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Abstract

K. Riemann, L. Becker, H. Struwe, H. Rübben, A. Eisenhardt and W. Siffert

¹Institute of Pharmacogenetics, ²Department of Urology, University Hospital Essen, Essen, Germany
Objective: Bladder cancer is a leading cause of morbidity and mortality. Despite intensive research efforts, histopathological diagnosis of grade and stage, the most important markers for predicting the outcome of the disease, is still necessary. Therefore, a new candidate gene was investigated with regard to its potential utility as a prognostic marker for the course of disease in bladder cancer. A functional insertion/deletion polymorphism has recently been identified in the promoter region of NFKB1 which regulates transcription of the transcription factor NF-(kappa)B. Several genes involved in oncogenic processes are controlled by NF-(kappa)B and might be influenced by alterations in its expression. Material and methods: Genotype distributions in patients with bladder cancer (n = 242), in a subgroup consisting only of patients with superficial bladder cancer (n = 101, stage pTa and pT1) and in a group of healthy control subjects (n = 307) were determined using pyrosequencing. The results were compared and the relationship between genotype and survival, and genotype and first recurrence were determined. NFKB1 expression was assessed using native tumor tissue and quantitative real-time PCR. Results: No statistically significant differences in genotype frequency between healthy controls and patients were detected. Survival was not dependent on the genotype of the polymorphism. Nevertheless, time to first recurrence differed significantly between genotypes (p = 0.037) and this difference could be ascribed to the patients with superficial tumors (p = 0.013). Moreover, multivariate analysis showed that this promoter variant was an independent risk factor. The risk of recurrence in patients with superficial tumors and the homozygous deletion was higher (HR 2.86, p = 0.005) than in those with the homozygous insertion. NFKB1 mRNA expression was highest in tumors from patients carrying the homozygous insertion genotype (p = 0.038). Conclusion: These results suggest that the NFKB1 promoter polymorphism is a useful marker for the identification of patients with superficial bladder cancer where the risk of recurrence is high.Correspondence to:
Dr. rer. nat. K. Riemann Institute of Pharmacogenetics University Hospital Essen Hufelandstraße 55 45147 Essen, Germany
Email: kathrin.riemann@uk-essen.de

Abstract

J. Rengelshausen, C. Göggelmann, J. Burhenne, K.-D. Riedel, G. Mikus, I. Walter-Sack and W.E. Haefeli

Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany
Objective: Urinary caffeine metabolic ratios used to quantify the activity of numerous drug-metabolizing enzymes are an established component of cocktail approaches for metabolic phenotyping. Because in vitro evidence suggests that 1-methylxanthine (1-MX), a major caffeine metabolite, is actively secreted into urine by organic anion transporters (hOATs), coadministration of renal hOAT inhibitors like probenecid may impair these procedures. Methods: In a randomized, placebo-controlled, double-blind crossover design, single oral doses of 300 mg caffeine with oral coadministration of placebo or 500 mg probenecid 3 times daily for 2 days were administered to 7 healthy men. The plasma and urine concentrations of caffeine and its major metabolites 1,7-dimethylxanthine (1,7-DMX) and 1-MX were determined by high-performance liquid chromatography. Results: Coadministration of probenecid resulted in a 34% reduction of the renal clearance of 1-MX (mean ± SD 190 ± 42 versus 290 ± 83 ml min–1, 95% CI on difference 0.2, 200, p = 0.04) with a 41% reduction in its estimated non-glomerular clearance. The renal clearances of caffeine and 1,7-DMX and the area under the plasma concentration-time curves of all substances were not significantly changed. Conclusions: 1-MX undergoes renal tubular secretion which is substantially reduced by probenecid, possibly due to inhibition of renal hOATs. This inhibition may explain the influence of probenecid on urinary caffeine metabolic ratios and, thus, its impact on the assessment of enzyme activities. It also suggests that 1-MX might serve as a model substrate for the renal tubular transport of organic anions.
Correspondence to:
W.E. Haefeli, MD
Department of Internal Medicine VI
Clinical Pharmacology and Pharmacoepidemiology
University of Heidelberg
Im Neuenheimer Feld 410
69120 Heidelberg, Germany
Email: walter.emil.haefeli@med.uni-heidelberg.de

