Volume 49, No. 7/2011(July)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Original Research
Effects of surgery and chronic disease states on the concentrations and phenotype distribution of α1-acid glycoprotein: studies in patients with breast cancer and patients with chronic inflammatory disease
K. Hanada, E. Yamanaka, N. Yamamoto, H. Minami, S. Kawai, Y. Sasaki and H. Ogata
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 7/2011 (415-421)
Effects of surgery and chronic disease states on the concentrations and phenotype distribution of α1-acid glycoprotein: studies in patients with breast cancer and patients with chronic inflammatory disease
K. Hanada1, E. Yamanaka1, N. Yamamoto1, H. Minami2, S. Kawai3, Y. Sasaki2,3 and H. Ogata1
1Department of Biopharmaceutics, Meiji Pharmaceutical University, 2Division of Oncology/Hematology, National Cancer Center Hospital East, and 3Second Division, Institute of Medical Science, St. Marianna University School of Medicine, Japan
Objective: Although the concentration of α1-acid glycoprotein (AGP) in serum increases under some conditions, the behavior of the individual genetic variants is not well understood. Therefore, we studied the relative changes in AGP variants pre- and postoperatively in patients with cancer and patients with chronic inflammatory disease states, as well as the distribution of AGP phenotypes in a Japanese population. Methods: Serum samples were taken before and after surgery from 25 female patients with early breast cancer. Serum samples were also obtained from 134 patients with rheumatoid arthritis (RA) and 33 with systemic lupus erythematosus (SLE), and from 103 healthy subjects. The relative concentrations of the individual genetic variants in the serum samples were determined by isoelectric focusing after desialylation with neuraminidase. Results: The postoperative AGP concentrations in patients with early breast cancer were 2-fold higher than before surgery. The relative concentrations of the F1 and S variants were significantly increased, whereas that of the A variant was not changed significantly. The relative concentrations of all the AGP variants in patients with RA and SLE were significantly higher than those in healthy subjects. The distribution of the AGP phenotypes did not differ significantly among the groups examined in this study. Conclusions: The F1/S variants of AGP, but not the A variant, were significantly increased after early breast cancer surgery, but all the variants were increased in patients with chronic inflammatory states such as RA and SLE. The distribution of the AGP phenotypes did not differ significantly among the disease groups studied.Correspondence to:
K. Hanada, PhD
Department of Biopharmaceutics
Meiji Pharmaceutical University
2-522-1 Noshio, Kiyose
Tokyo 204-8588, Japan
Email: hanada@my-pharm.ac.jp
Original Research
In vitro kinetics of delivery of tobramycin and ofloxacin from osmotic hydro gel expanders
R. Wacke, B. Drewelow, R.G. Mundkowski, R.F. Guthoff and M.P. Schittkowski
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 7/2011 (422-427)
In vitro kinetics of delivery of tobramycin and ofloxacin from osmotic hydro gel expanders
R. Wacke1, B. Drewelow1, R.G. Mundkowski1, R.F. Guthoff2 and M.P. Schittkowski2,3
1Institute of Clinical Pharmacology, 2Department of Ophthalmology, University of Rostock, Rostock, and 3Department of Ophthalmology, University of Göttingen, Göttingen, Germany
Objective: High-hydrophilic osmotic self-inflating hydro gel expanders are well-accepted for implantation to achieve tissue expansion in defined parts of the body like skin, breast and orbital soft tissue. To prevent post-implantation infections effective antibiotic prophylaxis might be helpful. The suitability of this hydro gel consisting of a co-polymer of N-vinyl-pyrolidone and methyl-methacrylate as a drug delivery system for antibiotics was investigated in a laboratory setting simulating the orbit in a newborn. Methods: In a first setting the dry expanders were incubated in a 0.3% solution (5 ml) of tobramycin and ofloxacin for 24 h (n = 10 for each substance, adsorbing 2.4 ml of the 0.3% solution, i.e. 