Volume 39, No. 8/2001(August)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Hypertension
Semipersonalized psychological evaluation of quality of life in hypertensive patients during a trial with two calcium antagonists: a multicenter Latin-American Study (LASTLHY)
M. Velasco, E. Lezama, R. Hernández-Hernández, M.J. Armas-Hernández, M.C. Armas-Padilla, L. Alcocer and A. Reyes
Abstract
M. Velasco1, E. Lezama1, R. Hernández-Hernández2, M.J. Armas-Hernández2, M.C. Armas-Padilla2, L. Alcocer3 and A. Reyes4
1Clinical Pharmacology Unit, Vargas Hospital and Department of Pharmacology, Vargas School of Medicine, Central University of Venezuela, Caracas 2Clinical Pharmacology Unit, School of Medicine, Universidad Centroccidental “Lisandro Alvarado”, Barquisimeto, Venezuela, 3Universidad Nacional Autónoma de Mexico, Servicio de Cardiología, Mexico, DF, and 4Instituto de Cardiología Teórica, Montevideo, Uruguay
Objective: The main objective of this study was to evaluate well-being and physical activity of 248 hypertensive patients, including 177 females, who had previously been included in the Latin-American Study on Lacidipine in Hypertension (LASTLHY). Subjects, materials and methods: This open study was carried out in 12 clinical centers in Argentina, Brazil, Colombia, Mexico and Venezuela, to compare, over a period of 16 weeks, the antihypertensive action of a fixed-dose, once daily of 4 mg lacidipine administered orally to 120 patients and 30 mg nifedipine GITS (Gastro-Intestinal Therapeutic System) administered to 128 patients, aged between 40 and 65 years. All patients had mild to moderate hypertension and treatment was begun at the end of a one-week placebo run-in period (end of week –1). Well-being and physical activity were assessed by means of single questionnaire, which reflected the physical and cultural diversities amongst the clinical centers and patients. The questionnaire included 13 multiple-choice and 8 contingent open questions. The score of each question was multiplied by a coefficient related to the importance of each question to the patient (semipersonalization); the coefficient was obtained from cultural and socioeconomic data collected at the time of enrollment. The semipersonalization was carried out by a blind psychological study with respect to the medication and had a high repeatability in the assignment of personalized coefficients to the score of each question. The scores of each question were added to obtain an overall well-being and activity scoring. The possible theoretical range for the overall scoring in this study was 10 – 124. Results: See Table 1. Conclusion: The study revealed that the administration of calcium channel blockers such as lacidipine and nifedipine GITS, and lacidipine in particular, produced low incidence of side effects, and lacidipine in particular induced significant improvement in the quality of life.Correspondence to:
Prof. Dr. M. Velasco; Apartado Postal 76333, El Marqués, Caracas 1070 A, Venezuela
Email: veloscom@cantv.net or mvelasco@reacciun.ve
Hypertension
Blood pressure reduction and tolerability of amlodipine versus nifedipine retard in Chinese patients with Type 2 diabetes mellitus and hypertension: a randomized 1-year clinical trial
G.T.C. Ko, H.C.K. Chan and C.H.S. Chan
Abstract
G.T.C. Ko, H.C.K. Chan and C.H.S. Chan
Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong
Objective: In this 1-year clinical study, we compared the efficacy and tolerability of amlodipine and nifedipine retard in 64 Chinese Type 2 diabetic patients with hypertension. Subjects and methods: There were 25 (39.1%) men and 39 (60.9%) women with mean age 60.7 ± 9.9 years. Thirty-four patients were randomized to receive amlodipine 5 mg daily and 30 to receive nifedipine retard 20 mg twice daily. The daily dose of amlodipine and nifedipine retard was increased from 5 mg to 10 mg daily and 20 mg to 40 mg twice daily, respectively, if sitting BP > 140/90 mmHg. Results: Of the 64 patients, 9 dropped out early because they experienced adverse effects related to the drugs. If all treatment-related adverse effects were taken into account, 6 (19.4%) patients were from the amlodipine group and 14 (53.8%) from the nifedipine group (p = 0.011). After 1 year, 48 patients finished the study, 28 were on amlodipine and 20 were on nifedipine retard. Of the 28 patients from the amlodipine group, 11 (39.3%) required additional anti-hypertensive agents. Of the 20 patients from the nifedipine group, 5 (25%, p value: NS, comparing the 2 groups) required additional antihypertensive agents. Both groups showed similar and significant reduction in blood pressure from Week 6 to Week 52. Conclusion: Both amlodipine and nifedipine retard are relatively safe and useful in the treatment of hypertension in Chinese Type 2 diabetic patients. Nifedipine retard, when compared to amlodipine, showed significantly more adverse effects and these may hamper long-term compliance.Correspondence to:
Dr. G.T.C. Ko; Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, 11, Chuen On Road, Tai Po, Hong Kong
Email: gtc_ko@hotmail.com
Adverse drug reactions
Adverse drug reaction monitoring – digitoxin overdosage in the elderly
M. Hippius, B. Humaid, T. Sicker, A. Hoffmann, M. Göttler and J. Hasford
Abstract
M. Hippius1, B. Humaid1, T. Sicker1, A. Hoffmann1, M. Göttler2 and J. Hasford2
1Department of Clinical Pharmacology, Friedrich Schiller University of Jena, and 2Department of Medical Informatics, Biometry and Epidemiology, Pharmacoepidemiology Research Group, Ludwig Maximilians University, Munich
Drug-related illness is an everlasting universal problem and also an important cause of admissions to hospitals. Adverse reactions are still grossly underreported by medical professions. Little information is available regarding the frequency or type of ADRs managed in hospitals. Since January 1997, we have taken part in a study, supported by the German Federal Institute for Drugs and Medical Device to improve the spontaneous drug information reporting system in Germany. Three German regionalized Departments of Clinical Pharmacology – Jena, Dresden, Rostock – serve as Pharmacovigilance Centers in collaboration with the Pharmacoepidemiology Research Group of the University of Munich. Since January 1997, the regional group in Jena has been monitoring the University Clinic of Internal Medicine for admissions caused by adverse drug reactions. All emergency cases and patients on intensive care units were checked for adverse drug reactions. We present our results, including clinical and demographic data, concerning intoxications and especially those involving digitoxin in 210 patients with ADR. Forty patients with digitoxin toxicity had an average age of 81 years (81.1 ± 6.3), a low body weight (59.7 ± 12.7 kg) and 3 out of 4 were women. 75% of all patients with digitoxin side effects had elevated serum digitoxin levels with concentrations higher than 25 mg/ml. The relatively high frequency of digitoxin intoxications in our hospital may reflect the advanced age and low body weight of patients. Patients received digitoxin regardless of age, weight and, sometimes, clinical indication. Physicians should be aware of drugs having a high risk when used in elderly patients. The use of digitoxin assays and keeping serum levels within or near the therapeutic range will diminish the incidence of overdoses.Correspondence to:
Dr. M. Hippius; Department of Clinical Pharmacology, Friedrich Schiller University Jena, Dornburger Straße 159, D-07740 Jena, Germany
Email: Marion.Hippius@med.uni-jena.de
Chemotherapy
Chemical instability and methods for measurement of cisplatin adducts formed by interactions with cysteine and glutathione
O. Heudi, H. Brisset, A. Cailleux and P. Allain
Abstract
O. Heudi, H. Brisset, A. Cailleux and P. Allain
Laboratory of Pharmacology and de Toxicology, University Hospital Center, Angers Cedex, France
Reactions between cisplatin or its aquated species and L-cysteine (L-cys) or glutathione (GSH) were studied in vitro using liquid chromatography on-line with inductively coupled plasma mass spectrometry (LC-ICPMS) and/or electrospray ionization mass spectrometry (LC-MS) in order to obtain information on the mechanisms occurring in treated patients. Reaction between cisplatin and L-cys yielded initially 4 adducts of which only 2 were stable and detectable after 24 hours incubation; their structures corresponded to bis-platinum cysteinyl adducts. Reaction of cisplatin with GSH proceeded via the formation of at least 11 glutathione-platinum adducts (G1 – G11) which underwent parallel reactions within 24 hours of incubation, probably to form higher molecular weight species. Of the 11 adducts, only 2, G3 and G7, whose structures correspond to [Pt(NH3)2Cl]2(SG) and [Pt(NH3)2OH]2(SG) were still present in the reaction mixture after 24 hours incubation. This study shows that GSH, and to a lesser extent L-cys, incubated with cisplatin in vitro forms unstable and reactive platinum compounds and that LC-ICPMS and LC-MS are 2 complementary techniques suitable for the study of organometallic compounds.Correspondence to:
Prof. P. Allain; Laboratoire de Pharmacologie et Toxicologie, Centre Hospitalier Universitaire, 4, rue Larrey, F-49033 Angers Cedex 01, France
Email: Piallain@chu-angers.fr
Bioequivalence
Limits of 80% – 125% for AUC and 70% – 143% for Cmax. What is the impact on bioequivalence studies?