Abstract

P. Lansky, P. Sanda and M. Weiss

¹Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic, ²Section Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, Halle, Germany
Objective: To evaluate the consequences for antibiotic efficacy of different types of poor adherence to a short-term dosing regimen. Ciprofloxacin was taken as an example. Method: A simulation study on a 2-compartment pharmacokinetic model and parameter estimates taken from the literature was performed. Two empirical efficacy measures as well as a specific pharmacodynamic model of the bacterial kill curve were used. Four patterns of non-adherence were investigated: dosage omission, irregular dosing intervals, delayed dosing and treatment discontinuation. Results: Errors in timing of doses with a standard deviation less than 2 h had a minor effect on antibiotic efficacy. Dosage omission, in contrast, has a significant influence on the antibacterial effect of ciprofloxacin. Conclusions: non-adherence patterns are difficult to measure experimentally, thus, recommended dosing regimens should be sufficiently robust against most of the nonintentional disturbances.Correspondence to:
P. Lansky Institute of Physiology Academy of Sciences of the Czech Republic Videnska 1083, 142 20 Prague 4, Czech Republic
Email: lansky@biomed.cas.cz

Abstract

ABSTRACT R.M. Menon, M.H. Adams, M.A. González, D.S. Tolbert, J.H. Leu and E.A. Cefali

¹Kos Pharmaceuticals, Weston, ²MH Adams and Associates, Davie, ³P’Kinetics, International, Pembroke Pines, FL, USA
Objective: To characterize plasma and urine pharmacokinetics of niacin and its metabolites after oral administration of 2,000 mg of extended-release (ER) niacin in healthy male volunteers. Methods: Niacin ER was administered to 12 healthy male subjects following a low-fat snack. Plasma was collected for 12 h post dose and was analyzed for niacin, nicotinuric acid (NUA), nicotinamide (NAM) and nicotinamide-N-oxide (NNO). Urine was collected for 96 h post dose and analyzed for niacin and its metabolites, NUA, NAM, NNO, N-methylnicotinamide (MNA) and N-methyl-2-pyridone-5-carboxamide (2PY). Results: Mean niacin Cmax and AUC0-t values were 9.3 µg/ml and 26.2 µg × h/ml and were the highest of all analytes measured. Peak niacin and NUA levels occurred at 4.6 h (median) while tmax for NAM and NNO were 8.6 and 11.1 h, respectively. The mean plasma terminal half-life for niacin (0.9 h) and NUA (1.3 h) was shorter as compared to NAM (4.3 h). Urine recovery of niacin and metabolites accounted for 69.5% of the administered dose; only 3.2% was excreted as niacin. The highest recovery was for 2PY (37.9%), followed by MNA (16.0%) and NUA (11.6%). Mean half-lives for 2PY and MNA calculated in urine were 12.6 and 12.8 h, respectively. Conclusions: Niacin was extensively metabolized following oral administration, and about 70% of the administered dose is recovered in urine in 96 h as niacin, NUA, MNA, NNO, NAM and 2PY. The plasma levels of the parent niacin were higher than its metabolites though only about 3% of the unchanged drug is recovered in urine.Correspondence to:
R.M. Menon, PhD Kos Pharmaceuticals, Inc. 2100 North Commerce Parkway, Suite 300 Weston, FL 33326, USA
Email: menonrm2000@gmail.com