7,200 μg antibiotic). Addressing the release of both antibiotics, the concentrations in 15 ml elution medium (0.9% sodium chloride, renewed after every sampling) were measured after 0.25, 1, 2, 6, 24, 48 and 72 h of elution. To simulate the clinical use in a second setting the expanders were dried after incubation in a 0.3% and 0.03% solution of tobramycin (n = 5 for each concentration) before measuring the release. Results: The cumulative amount of tobramycin released after 72 h reached 7,157 μg, i.e. 99% of the initially loaded antibiotic. The cumulatively released amount of ofloxacin was 5,505 μg (76% of loading dose). Main fraction of release (about two thirds) was detected for both antibiotics for a elution period 0 – 24 h. In the periods 24 – 48 and 48 – 72 h the released amount of tobramycin was significantly higher than for ofloxacin. The release from expander dried after loading tobramycin was comparable: The cumulatively released amount of 0.3% and 0.03% incubation solution was 99% and 79% of loading dose, respectively. Conclusions: The investigated hydro gel expanders soaked in antibiotic solution can store and further on release sufficient amounts of tobramycin or ofloxacin to produce antimicrobial effective concentrations in vitro in the surrounding environment according to the breakpoints reported by EUCAST [14]. This principle, when used in a clinical setting, might help to eliminate post-implantation infection, which is one of the major complications in clinical use.Correspondence to:
Dr. R. Wacke
Institute of Clinical Pharmacology
Center of Pharmacology and Toxicology
University of Rostock
Schillingallee 70, 18057 Rostock, Germany
Email: rainer.wacke@med.uni-rostock.de
Original Research
Factors influencing carbamazepine pharmacokinetics in children and adults: population pharmacokinetic analysis
J.R. Milovanovic and S.M. Jankovic
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 7/2011 (428-436)
Factors influencing carbamazepine pharmacokinetics in children and adults: population pharmacokinetic analysis
J.R. Milovanovic and S.M. Jankovic
Department of Pharmacology, Medical Faculty, University of Kragujevac, Kragujevac, Serbia
Objective: The aim of the present study was to build population pharmacokinetic models for the clearance of carbamazepine (CBZ) in two separate populations of Serbian patients with epilepsy, children and adults. Methods: Analysis was performed using 114 and 53 steady-state concentrations of CBZ collected from 98 children and 53 adult epileptic patients, respectively. Mean values of total body weight and age were 31 ±13 kg and 8 ± 3 years in the population of children, and 67 ± 13 kg and 32 ±15 years in the population of adults. The one-compartment model with first order elimination and without absorption was used from the PREDPP (Prediction for Observation Population Pharmacokinetics) library of NONMEM software. Results: The derived final models of CBZ clearance were similar in the target populations. The most important factors which affected typical mean value of CBZ clearance in both populations studied were age of the patients and total daily dose; the CBZ clearance linearly followed increase of these factors. However, the influence of the patients’ age was almost 3.4 times higher in the pediatric population than that in adults while the influence of total daily dose of CBZ is similar. On the other hand, final model in the adult population revealed also influence of concomitant therapy with phenobarbital (PB). The magnitude of this effect was +1.61 l h–1. The pharmacokinetic models obtained were validated in groups of 18 children and 13 adults with epilepsy. Conclusions: The derived models describe well CBZ clearance in terms of Serbian pediatric and adult epileptic patient characteristics, offering a basis for rational individualization of CBZ dosage regimens.Correspondence to:
J.R. Milovanovic
Department of Pharmacology
Medical Faculty, University in Kragujevac
34000 Kragujevac, Serbia
Email: Jasminamilo@yahoo.com
Original Research
Hyponatremia associated with selective serotonin reuptake inhibitors, mirtazapine, and venlafaxine in Korean patients with major depressive disorder
