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Abstract

K.-O. Haustein

Institute for Nicotine Research and Smoking Cessation, Erfurt, Germany
Withdrawal treatment of cigarette smokers is a task of the utmost urgency in view of the consequences for national health programs and legislative policies of the high morbidity and mortality rates caused by smoking. Smokers need medical consultation in addition to drug-based treatment, but this results in self-willed quitting of the smoking habit in a limited number of smokers only. From the point of view of the criteria of “evidence-based medicine”, non-drug methods such as hypnosis therapy and acupuncture are not effective (odds ratio = 1.22). Among the drug-based methods, treatment with nicotine substitution preparations has shown confirmed efficacy in numerous studies (odds ratio 1.63 to 2.67, depending on the application form used) and results in successful withdrawal from the smoking habit in 30 – 40% of cases. A decisive problem in the initial therapeutic phase appears to be the amount of the applied nicotine dose, but beyond that can be mastered above all by combining 2 or 3 application forms (patchs, chewing gum, nasal spray). Treatment is then continued for 4 – 12 weeks, depending on the degree of dependence, with successively reduced nicotine dosage. Two controlled studies with disparate designs have been done on bupropion (odds ratio 2.3/3.0). However, further studies are desirable due to concern about undesirable effects of bupropion described recently. Other substances subjected to trials in years past, such as clonidine, lobeline, mecamylamine and antidepressants including buspirone cannot be recommended on the basis of current data for treatment of smokers seeking a withdrawal cure.Correspondence to:
Prof. Dr. K.-O. Haustein; Institute for Nicotine Research and Smoking Cessation, Johannesstraße 85-87, D-99084 Erfurt, Germany

Abstract

N.V. Nagaraja¹, Y.J. Park², S. Jeon², C.D. Sands³ and H. Derendorf¹

¹College of Pharmacy, University of Florida, Gainesville, FL, USA, ²Wallace Memorial Baptist Hospital, Pusan, Korea, and ³McWhorter School of Pharmacy, Samford University, Birmingham
Aim: Digoxin possesses a narrow therapeutic index and shows a large inter-patient pharmacokinetic variability. The purpose of this study was to develop a population model for the pharmacokinetics of digoxin in Korean patients. Methods: Plasma concentrations of digoxin after multiple administration at varying dosing schedules in Korean patients were used for population modeling. Data analysis was performed with the P-Pharm software. The data were best fitted by a one-compartment model. The effect of demographic and clinical factors like sex, age, weight, disease state, and renal function on the pharmacokinetic parameters of digoxin was investigated. Results: The study indicated that the clearance of digoxin was influenced by creatinine clearance, while body weight and creatinine clearance were the covariates for its volume of distribution. The population mean estimates for CL and V were 4.4 l/h and 535 l, respectively. Absorption rate constant was lower in females and in the presence of concomitant drug treatment. Conclusion: A population pharmacokinetic model for the digoxin pharmacokinetics in a section of Korean patients was developed. The relationships between the pharmacokinetic parameters and the demographic data and the patient-specific covariates were established.Correspondence to:
Prof. Dr. H. Derendorf; Department of Pharmaceutics, College of Pharmacy, University of Florida, 1600 SW Archer Road, P. Box 100494, Gainesville, FL-32610-0494, USA

