Volume 40, No. 6/2002(June)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Editorial
Private funding in Clinical Pharmacology
B.G. Woodcock
UGTpolymorphism and liver disease
Predicting the risk of sporadic elevated bilirubin levels and diagnosing Gilbert’s syndrome by genotyping UGT1A1*28 promoter polymorphism
S.K. Rauchschwalbe, M.T. Zühlsdorf, U. Schühly and J. Kuhlmann
Abstract
S.K. Rauchschwalbe1, M.T. Zühlsdorf2, U. Schühly2 and J. Kuhlmann2
1Institute of Pharmacology and Toxicology, Julius Maximilian University Würzburg, and 2Pharmaceutical Research Center, Institute of Clinical Pharmacology, Bayer AG, Wuppertal, Germany
Elevated fluctuating levels of bilirubin are a common problem in clinical studies. Differentiation between a drug-related adverse event and the diagnostic symptom for Gilbert’s syndrome (GS), an idiopathic unconjugated hyperbilirubinemia, is more or less impracticable since the diagnosis of GS is by exclusion. The aim of this investigation was to evaluate the correlation of unspecific elevated bilirubin levels and the occurrence of GS with a described polymorphism in the uridine diphosphat glucuronosyltransferase 1A1 (UGT1A1) in a predominately Caucasian population. 304 volunteers (152 male, 152 female) were genotyped for the UGT1A1 promoter polymorphism by PCR amplification and polyacrylamide gel electrophoresis. Serum bilirubin levels and liver enzymes were determined and GS was diagnosed using clinico-chemical criteria. 23/13 subjects displayed the homocygote variant, 73/66 the heterozygote variant and 56/72 wildtype (male/female, respectively). 23 male and 3 female volunteers fulfilled the clinical criteria for GS (15.1, respectively 2.0%). Men exhibited higher serum bilirubin levels than women with a mean (SD) of 14.37 (8.92) mmol/l compared to 10.17 (5.37) mmol/l, respectively (p < 0.001). The homocygote mutant promoter length correlated well with serum bilirubin levels and with the clinical diagnosis of GS (p < 0.001 each). Genotyping of the UGT1A1 promoter polymorphism is a cheap and unequivocal method for predicting elevated and fluctuating bilirubin levels. It is better suited to this purpose than the clinical diagnosis which is based on exclusion. The genotyping of UGT1A1 promoter polymorphism can help to improve safety and the reliable assessment of adverse events in clinical studies. Our data additionally support the demand to refine the bilirubin reference values.Correspondence to:
Dr. S. Rauchschwalbe
Richard-Strauss-Straße 11, D-97074 Würzburg
Email: sonja@rauchschwalbe.net
Pharmacovigilance
A post-marketing observational study to assess the safety of mibefradil in the community in England
J. Riley, L.V. Wilton, and S.A.W. Shakir
Abstract
J. Riley1, L.V. Wilton1,2 and S.A.W. Shakir1,3
1Drug Safety Research Unit, Bursledon Hall, Southampton, 2School of Medicine, University of Southampton, and 3London School of Hygiene and Tropical Medicine, London, UK
Objectives: To conduct a post-marketing observational cohort study to assess the safety of mibefradil in the community, using Prescription-Event Monitoring (PEM). Method: Data were collected and analyzed on patients prescribed mibefradil by 1,996 General Practitioners (GPs) throughout England. Incidence densities were calculated for all reported events and selected events were followed-up by means of further questionnaires. Results: The study was terminated early due to the voluntary withdrawal of mibefradil from the market because of potential drug interactions. A cohort of 3,085 patients was recruited, with a mean age of 64.5 years. The major indication for use was hypertension (55% of the cohort), the indication was not specified in 33% of patients. 80% of GPs expressing an opinion rated mibefradil as effective. The major reason for stopping was withdrawal from the market (2,342 patients). The commonest reported adverse events and reasons for stopping were malaise/lassitude, dizziness, edema and headache. Seven clinically serious reports of bradycardia/collapse were considered to be possible adverse drug reactions (ADRs) to mibefradil. All were in the elderly (> 65 years), 6 were considered to be a result of possible drug interactions. In total, 11 possible drug interactions occurred. Nine (8 reports of bradycardia and 1 of syncope) involved b-blockers. Another, a report of collapse and severe bradycardia, occurred in a patient who had started a dihydropyridine calcium channel blocker within 24 hours of stopping mibefradil and the other was a report of palpitations and dyspnea in a patient on concomitant digoxin and sotalol. None of the 53 deaths occurring during the study was attributed to mibefradil. Conclusion: Mibefradil was only available on the UK market for 6 months before it was withdrawn from the market because of potential drug interactions. With respect to the reasons leading to its withdrawal, in this cohort of 3,085 patients, 11 possible drug interactions were detected (6 clinically significant) involving b-blockers, a dihydropyridine calcium channel blocker and digoxin and/or sotalol. PEM can contribute to the understanding of ADRs caused by drug interactions occurring in real-life settings.Correspondence to:
Dr. L. Wilton; Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton SO31 1AA, UK
Email: lynda.wilton@dsru.org
Pharmacology of smoking
Hubble-bubble (water pipe) smoking: levels of nicotine and cotinine in plasma, saliva and urine
Y.A. Shafagoj, F.I. Mohammed and K.A. Hadidi
Abstract
Y.A. Shafagoj1, F.I. Mohammed1 and K.A. Hadidi2
1Department of Physiology and Biochemistry, and 2Department of Forensic Medicine and Toxicology Division, Faculty of Medicine, University of Jordan, Amman, Jordan
Objectives: The purpose of the present study was to assess the levels of nicotine and cotinine in biological fluids (plasma, saliva, and urine) following hubble-bubble (HB) smoking. Methods: Fourteen healthy male volunteers, aged 28 ± 8 years, body weight of 82.7 ± 13.53 kg, participated in the study. All volunteers were habitual HB smokers for 3.29 ± 1.90 years who smoked at least 3 runs per week with an average of 20 g Mua’sel per run. Volunteers were requested to avoid smoking, at least 84 hours prior to the time of the study. After baseline samples were taken, volunteers started smoking 20 g of Mua’sel for a period of 45 minutes. Heparinized blood samples (5 or 10 ml each) were drawn for nicotine and cotinine analysis before, during and after the smoking period. Saliva samples were collected just before smoking (time 0) and at the end of smoking (45 min). Urine also was collected at time 0 and 24-hour urine collection was also taken to measure nicotine and cotinine excretion. Nicotine and cotinine were extracted from samples and assayed by gas chromatography. All data are presented as mean ± SEM throughout the text, Tables and Figures unless indicated otherwise. Results: Plasma nicotine levels rose from 1.11 ± 0.62 ng/ml at baseline to a maximum of 60.31 ± 7.58 ng/ml (p < 0.001) at the end of smoking (45 min). Plasma cotinine levels increased from 0.79 ± 0.79 ng/ml at baseline to its highest concentration of 51.95 ± 13.58 ng/ml (p < 0.001) 3 hours following the end of smoking. Saliva nicotine levels significantly rose from 1.05 ± 0.72 to 624.74 ± 149.3 ng/ml and also saliva cotinine levels significantly increased from 0.79 ± 0.79 ng/ml to 283.49 ± 75.04 ng/ml. Mean amounts of nicotine and cotinine excreted in urine during the 24-hour urine collection following smoking were equal to 73.59 ± 18.28 and 249 ± 54.78 mg, respectively. Conclusion: Following a single run of HB smoking, plasma, saliva and urinary nicotine and cotinine concentration increased to high values. This observation suggests that HB may not be an innocent habit, as people believe.Correspondence to:
Dr. Y.A. Shafagoj; Department of Physiology and Biochemistry, Faculty of Medicine, University of Jordan, P.O. Box 13370, Amman 11942, Jordan
Email: yanals@ju.edu.jo
Asthma therapy
A comparison of non-tapering vs. tapering prednisolone in acute exacerbation of asthma involving use of the low-dose ACTH test
R.S. Karan, P. Pandhi, D. Behera, R. Saily and V.K. Bhargava
Abstract
R.S. Karan1, P. Pandhi1, D. Behera2, R. Saily3 and V.K. Bhargava1
1Department of Pharmacology, 2Department of Internal Medicine, and 3Department of Endocrinology, PGIMER, Chandigarh, India
Objective: To determine if there is a difference in early relapse rates and adrenal suppression between patients receiving an 8-day course of 40 mg/day prednisolone and those receiving an 8-day tapering course of prednisolone. Methods: This was a prospective, randomized, open clinical trial conducted in a tertiary care center. All asthmatic patients with exacerbation who were judged well enough for discharge home from the emergency department were eligible for participation. Patients with a history of chronic obstructive pulmonary disease, congestive heart failure, pneumonia, pneumothorax, or other pulmonary process and asthmatics already using inhaled or oral steroids within 2 weeks of admission to the emergency department were excluded. Patients on discharge were administered either on 8-day course of 40 mg/day prednisolone or an 8-day tapering course of prednisolone (tapering from 40 mg to 0 mg). Patients were asked to return on Day 12 for cosyntropin stimulated test and pulmonary function testing and on Day 21 for pulmonary function testing only. Results: A group of 13 patients treated with non-tapering course (40 mg/day) of prednisolone for 8 days were compared to a group of 13 patients treated with a tapering course (40 mg taper by 5 mg/day) for 8 days. There were no differences in the FEV1 percent predicted (Days 12 and 21), the incidence of relapse, or the incidence of adrenal suppression between the 2 groups. Conclusion: In this small study, we found no significant difference in relapse rate or adrenal suppression between asthmatics receiving an 8-day tapering dose of prednisolone and those receiving 40 mg/day prednisolone upon discharge from the emergency department.Correspondence to:
Dr. (Mrs.) P. Pandhi, Additional Professor; Department of Pharmacology, PGIMER, Chandigarh-160 012, India
Email: medinst@pgi.chd.nic.in, rajeshkaran@hotmail.com
Hypertension
Comparison of benazepril-amlodipine and captopril-thiazide combinations in the management of mild-to-moderate hypertension
E. Malacco, S. Piazza, R. Carretta, S. Di Somma, A. Mugellini, F. Bertocchi and P. Palatini for the Italian Blood Pressure Study Group
Abstract
E. Malacco1, S. Piazza1, R. Carretta2, S. Di Somma3, A. Mugellini4, F. Bertocchi5 and P. Palatini6 for the Italian Blood Pressure Study Group
1Third Division of Internal Medicine, Ospedale “L. Sacco”, University of Milan, Milan, 2Ospedale di Cattinara, Trieste, 3Università Federico II, Napoli, 4Polo Universitario, Città di Pavia, Pavia, 5Novartis Farma SpA, Origgio, and 6Department of Clinical and Experimental Medicine, University of Padova, Italy
Objective: To compare the efficacy and tolerability of benazepril 10 mg + amlodipine 5 mg combination (BZ+AM) versus captopril 50 mg + hydrochlorothiazide 25 mg (CP+HT) combination. Material: 405 outpatients with mild-to-moderate arterial hypertension not adequately controlled by a monotherapy with ACE inhibitors or calcium channel blockers or diuretics entered this multicenter, double-blind, randomized, parallel-group study. Method: After a 2-week placebo run-in, 397 patients with sitting diastolic (D) blood pressure (BP) > 95 mmHg and/or sitting systolic (S) BP > 160 mmHg were randomized to receive either BZ+AM (201 patients) or CP+HT (196 patients) once daily for 12 weeks. Main outcome measure was sitting DBP and SBP values at the end of active treatment. The response rate was defined as the proportion of patients with either a final sitting DBP < 90 mmHg or decreased by at least 10 mmHg or a sitting SBP < 150 mmHg or decreased by at least 20 mmHg from baseline. Results: The DBP and SBP values obtained with BZ+AM were, respectively, 2.7 and 3.7 mmHg lower than those obtained with CP+HT (both p < 0.001 vs. CP+HT). The response rate in the BZ+AM group (94.8%) was better than that observed in the CP+HT group (86.0%, p = 0.004). The incidence of adverse events was similar with the 2 treatment regimens (17.9% for both). Conclusions: These data suggest a higher antihypertensive efficacy of the fixed combination BZ 10 mg+AM 5 mg as compared with CP 50 mg+HT 25 mg.Correspondence to:
Prof. P. Palatini; Clinica Medica 4, University of Padova, Via Giustiniani, 2, I-35128 Padova, Italy
Email: palatini@unipd.it
Pharmacokinetic modelling
Pharmacokinetic modelling of total and unbound plasma carboplatin – a population study in 75 children
S. Urien, F. Doz, F. Namouni and G. Bastian
Abstract
S. Urien1, F. Doz2, F. Namouni2 and G. Bastian1
1Laboratoire de Pharmacologie, Centre René Huguenin, Saint-Cloud, and 2Oncologie Pédiatrique, Institut Curie, Paris, France
Aims: A compartmental open model was developed to describe the relationship between plasma unbound (Cu) and bound (CT) carboplatin concentrations. A population pharmacokinetic study was then undertaken to investigate the effect of demographic covariates on unbound and bound carboplatin clearance and volume parameters. Methods: Carboplatin and demographic data were collected from 75 children (1 – 17 years old, 10 children with unilateral nephrectomy) treated using 1-hour daily infusions for various malignancies. Concentration-time data, CU and CT, from children with rich data were used to develop the model. The data from all children were then simultaneously analyzed using a population approach. Results: The average population values for total unbound carboplatin clearance, CLU, and distribution volume of unbound carboplatin, V1, were 3.87 l/h and 6.26 l/h, respectively. The clearance of plasma-bound carboplatin was comparatively low, 0.11 l/h. CLU was dependent on weight, nephrectomy status and serum creatinine. A constant fraction of CLU, 0.17 l/h, included the disappearance of unbound compound due to irreversible plasma binding. V1 was dependent on body weight. The unbound plasma carboplatin fraction (fU) was simulated and rapidly decreased with post-infusion time. Conclusions: The body weight was a better predictor for unbound carboplatin clearance than body surface area, and UNP and SCr caused a reduction in clearance of unbound carboplatin, as previously reported. The rate of carboplatin plasma binding was low and not dependent on demographic patient characteristics. The fU of plasma carboplatin could be predicted as a function of time, infusion rate and covariates affecting CLU, weight, UNP and SCr.Correspondence to:
Dr. S. Urien; Laboratoire de Pharmacologie, Centre René Huguenin, 35 rue Dailly, F-92210 Saint-Cloud, France
Email: s.urien@ stcloud-huguenin.org