Y.-E. Jung, T.-Y. Jun, K.-S. Kim and W.-M. Bahk
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 7/2011 (437-443)
Hyponatremia associated with selective serotonin reuptake inhibitors, mirtazapine, and venlafaxine in Korean patients with major depressive disorder
Y.-E. Jung, T.-Y. Jun, K.-S. Kim and W.-M. Bahk
Department of Psychiatry, The Catholic University of Korea, College of Medicine, Seoul, Korea
Objective: Several reports of hyponatremia associated with the use of antidepressants such as selective serotonin reuptake inhibitors (SSRIs) have been published. This study compared the incidence of hyponatremia associated with SSRIs to that associated with mirtazapine and with venlafaxine in patients with major depressive disorder (MDD). Material and methods: This retrospective study examined MDD in patients treated with an antidepressant over at least 4 weeks. Using medical records of 93 patients treated with an SSRI (paroxetine, sertraline, escitalopram, and fluoxetine), 76 patients treated with mirtazapine, and 71 patients treated with venlafaxine, we analyzed demographic variables and changes in serum sodium levels (at baseline and Week 4). Results: Eight SSRIs group patients (8.6%) and three venlafaxine group patients (4.2%) exhibited mild hyponatremia during the study period. The SSRIs group’s serum sodium level decreased only slightly, but significantly during treatment; however serum sodium levels in the mirtazapine and venlafaxine groups did not change significantly. The risk of developing hyponatremia while on an SSRI was greater in elderly subjects (60 years and older). Conclusion: These results indicate that, among patients with MDD, SSRIs treatment may be associated with decreased serum sodium levels, and the elderly patients are at greater risk for hyponatremia. Further prospective studies would help clarify the relative risks of hyponatremia among various antidepressants.Correspondence to:
W.-M. Bahk, MD, PhD
Department of Psychiatry
Yeouido St. Mary’s Hospital
The Catholic University of Korea
College of Medicine
62, Yeouido-dong, Youngdeungpogu
Seoul, 150-713, Korea
Email: wmbahk@catholic.ac.kr
Original Research
Pharmacokinetic-pharmacodynamic equivalence of three gliclazide formulations in healthy human male subjects
A. Samad, N. Saha, T. Monif, P.L. Sharma and K.K. Pillai
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 7/2011 (444-450)
Pharmacokinetic-pharmacodynamic equivalence of three gliclazide formulations in healthy human male subjects
A. Samad1, N. Saha2, T. Monif3, P.L. Sharma1 and K.K. Pillai1
1Department of Pharmaceutical Medicine, Faculty of Pharmacy, Hamdard University, 2Clinical Pharmacology Unit, Ranbaxy Research Laboratories, Majeedia Hospital, Hamdard Nagar, New Delhi, and 3Clinical Pharmacology and Pharmacokinetcs, Ranbaxy Research Laboratories, Haryana, India
Aims: To find out the pharmacokinetic (PK) and pharmacodynamic (PD) parameters for assessing the bioequivalence of three marketed products. To study the relationship between the pharmacokinetics of gliclazide and pharmacodynamic effect in healthy male volunteers. Methods: This was an open label, balanced, randomized, 3-treatment, 3-sequence, 3 period, single-dose, cross-over bioavailability study in which 18 healthy adults were randomized to receive gliclazide 80 mg with 7 days wash out between treatments. The drug was administered with 240 ml of 20% glucose solution after a 10 h overnight fasting. Pharmacokinetic parameters like tmax, Cmax, AUC0–t, AUC0–∞, AUC0–t / AUC0–∞ and t1/2 and pharmacodynamic parameters like maximum effect (minimum glucose level in the body, Cminglu), time to minimum glucose level in the body (Tcminglu) and partial AUC were calculated for all the products. Results: The values for mean ± SD for age, height and weight of the volunteers were 28.00 ± 22.68, 165.78 ± 5.56 and 56.78 ± 13.37 respectively. There were total 4 withdrawn subjects and 1 drop out. Within batch accuracy of the method were in the range of 95.5 – 101.7%, 99.1 – 106.1% and 96.2 – 104.2% for three consecutive batches. The 90% CI for log transformed data of the PK and PD were within the acceptance range of 80.0 – 125.0%. Conclusions: This population PKPD analysis has characterized the relationship between the exposure to gliclazide and its hypoglycemic effect. The test products A & B compared to reference product R were bioequivalent on the basis of pharmacokinetic and pharmacodynamic parameters. Finally it is recommended that the more costly product R can be safely switched with less costly products i.e. A and B.Correspondence to:
A. Samad
Department of Pharmaceutical Medicine
Faculty of Pharmacy
Hamdard University
Hamdard Nagar, New Delhi, 110062 India
Email: samadpharma@yahoo.com
Original Research
Study investigating pharmacokinetic interaction between theophylline and roflumilast in healthy adults
G. Böhmer, C.H. Gleiter, A. Hünnemeyer, G. Lahu and T.D. Bethke
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 7/2011 (451-460)
Study investigating pharmacokinetic interaction between theophylline and roflumilast in healthy adults
G. Böhmer1, C.H. Gleiter1, A. Hünnemeyer2, G. Lahu2 and T.D. Bethke2
1Department of Clinical Pharmacology, University of Tübingen, Tübingen, and 2Nycomed GmbH, Konstanz, Germany
Objective: To investigate whether a pharmacokinetic drug-drug interaction exists between theophylline (THEO), a CYP1A2 substrate with a narrow therapeutic index, and the concomitant substrate roflumilast (ROF), a novel selective PDE4 inhibitor partially metabolized by CYP1A2. Materials and methods: In an open-label, 2-period, crossover study, Treatment A (oral ROF 500 μg q.d. on Days 6 – 10 in addition to oral THEO 375 mg b.i.d. on Days 1 – 10) and treatment B (oral ROF 500 μg q.d. on Days 1 – 5) were administered consecutively in random order to each of 24 healthy adult subjects. Both periods were separated by a wash-out phase of at least 10 days. Plasma samples for pharmacokinetic evaluation (AUC, Cmax, t1/2, tmax) including percent peak-trough fluctuation (%PTF) of THEO were taken. Point estimates and the 90% confidence interval of the geometric mean ratios were calculated for AUC and Cmax and descriptive statistics for other pharmacokinetic parameters. Results: Concomitant administration of ROF did not alter pharmacokinetics of THEO. With coadministered THEO, only steady-state total exposure to ROF (AUC) was increased by 28% whereas other pharmacokinetic parameters (t1/2, Cmax, tmax) of ROF and of the active metabolite roflumilast-N-oxide (R-NO), its main contributor to the pharmacodynamic effects, remained unchanged. Conclusions: Neither ROF nor its main metabolite had any impact on the metabolism of the concomitant CYP1A2 substrate THEO in humans. Though co-administration of THEO resulted in a minor increase (28%) in total ROF exposure, no safety or tolerability concerns and no altered total PDE4 inhibition of both ROF and R-NO, were observed.Correspondence to:
Dr. T.D. Bethke
Nycomed Deutschland GmbH
Moltkestrasse 4
78467 Konstanz, Germany
Email: thomas.bethke@nycomed.com
Case Report and Literature review
Successful treatment of erlotinib-induced acute hepatitis and acute interstitial pneumonitis with high-dose corticosteroid: a case report and literature review
Y.-C. Lai, P.-C. Lin, J.-I. Lai, S.-Y. Hsu, L.-C. Kuo, S.-C. Chang and W.-S. Wang
Abstract
In ter na tional Jour nal of Clin i cal Phar ma col ogy and Ther a peu tics, Vol. 49 – No. 7/2011 (461-466)
Successful treatment of erlotinib-induced acute hepatitis and acute interstitial pneumonitis with high-dose corticosteroid: a case report and literature review
Y.-C. Lai1, P.-C. Lin1, J.-I. Lai1, S.-Y. Hsu2, L.-C. Kuo1, S.-C. Chang1 and W.-S. Wang1,3
1Department of Medicine, National Yang-Ming University Hospital, 2Kaohsiung Medical University, and 3Associate Professor and Director of Department of Medicine, National Yang-Ming University Hospital, Yilan, Taiwan, China
