontinued. As such, plasma concentration was measured even when the fever had subsided. Results: On Day 9 of treatment, the dose was increased from 400 to 600 mg, but the patient had a fever of about 38 – 39 °C. When the treatment was discontinued, it took 9 days for the fever to subside to a temperature of about 37 °C. The half-life of elimination of teicoplanin in the elimination phase is about 108 h, which is long. The fever persisted until the plasma concentration decreased to below 10 µg/ml, which is the effective trough concentration, and subsided when the estimated blood concentration was 7.5 µg/ml. Conclusions: We suggest that there is the possibility that the drug-induced fever due to teicoplanin persisted until the plasma concentration had decreased adequately. Close monitoring of plasma concentration is necessary, particularly when teicoplanin clearance is decreased such as in patients with renal dysfunction.Correspondence to:
H. Ochi, BS
Department of Pharmacy
National Cardiovascular Center
5-7-1, Fujisirodai, Suita-city, Osaka 565-873, Japan
Email: ochih@hsp.ncvc.go.jp
Book Review
Modern Trends in Pharmacopsychiatry, Vol. 27: Depression: From Psychopathology to Pharmacotherapy
C. Kelly
Abstract
Modern Trends in Pharmacopsychiatry, Vol. 27: Depression: From Psychopathology to Pharmacotherapy
C. Kelly
