Volume 39, No. 1/2001(January)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Personal View
Evidence based medicine, RCTs and their natural enemies: the clinical pharmacologist’s role
H.-G. Eichler
Review
Antiviral drugs in chronic hepatitis B: review and meta-analysis
M. Malaguarnera, S. Restuccia, L. Ferlito, G. Mazzoleni, I. Giugno and G. Pistone
Abstract
M. Malaguarnera, S. Restuccia, L. Ferlito, G. Mazzoleni, I. Giugno and G. Pistone
Department of Internal Medicine and Geriatrics, University of Catania, Italy
Abstract. Many researchers have attempted to identify the drugs capable of acting on the viral replication cycle and maintaining clinical remission in chronic hepatitis B. We evaluated the efficacy of antiviral drugs in chronic hepatitis B, by examination of 20 controlled and non-controlled trials conducted between 1985 and 1996. In chronic hepatitis B, adenine arabinoside and its monophosphate did not achieve satisfactory results, even though combination therapy with cortisone seemed to achieve very good results (remission rates ranging from 45% to 66% in patients treated). Lamivudine did not seem to furnish lasting effects in chronic hepatitis B, because many patients relapse after suspension of the treatment due to the appearance of HBV variants resistant to the drug. Contrasting results were observed with famciclovir. Treatment of chronic hepatitis B, with this drug seemed capable of reducing HBV-DNA serum levels by a mean of 50% compared to pretreatment values, with normal alanine aminotransferase levels in about 30% of treated patients. Ganciclovir treatment of chronic hepatitis B seemed to furnish good, but transient, results. Even if no antiviral drug represented a valid alternative to interferon, antivirals may become the drugs of choice in chronic hepatitis B, because they are aimed at the etiology of disease.Correspondence to:
Dr. M. Malaguarnera; Institute of Internal Medicine and Geriatrics, University of Catania, Via Messina 829, I-95126 Catania, Italy
Original
Drug-related visits to the medical emergency department: a prospective study from India
S. Malhotra, S. Jain and P. Pandhi
Abstract
S. Malhotra1, S. Jain2 and P. Pandhi1
1Department of Pharmacology, and 2Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Objective: To analyze the contribution of adverse drug events (ADEs) to the overall number of visits to the medical emergency and to determine the proportion of events leading to hospital admissions. Patients and methods: All visits to the medical emergency were recorded in a prospective, non-interventional design study over a period of 8 months. The ADEs were divided into 5 categories: adverse drug reactions (ADRs), drug interactions, patient non-compliance, physician non-compliance, and drug overdose. The cases were then followed-up to assess the prorportion of ADEs lead to hospitaliztion. Results: A total of 4764 patients were included in the study. 5.9% of all visits were considered to be drug-related. The highest percentage of ADEs was observed in the age group less than 20 and more than 80 years. ADRs accounted for 45% of all ADEs, followed by patient non-compliance (28%). Patient and physician non-compliance were the main causes of drug-related hospital admissions. 52% of all ADE-related visits and 55% of ADE-related admissions were considered to be preventable. Non-steroidal anti-inflammatory agents, oral hypoglycemics and antitubercular drugs were responsible for 37% of all ADRs. Non-compliance was mainly seen in hypertensives, asthmatics and epileptics. Conclusion: ADEs account for a sizable proportion of all visits to a medical emergency unit and some are serious enough to require hospitaliztion. A large number of ADE-related visits and admissions are preventable which highlights the importance of public education on the proper use of drugs, and also the need for regulation of the practice of unregistered medical practitioners in developing countries.Correspondence to:
Dr. P. Pandhi; Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
Original
Effect of calcium antagonists on stress- induced rise in blood pressure and heart rate: a double-blind, placebo-controlled study
S. Malhotra, S. Kumari and P. Pandhi
Abstract
S. Malhotra1, S. Kumari2 and P. Pandhi1
1Department of Pharmacology, and 2Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Objective: The current study was designed to evaluate the effect of treatment with calcium antagonists on stress-induced increases in blood pressure and heart rate. Subjects, material and methods: Two models of stress were chosen, cold stress and isometric handgrip exercise. Six healthy volunteers were randomized to receive amlodipine (5 mg), lacidipine (4 mg) for a two-day period in a double-blind, crossover design. Thirty hypertensive patients received the same treatment for a period of one week in a double-blind, parallel design. The effects of stress on blood pressure and heart rate were taken at baseline and after drug treatment. Results: Cold stress and handgrip exercise significantly increased the systolic and diastolic blood pressure as well as the heart rate. In normotensive volunteers, the resting heart rate and blood pressure were not altered by the drugs. The increase in systolic and diastolic blood pressure produced by cold stress and isometric exercise were unchanged by amlodipine and lacidipine. In hypertensive patients, both drugs reduced the resting blood pressure (p < 0.05). As in normotensive individuals, the pressor response to stress was not altered by the drugs. Conclusion: Cold stress and handgrip exercise produced a significant rise in blood pressure and heart rate in normotensive volunteers and patients with hypertension. Cardiovascular reactivity to cold stress and handgrip exercise is not altered by the administration of amlodipine and lacidipine.Correspondence to:
Dr. P. Pandhi; Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
Original
Caffeine metabolism in a group of 67 patients with primary biliary cirrhosis
H. Lelouët, Y.C. Bechtel, G. Paintaud, M.P. Brientini, J.P. Miguet and P.R. Bechtel
Abstract
H. Lelouët1, Y.C. Bechtel1, G. Paintaud2, M.P. Brientini1, J.P. Miguet3 and P.R. Bechtel1
1Pharmacologie Clinique, Faculté de Médecine et de Pharmacie, Besançon, 2Service de Pharmacologie Clinique et de Toxicologie, Hôpital Universitaire, Tours, and 3Service d’Hépatologie, Hôpital Universitaire, Besançon, France
Objective: To evaluate the polygenic regulated caffeine metabolism in a group of 67 patients with a documented primary biliary cirrhosis (PBC) classified according to the histologic stage proposed by Scheuer. Methods: Over a 14-year period, drug liver metabolism, using caffeine as a probe drug, has been systematically carried out in addition to the usual clinical, histological and biochemical investigations performed in patients with PBC. The “Caffeine test” consisted of a 200 mg caffeine oral intake. Urines were collected over 24 hours: caffeine (137X), 1-7-dimethylxanthine (17X), 1-3-dimethylxanthine (13X), 1-3-dimethylurate (13U), 3-7-dimethylxanthine (37X), 1-7-dimethylurate (17U), 1-methylxanthine (1X), 1-methylurate (1U), 7-methylxanthine (7X), 3-methylxanthine (3X), and 5-acetylamino-6-formylamino-3-methyluracyl (AFMU) were analyzed by high performance liquid chromatography (HPLC). Total and individual metabolite urinary elimination rates were expressed in mmol/24 hours. Enzyme activities were evaluated from the following urinary metabolite ratios: (AFMU+1U+1X)/17U for CYP1A2, 17U/ 17X for CYP2A6, AFMU/(AFMU+1U+1X) for NAT-2, 1U/1X for XO. Results: Compared to healthy subjects, patients with PBC presented a reduced metabolism of caffeine due to a decreased CYP1A2 activity, all the more important since the patients had an advanced histological stage. This picture was nearly identical to the observed picture in chronic liver diseases from various origins. PBC affected the various metabolic pathways of caffeine in a differential manner. CYP1A2 activity was decreased but XO and mainly CYP2A6 activities were increased as shown by the raised urinary ratio 17U/total metabolite elimination. In contrast to the described loss of bimodality of the NAT-2 index distribution in patients with alcoholic cirrhosis, we found a clear-cut, bimodal distribution in patients with PBC, without a high incidence of slow acetylator status. Conclusion: Metabolism of caffeine is strongly and differentially disturbed in patients with PBC and apparently not exactly in the same way as that in alcoholic cirrhosis which is more often taken as an index of chronic liver disease. This suggests the need for caution with medicines whose metabolism is under polygenic regulation. Because of the relationships between caffeine metabolism modifications and histological stages, the caffeine test might be used along with the usual tests to safely follow-up the evolution of the disease.Correspondence to:
Prof. Dr. P.R. Bechtel; Pharmacologie Clinique, Faculté de Médecine, Place Saint Jacques, F-25030 Besançon Cédex, France
Original
Piroxicam concentrations in plasma and synovial fluid after a single dose of piroxicam-b-cyclodextrin
B. Bannwarth, P. Bertin, F. Péhourcq, T. Schaeverbeke, P. Gillet, G. Lefrançois, R. Trèves, J. Dehais, P. Netter and A. Gaucher
Abstract
B. Bannwarth1,4, P. Bertin2, F. Péhourcq4, T. Schaeverbeke1, P. Gillet3, G. Lefrançois5, R. Trèves2, J. Dehais1, P. Netter3 and A. Gaucher3
1Rheumatology Departments of Groupe Hospitalier Pellegrin, Bordeaux, 2Hôpital Dupuytren, Limoges, 3CHU Brabois, Vandoeuvre-les-Nancy, 4Equipe d’Accueil 525, Université Victor Segalen, Bordeaux, and 5Laboratoires Promedica-Chiesi, Courbevoie, France