Abstract

B.S.W. Chan, M.W. Tsang, V.W.Y. Lee and K.K.C. Lee

¹School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China, and ²Department of Medicine and Geriatrics, United Christian Hospital, Hong Kong, China
Objective: Hong Kong (HK) is a special administrative region of China as well as being a metropolitan city. In HK, like in many developed countries, Diabetes mellitus, with over 97% of diabetic patients having Type 2 Diabetes mellitus (Type 2 DM), is a growing public health problem but the local financial burden has never been investigated. The primary objectives of this study were to evaluate from the social perspective the costs of Type 2 DM, to identify the major cost drivers, and the proportion of the burden shared by the government, patient and the society. The study was carried out in a group of Hong Kong Chinese patients attending a government hospital. The economic impact of Type 2 DM on local and governmental healthcare expenditure was also examined. Methods: A retrospective cohort observational study was conducted in Type 2 DM patients attending the Diabetes Mellitus Outpatient Clinic at a public hospital in the period January 2004 to May 2004, in which 204 patients were randomly selected and invited to join this study. A total of 147 patients were subsequently enrolled giving an inclusion rate of 72%. Results: Annual total cost of Type 2 DM in a patient was US$ 1,725 ± 2,044 (HK$ 13,457 ± 15,943) with direct costs accounting for > 87.9%. The government was the major payer with over 78.4% of the total costs. Annual total direct medical costs per patient were US$ 1,492 ± 1,716 (HK$ 11,638 ± 13,386) of which the government paid 90.6%. Direct medical costs increased markedly if complications were present. In patients with microvascular or macrovascular complications only, the costs increased 1.1-fold compared to those for patients without complications. If both microvascular and macrovascular complications were present in the same patient, the costs were 1.3-fold higher than in patients without complications. Conclusion: Costs of Type 2 DM have a significant impact on the local healthcare budget. It contributed in 2004 up to 3.9% of the total HK healthcare expenditure and 6.4% of the HK Hospital Authority’s (public sector) expenditures on health.Correspondence to:
B.S.W. Chan, BSc, MPhil
School of Pharmacy
Faculty of Medicine
The Chinese University Hospital of Hong Kong
Hong Kong, China
Email: bonnyswchan@yahoo.com.hk

Abstract

T. Monif, S.K. Tippabhotla, M. Garg and A.K. Singla

¹Department of Clinical Pharmacology and Pharmacokinetics,
²Department of Product Development and Research, Ranbaxy Laboratories, Gurgaon, Haryana, India
Purpose: The aim of this study was to compare the single-dose oral bioavailability of two formulations of stavudine 40 mg capsules in healthy human subjects. Methods: A bioequivalence study of two oral capsule formulations of 40 mg stavudine was carried out in 40 healthy volunteers following a single-dose, 2-sequence, crossover and randomized design. The two formulations were stavudine 40 mg capsules (Ranbaxy Laboratories Ltd., Haryana, India) as test and zerit 40 mg capsules (Bristol-Myers Squibb, Princeton, NJ, USA) as reference product. Test and reference capsules were administered to each subject in each period separated by a 3-day washout period. Serial blood samples were collected for a period of 10 h. Blood plasma was analyzed for stavudine using a sensitive, reproducible, accurate and validated LC-MS/MS method. Pharmacokinetic parameters, including AUC0-t, AUC0-inf, Cmax, tmax, t1/2 and (Lambda)z, were determined from plasma concentrations for both formulations. AUC0-t, AUC0-inf and Cmax were tested for bioequivalence after log-transformation of data. Results: The LC-MS/MS method, used to quantify stavudine in human plasma, was specific and sensitive for stavudine. Plasma concentration profiles of stavudine test and reference treatments were similar. Geometric mean ratios and 90% confidence intervals for Cmax, AUC0-t and AUC0-inf for stavudine were 99.9 (93.9 – 106), 99.9 (98.4 – 101) and 99.8 (98.2 – 101), respectively. Untransformed results for the same parameters were consistent with the natural log-transformed data. Conclusion: The two stavudine 40 mg capsule formulations examined were bioequivalent and may be used interchangeably in medical practice.Correspondence to:
T. Monif, PhD
Department of Clinical Pharmacology and Pharmacokinetics
Ranbaxy Laboratories Ltd.
Plot No. 20, Sector-18
Udyog Vihar Industrial Area
Gurgaon 122 001, Haryana, India
Email: tausif.monif@ranbaxy.com

Abstract

I. Kilic, I. Cakaloz and E. Atalay

¹Department of Pediatrics and ²Department of Biophysics, Pamukkale University, Faculty of Medicine, Denizli, Turkey
Correspondence to:
I. Kilic Professor of Pediatrics Division of Neonatology Pamukkale University Faculty of Medicine Denizli, Turkey
Email: iakilic@superonline.com

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Volume 45, No. 8/2007(August)