Erlotinib, a kind of epidermal growth factor receptor tyrosine kinase inhibitor, is a target therapy and approved for the treatment of metastatic non-small cell lung cancer (NSCLC) and advanced pancreatic cancer. Among these EGFR-TKI agents, including gefitinib and erlotinib, the common dose-limiting toxicities are diarrhea, mucositis and skin rash (Acneform eruptions). In addition to the above adverse effects, infrequent but potentially fatal and lethal entity complications include acute interstitial lung disease (ILD) and acute hepatitis. The incidence of EGFR-TKI agents (gefitinib and erlotinib) induced acute hepatitis is rare and hepatotoxicity of EGFR-TKI agent was rarely discussed. The treatment of EGFR-TKI agents induced acute hepatitis remains uncertain and cessation medication is current policy. Here we reported a case of erlotinib induced interstitial pneumonitis and acute hepatitis with clinical appearance of hypoxemia and general weakness, treated with high dose pulse therapy and showed good recovery.Correspondence to:
Dr. P.-C. Lin
Department of Internal Medicine
National Yang-Ming University Hospital, No.152
Xin-Min Road, Yilan City 260, Taiwan
Email: nicklin1103tw@yahoo.com.tw
Letter to the Editor
Silymarin as a potential novel addition to the limited anti-vitiligo weaponry: an untested hypothesis
A Feily1 and M.R. Namazi2
Abstract
Int. J. of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 7/2011 – Letter to the editor
Silymarin as a potential novel addition to the limited anti-vitiligo weaponry: an untested hypothesis
A Feily and M.R. Namazi
1Department of Dermatology, Jundishapur University of Medical Sciences, Ahvaz, and 2Shiraz skin research center, Shiraz University of Medical Sciences, Shiraz, Iran
Correspondence to:
M.R. Namazi
Assistant Professor of Dermatolog
Setad Street
Faghihi Hospital
Department of Dermatology, Shiraz, Iran
Email: namazi_mr@yahoo.com
Bioavailability Section
Solid state NMR and bioequivalence comparison of the pharmacokinetic parameters of two formulations of clindamycin
Z.A. Al-Talla, S.H. Akrawi and A.-H.M. Emwas
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 7/2011 (469-476)
Solid state NMR and bioequivalence comparison of the pharmacokinetic parameters of two formulations of clindamycin
Z.A. Al-Talla1, S.H. Akrawi2 and A.-H.M. Emwas3
1Analytical Core Lab, King Abdullah University of Science and Technology, KAUST, Thuwal, Kingdom of Saudi Arabia, 2College of Pharmacy, Al-Ain University, Al-Ain, United Arabs Emirates, and 3NMR Core Lab, King Abdullah University of Science and Technology, KAUST, Thuwal, Kingdom of Saudi Arabia
Objective: The purpose of this study was to compare the pharmacokinetic parameters and determine the bioequivalence of a generic formulation of clindamycin that is sold in the local markets in the Middle East (Clindox® 150 mg capsule; test) with a reference formulation (Dalacin C® 150 mg capsule) in healthy adult male volunteers. Methods: A single-dose, open-label, 2-period crossover study was conducted. Healthy male volunteers were randomly assigned to oral administration of a single treatment of the reference and test formulations. The same groups were given the alternate formulation. After dosing, serial blood samples were withdrawn for a period of 24 h. Serum harvested from the blood samples was analyzed for clindamycin by high performance liquid chromatography (HPLC) with ultraviolet detection. Pharmacokinetic parameters, including AUC0–∞, AUC0–t, Cmax, Ke, tmax and t1/2 were determined from the serum concentrations for both formulations (test and reference). The products were tested for bioequivalence after log-transformation of the data. Results: 24 healthy adult male volunteers from Jordan (mean [SD] age, 28.8 (7.7) years (range 19 – 45 years); height, 175.8 (10.6) cm (range 159.0 – 192.0 cm); weight, 75.6 (11.0) kg (range 58 – 101 kg); and body mass index, 24.4 (1.8) kg/m2 (range 21.3 – 28 kg/m2)) were enrolled in and completed the study. The 13C NMR spectra for both Dalacin C® and Clindox® showed 18 distinct lines associated with the 18 different carbon atoms. Conclusion: The statistical comparison suggested that Clindox® capsules are bioequivalent to Dalacin C® capsules. The 13C CPMAS results confirmed that the two drugs exhibit typical clindamycin spectra.Correspondence to:
Z.A. Al-Talla, PhD
Analytical Chemistry and NMR Core Labs
King Abdulla University of Science and Technology
KAUST, Thuwal 23955-6900
Kingdom of Saudi-Arabia
Email: zeyad.talla@kaust.edu.sa