Aims: The efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) in rheumatic diseases depends on their concentrations within the joint. We determined piroxicam concentrations in plasma and synovial fluid (SF) after a single oral dose of 20 mg in the form of one tablet of piroxicam-b-cyclodextrin. Methods: 45 patients, aged 21 to 84 years, presenting with an effusion of the knee, related to degenerative or inflammatory joint disease, were included in this study after having given their written consent. One blood and one SF sample were drawn concomitantly in each patient from 0.5 to 48 h after NSAID administration. Piroxicam assays were performed by high performance liquid chromatography. Pharmacokinetic parameters were obtained from the mean plasma and synovial concentrations measured at various sampling times. Results: The peak concentration was higher in plasma (2.51 ± 0.25 mg/ml) than in SF (1.31 ± 0.76 mg/ml), but the elimination half-life was much longer in SF (90.7 h) than in plasma (32.5 h). The SF/plasma area under the concentration-time curve ratio (evaluating the quantity of NSAID transferred from the blood to the joint) was equal to 0.39. Conclusions: Piroxicam contained in piroxicam-b-cyclodextrin diffused well into the SF where its pharmacokinetic profile corresponded to that of a long half-life NSAID.Correspondence to:
Prof. Dr. B. Bannwarth
Department of Therapeutics, EA 525, Université Victor Segalen, 146, rue Léo Saignat, F-33076 Bordeaux Cedex, France
Original
Estimated coefficient of variation values for sample size planning in bioequivalence studies
K.H. Yuen, J.W. Wong, S.P. Yap and N. Billa
Abstract
K.H. Yuen, J.W. Wong, S.P. Yap and N. Billa
School of Pharmaceutical Sciences, University of Science Malaysia, Penang, Malaysia
Objective: The aim of the present communication is to provide information regarding the intrasubject coefficent of variation obtained from 30 bioequivalence studies covering 16 drugs which can be used for estimation of sample size. Additionally, an attempt was also made to estimate the test power of each of the studies conducted. Methods: The intrasubject coefficient of variation was estimated from the residual mean square error obtained from analysis of variance of the parameters AUC0-¥, Cmax and Cmax/AUC0-¥ after logarithmic transformation. The test power in the analyses of the above parameters was subsequently estimated using nomograms provided by Diletti et al. [1991]. Results and conclusion: Thirty products covering 16 drugs were studied in which 22 were immediate-release (including one dispersible tablet) and 8 were sustained-release formulations. The intrasubject coefficient of variation for the parameter AUC0-¥ was smaller than Cmax, and hence considerably more studies were able to attain a power of greater than 80% using 12 volunteers for the AUC0-¥, compared to the Cmax. However, the variability in the Cmax could be reduced by using the parameter Cmax/ AUC0-¥, and thus, provide a more realistic estimation of sample size, since the latter reflects only the rate of absorption and not both the rate and extent as in the case of Cmax [Endrenyi et al. 1991].Correspondence to:
Dr. K.H. Yuen; School of Pharmaceutical Sciences, University of Sciences Malaysia, 11800 Penang, Malaysia
Original
Bioequivalence and relative bioavailability of three estradiol and norethisterone acetate-containing hormone replacement therapy tablets
M. Zdravkovic, M. Müller, S. Larsen, J. Degenkolb and G. Pabst
Abstract
M. Zdravkovic1, M. Müller2, S. Larsen3, J. Degenkolb4 and G. Pabst2
1Department of Clinical Pharmacology, Novo Nordisk A/S, Bagsvaerd, Denmark, 2AAI Deutschland GmbH and Co KG, Neu-Ulm, Germany, 3Department of Statistics, Novo Nordisk A/S, Bagsvaerd, Denmark, and 4Novo Nordisk Pharma GmbH, Mainz, Germany
Objective: The primary objective was to demonstrate bioequivalence between the estrogen components of Activelle® (1 mg estradiol (E2) + 0.5 mg norethisterone acetate (NETA)) and the combined phase of NovofemTM (1 mg E2 + 1 mg NETA) and between the NETA components of the combined phase of NovofemTM (1 mg E2 + 1 mg NETA) and Trisequens® (2 mg E2 + 1 mg NETA). Subjects, materials and methods: The study design was double-blind, randomized, three-way, balanced six-sequence crossover. The washout period was 14 days between treatments. Single doses of the above-described tablets were administered in the morning following an overnight fast to 24 healthy postmenopausal or bilaterally oophorectomized women. Plasma concentration profiles of E2, estrone (E1; pharmacologically active metabolite of E2) and norethindrone (NET; NET was determined since NETA is very rapidly metabolized to NET) were measured over 72 h, and 36 h, respectively. For the two former substances a baseline correction was performed by subtracting the mean of two predose measurements from the concentrations measured after dosing. Results: One subject dropped out of the study, completing only one treatment sequence; therefore, the results are based on 23 subjects. The baseline-corrected E2 and E1 AUC0-t (NovofemTM)/ AUC0-t (Activelle®) ratios were 105% and 100%, respectively; and the Cmax ratios 100% and 105%, respectively. Identical median tmax was observed for E2 (6 h) and for E1 (5 h). The NET AUC0-t (NovofemTM)/AUC0-t (Trisequens®) ratio was 95%, and the corresponding Cmax ratio 98%. The median tmax for NovofemTM was 0.75 h and for Trisequens® 1.0 h. Conclusion: Bioequivalence was demonstrated for E2, E1 and NET in accordance with the study objectives.Correspondence to:
Dr. M. Zdravkovic; Novo Nordisk A/S, Department of Clinical Pharmacology, Building 9E, DK-2880 Bagsvaerd, Denmark