Abstract

W. Mück, R. Frey, S. Unger and B. Voith

Institute of Clinical Pharmacology, Bayer AG, Wuppertal, Germany
Objective: The influence of food and time of drug dosing on the pharmacokinetics of cerivastatin, a potent HMG-CoA reductase inhibitor, was evaluated in 24 healthy male subjects between 21 and 44 years of age. Methods: A single-dose, four-way crossover design was employed, with each subject receiving cerivastatin 0.8 mg at weekly intervals under each of four conditions: 8 a.m. dosing after an overnight fast (reference), 8 a.m. dosing with a high-fat breakfast (test), 6 p.m. dosing with the evening meal (low-fat; test), and 10 p.m. dosing 4 h after dinner (reference). Plasma concentrations of the parent compound and its active metabolites were measured by high performance liquid chromatography with fluorescence detection subsequent to post-column derivatization. Results: The calculated 90% confidence intervals for cerivastatin AUC and Cmax were completely contained within the range 0.8 to 1.25. Thus, no relevant influence of food could be detected, although the presence of food increased the Cmax of cerivastatin on average by 12% (90% confidence interval: 1.04 – 1.21) under morning, but not evening dosing. With respect to the effect of daytime on cerivastatin pharmacokinetics, AUCs were bioequivalent for all treatment conditions, with Cmax values slightly lower (8 – 19%) following evening dosing, irrespective of food intake. Cerivastatin was well tolerated by the subjects in the study. Conclusion: Food effect bioequivalence according to current guidelines could be demonstrated. Cerivastatin can be administered independent of meal intake at dinner or at bedtime, the preferred time of dosing for statins because the rate of hepatic cholesterol synthesis is greatest at night.Correspondence to:
Dr. W. Mück; Institute of Clinical Pharmacology, Bayer AG, Pharma Research Center, Aprather Weg, D-42096 Wuppertal, Germany

Abstract

Y. Ohya, I. Abe, Y. Ohta, U. Onaka, K. Fujii, S. Kagiyama, Y. Fujishima-Nakao and M. Fujishima

Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan
Objective: To evaluate the effect of barnidipine hydrochloride, a long-acting dihydropyridine calcium channel blocker on urinary sodium excretion in patients with essential hypertension. Patients: Twelve patients (2 males, 10 females) with mild to moderate essential hypertension. Methods: A single-blinded study. After the control (placebo) period, 10 to 15 mg barnidipine hydrochloride was administered for 7 days, followed by a post-treatment (placebo) period. Daily changes in blood pressure, urinary volume, and urinary electrolyte excretions were evaluated. Plasma levels of atrial natriuretic peptide (ANP) and aldosterone were also determined in each period. Daily sodium intake was kept at 120 mEq. Results: Blood pressure decreased from 161 ± 4/92 ± 2 mmHg to 146 ± 4/85 ± 2 mmHg (p<0.05) after 7-day-treatment with barnidipine. Barnidipine significantly increased urinary sodium excretion; the change was evident on the first day of administration (control period 41 ± 3 mEq/day, and first day 59 ± 3 mEq/day, p < 0.05). Drug discontinuation transiently decreased sodium excretion to 35 ± 3 mEq/day. Cumulative sodium balance after 7-day-treatment reached –47 ± 19 mEq. Urine volume, potassium excretion, and creatinine excretion did not change during the treatment period. The plasma levels of ANP tended to increase, but those of aldosterone did not change with barnidipine. Conclusion: Barnidipine administration for a week decreased the blood pressure and made the sodium balance negative by increasing the urinary sodium excretion in patients with essential hypertension. The natriuretic effect of this drug could contribute at least in part to its antihypertensive effect.Correspondence to:
Dr. Yusuke Ohya; Second Department of Internal Medicine, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan

Abstract

I. Niopas¹, A.C. Daftsios², I. Xanthakis² and N. Nikolaidis²

¹Department of Pharmacy, School of Health Sciences, Aristotle University of Thessaloniki, and ²Analyses of Pharmaco-Chemical Products, American Farm School of Thessaloniki, Thessaloniki, Greece
Objective: To assess the bioequivalence of two oral formulations containing 10 mg of nifedipine. The test preparation were Macorel tablets, the reference preparation were Adalat tablets. Subjects, material and methods: The study was designed as a single-dose, three-period crossover randomized design to 18 non-smoker, healthy male volunteers under fasting conditions. Seventeen volunteers completed the study. Plasma samples were analyzed for nifedipine by HPLC after solid-phase extraction. The pharmacokinetic parameters used to assess the bioequivalence of the two formulations were AUC0-¥ and AUC0-t for the extent of absorption and Cmax and Tmax for the rate of absorption. Statistical comparisons of AUC0-¥ AUC0-t, and Cmax data were evaluated after logarithmic transformation by two-way analysis of variance (ANOVA), and differences of Tmax were tested non-parametricaly. Results: Point estimates (90% confidence intervals) of the test/reference ratios were 97.4% (87.6% – 108.3%) for AUC0-¥ 97.0% (85.6% – 110.1%) for AUC0-t, and 107.7% (89.1% – 130.7%) for Cmax. No statistically significant difference was found for Tmax and elimination half-life values. Conclusion: Therefore, in accordance with the European Union bioequivalence requirements, the test and reference nifedipine preparations are bioequivalent for both the extent and the rate of absorption.Correspondence to:
Dr. I. Niopas; Department of Pharmacy, School of Health Sciences, Aristotle University of Thessaloniki, GR-54006 Thessaloniki, Greece