W.W. Hauck, A. Parekh, L.J. Lesko, M.-L. Chen and R.L. Williams
Abstract
W.W. Hauck1, A. Parekh2, L.J. Lesko2, M.-L. Chen3 and R.L. Williams3,4
1Biostatistics Section, Division of Clinical Pharmacology, Thomas Jefferson University, Philadelphia, 2Office of Clinical Pharmacology and Biopharmaceutics, Office of Pharmaceutical Science, 3Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration, and 4US Pharmacopeia, Rockville, MD, USA
Objective: The US Food and Drug Administration (FDA) currently uses bioequivalence (BE) limits for fasting BE studies that are based on the 90% confidence interval for the ratio of difference of the test and reference products Cmax and AUC falling within 80% to 125%. The FDA has also proposed that BE limits be used similarly for AUC and Cmax measurements from fed BE studies. In some cases, regulatory agencies have considered a wider BE limit for Cmax, because of the typically higher variability of Cmax compared to AUC. We investigated the consequences of changing from an 80%/ 125% limit for both pharmacokinetic measures to one that uses a limit of 80%/125% for AUC and 70%/143% for Cmax. Methods: We computed the sample sizes required for BE studies using 80%/ 125% for AUC and 70%/143% for Cmax as BE limits. We also determined the range of the ratios of Cmax and AUC values in a study that could meet the 70%/143% and 80%/125% BE limits. Results: The sample size for the study, in order to have adequate power with 80%/125% for AUC and 70%/143% for Cmax, will be determined primarily by the intrasubject variability of AUC, though with a substantial proportion of studies (about one third) still determined by the variability of Cmax. The ratio of mean Cmax values that can pass a wider 70%/143% BE limit could easily be as high as 128%. Conclusion: Without further scientific or clinical rationale, we find it difficult to justify widening the bioequivalence limit for Cmax to 70%/143% for either fasting or fed BE studies.Correspondence to:
Dr. W.W. Hauck; Biostatistics Section, Division of Clinical Pharmacology, Thomas Jefferson University, 125 South 9th Street, #402, Philadelphia, PA 19107, USA
Email: whauck@lac.jci.tju.edu
Bioequivalence
Bioequivalence of clarithromycin tablet formulations assessed in Korean males
Y.G. Kim, H.J. Kim, J.W. Kwon, W.B. Kim and M.G. Lee
Abstract
Y.G. Kim1, H.J. Kim2, J.W. Kwon2, W.B. Kim2 and M.G. Lee1
1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, and 2Research Laboratory, Dong-A Pharmaceutical Company, Yongin, Korea
Aim: Determination of the bioequivalence of 2 clarithromycin tablet formulations manufactured in Korea. Patients and methods: Twenty-four healthy male Korean volunteers received each of the 2 clarithromycin formulations at a dose of 250 mg in a 2 × 2 crossover study. There was a one-week washout period between doses. Plasma concentrations of clarithromycin were monitored by high-performance liquid chromatography over a period of 12 hours after administration. AUCinf (the area under the plasma concentration-time curve from time zero to time infinity) was calculated using the linear-log trapezoidal method. Cmax (maximum plasma drug concentration) and Tmax (time to reach Cmax) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUCinf and Cmax and untransformed Tmax. Results: The point estimates and 90% confidence intervals for AUCinf (parametric) and Cmax (parametric) were 0.971 (0.886 ~ 1.063) and 0.982 (0.868 ~ 1.107), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration guidelines. The corresponding value of Tmax was 0.000 (–0.250 ~ 0.250). Conclusion: These results indicate that the 2 medications of clarithromycin are bioequivalent and, thus, may be prescribed interchangeably.Correspondence to:
Dr. M.G. Lee; College of Pharmacy, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, Korea
Lifestyle drugs
Party-drugs: Sociocultural and individual background and risks
H. Gerhard
Abstract
H. Gerhard
Beratungszentrum Grünberg, Grünberg, Germany
Since the Nineties there has been an increase in the use of drugs at public and private parties. The consumption as well as the consumers cannot be allocated to precise youth groups or other subcultures as in the past, and the habits of consumption are more differentiated. These aspects reflect general tendencies of social change which lead in the direction of individualization and pluralisation in the way of life. Young people often consume drugs without being conscious that they are practicing something illegal. Drug (ab)use in these cases is an expression of a pleasure- and experience-seeking lifestyle, with problems and pathological patterns among certain groups of consumers. This review traces the causes, the patterns of consumption and the purpose of party-drug(ab)use in an interdisciplinary sociological-psychological analysis. The terms “party-drugs” and “designer-drugs” need to be explained. We will then focus on “Ecstasy”, at present the most common so-called designer drug. The effects of this substance will be described with regard to the (medical/ psychiatric) risks and dangers of consumption. This is followed by a short insight into cultural and historical patterns and tendencies of consumption concerning the (ab)use of illegal drugs during the last 30 years. Psychological considerations on the function of drug (ab)use during adolescent development is the next theme. Finally, we will focus on common environmental aspects (Techno-generation) as well as typical groups of drug (ab)users.Correspondence to:
H. Gerhard, MA; Beratungszentrum Grünberg, Alsfelder Straße 8, 35305 Grünberg, Germany
Email: h.gerhard@t-online.de