Abstract

S. Singh¹, C.K Nain², M. Verma², C.O. Leelamma¹ and R.C. Goel³

¹Department of Internal Medicine, ²Experimental Medicine, and ³Medical Education, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Objective: To determine the activity of aspirin esterases in North-West Indian population and to find the effect of age and nutrition on it. Subjects, material and methods: The serum albumin, plasma cholinesterase (PChE), aspirin esterase (ASPES) and phenyl acetate esterase (PAE) were determined in 175 subjects: young (< 40 years) and healthy (BMI > 19) = 74; elderly (> 50 years) and healthy (BMI > 19) = 32; young (< 40 years) and emaciated (BMI < 19) = 44; elderly (> 50 years) and emaciated (BMI < 19) = 25). Results: The serum albumin levels significantly decreased with increase in age (r = –0.384, p < 0.01) and with decrease in body mass index (r = 0.457, p < 0.01). When the activity of esterases in four groups was compared, the PAE activity was not found to be affected by age or nutrition and the ASPES and PChE activity were significantly lower only in elderly emaciated (p < 0.01). Conclusion: As elderly emaciated have decreased serum albumin, ASPES and PChE activity, they may need a lower dose of aspirin to achieve the desired antiplatelet and analgesic effect. The young emaciated subjects, in spite of their lower serum albumin levels, may not require a lower dose of aspirin.Correspondence to:
Dr. S. Singh; Department of Internal Medicine, Nehru Hospital, 4th Floor, F-Block, Room 16, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India

Abstract

M.N. Gai, A.M. Thielemann and A. Arancibia

Department of Science and Pharmaceutical Technology, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile
Background: Food-induced changes on the bioavailability of a sustained release lithium carbonate matrix tablet, which uses an acrylic matrix of Eudragit RSPM as sustaining agent, have been studied in healthy male volunteers. The tablet was developed in our laboratory using conventional technology. Subjects, materials and methods: The study design was a 4 × 4 Latin square involving 12 subjects who received a single dose of the tablet while fasting or with a standarized normal, high fat or high fat/high protein meal. Results: The results showed no differences in half-lifeb, renal clearance, Vdb, AUC, tmax, , fraction absorbed and MRT. Higher Cmax (mg/l) were obtained when the tablet was administered with any kind of meal: 2.09 ± 0.47 (fast), 2.95 ± 1.04 (normal diet), 2.64 ± 0.54 (high fat diet) and 2.87 ± 0.67 (high fat/high protein diet). The analysis of the ratio Cmax/AUC indicated that changes in Cmax were more probably due to changes in the rate of absorption. To evaluate if the magnitude of the change could be clinically relevant, Cmax and C at 12 hours (dosing interval) were treated by the superposition method in order to establish maximum and minumum concentrations at steady-state. For all the experimental conditions both concentrations would remain in the therapeutic range (4.2 – 10 mg/l or 0.6 – 1.4 mEq/l). Conclusion: The behavior of the formulation is appropriate for a sustained release tablet and fasting or non-fasting state seems not to be a major consideration for bioavailability when deciding on the regimen administration.Correspondence to:
Dra. M.N. Gai; Department of Science and Pharmaceutical Technology, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Avda. Vicu¤a Mackenna 20, Santiago 1, Chile Casilla 233, Santiago 1, Chile

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Volume 38, No. 6/2000(June)