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Abstract

N.V. Acharya¹, L.V. Wilton¹,² and S.A.W. Shakir¹,²

¹Drug Safety Research Unit, Southampton, and ²University of Portsmouth, UK
Aims: This is an interim report of a prospective observational cohort study to monitor the safety and tolerability of carvedilol in clinical practice when prescribed for heart failure in England. The utilization of carvedilol, management of adverse events in the community and the symptomatic progression of heart failure were examined. It is a non-interventional, observational cohort surveillance study using questionnaires sent to the patients’ general practitioners. Methods: The general practitioners (GPs) of the patients identified by the Prescription Pricing Authority were sent an eligibility questionnaire if the patient had been newly prescribed carvedilol between September 1999 and July 2001. Further questionnaires requesting baseline clinical information about eligible patients (carvedilol indicated for cardiac failure) and subsequent event data were sent to consenting GPs at 12 months. The questionnaires also requested specific information about initiation and supervision of treatment, including severity of heart failure and treatment withdrawal. The data were analyzed by using descriptive statistics. In addition, the incidence densities (ID) of each event (per 1000 person-months of treatment) were calculated, ranked and the difference between the ID of each event in the first (ID1) and subsequent 5 months of exposure (ID2) was tested by constructing 99% confidence intervals (CI). Selected events of clinical interest would be followed-up for further information to enable causal association with carvedilol to be assessed. Results: In this interim report we have data on a cohort of 847 eligible patients for whom we have received information from the first follow-up questionnaire. The treatment of carvedilol was initiated in a majority of cases by hospital specialists (87%, n = 735), however, for most of them, further supervision of treatment was done under shared care between GPs and hospitals (70%, n = 595). More than 90% of the patients were started on carvedilol in the recommended dose range for the management of cardiac failure. Amongst the patients where NYHA grade of cardiac failure was expressed, the majority of patients treated with carvedilol had NYHA II (37%, n = 281) and III (40%, n = 297) symptoms at the start of carvedilol treatment. On treatment with carvedilol, improvement in NYHA status was reported for 43% (n = 364) of this cohort, whilst less than 2.5% (n = 20) of the patients deteriorated. The events reported with the highest ID1 were malaise/lassitude (14.6), dizziness (12.2), cardiac failure (9.7), dyspnea (9.7) and hypotension (8.5). The most common events reported as reasons for stopping carvedilol were “drug not effective”, “dyspnea”, “dizziness” and “lassitude”. No events were identified as new signals (according to the ID1 – ID2 statistic) of adverse events associated with carvedilol. There have been no events identified in this cohort that have required specific follow-up at the time of writing this paper. Conclusions: In summary, the interim results show that there is effective cooperation between hospital specialists and GPs in the use of carvedilol in the management of patients with heart failure. It also shows that carvedilol was well-tolerated and that patients with mild and moderate heart failure benefit symptomatically when treated with carvedilol in routine clinical practice.Correspondence to:
Prof. S.A.W. Shakir

Drug Safety Research Unit

Bursledon Hall, Blundell Lane

Southampton, SO31 1AA, UK
Email: saad.shakir@dsru.org

Abstract

R.P. Baughman, D.A. Bradley and E.E. Lower

Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, OH, USA
Objective: Infliximab is a chimeric antibody which binds tumor necrosis factor (TNF). It is effective in several chronic inflammatory conditions, including sarcoidosis. Methods: We report our experience with infliximab in chronic ocular inflammation as part of a retrospective review of all patients treated for chronic inflammatory ocular conditions seen over a 2-year period at our institution. Results: 14 patients with various underlying ocular conditions were treated during the previous two years including patients with sarcoidosis (7), Crohn’s disease (2), birdshot choroiditis (2), idiopathic disease (2), Volt-Koyanagi-Harada (1) and Behçet’s disease (1). All patients had persistent inflammation despite systemic immunosuppressive agents and all but one patient experienced marked improvement in ocular inflammation with infliximab. One patient was non-compliant and non-evaluable; four patients, who had previously received etanercept with either no response (3 patients) or subsequent relapse (1 patient), responded to infliximab. Conclusion: Infliximab is an effective therapy in chronic inflammatory eye disease, especially when related to sarcoidosis.Correspondence to:
R.P. Baughman, M.D.
Department of Internal Medicine
University of Cincinnati Medical Center
1001 Holmes, Eden Ave
Cincinnati, OH 45267-0565, USA
Email: bob.baughman@uc.edu

Abstract

G. Fronio, E. Malecka-Tendera, M. Rojek and J. Janowska

¹Outpatient Endocrinology Clinic, Sosnowiec, ²Department of Pediatrics, Endocrinology and Diabetes, and ³Department of Pathophysiology, Silesian University School of Medicine, Katowice, Poland
Objective: Treatment of benign thyroid tumors with percutaneous ethanol injections (PEI) is an alternative to radioiodine and surgery. This procedure causes a release of large amounts of denaturated thyroglobulin within the gland which may become an autoantigen, triggering the mechanism of autoimmunization. The aim of the study was to investigate whether ethanol injections can induce increased levels of thyroid autoantibodies and tumor necrosis factor-a (TNF-a) in patients with nonfunctioning or pre-toxic thyroid nodules. Material and methods: Thirty-four patients (31 F, 3 M) with single benign thyroid tumors were enrolled, 23 (20 F/3 M) with nonfunctioning nodule (group 1) and 11 (F) with pre-toxic nodule characterized by normal free thyroid hormones and low TSH (group 2). Under sonographic guidance, sterile 96% ethanol solution was injected into thyroid nodules at 2-week intervals up to a dose of 0.7 – 1.0 ml of ethanol per 1.0 ml nodule volume. TSH, fT4, thyroglobulin antibodies and thyroperoxidase antibodies as well as TNF-a levels were assessed prior to alcohol administration and 3, 6, and 12 months after the end of treatment. Results: PEI treatment decreased tumor volume by 75.8% in group 1 and by 80.4% in group 2, and normalized TSH level in 90.9% of patients with pre-toxic nodules. No statistically significant differences in thyroperoxidase antibodies and TNF-a levels were observed during the study period in both groups. Thyroglobulin antibody levels increased significantly 6 months after treatment in both groups, but returned to the baseline levels after 12 months. No significant difference in peak thyroglobulin antibody levels between the two groups was seen. Conclusion: PEI procedure is a safe method for treating nonfunctioning and pre-toxic thyroid nodules since this treatment reduces tumor size significantly without inducing long-lasting autoimmune reactions in the thyroid gland. Transient increase in thyroglobulin antibodies indicates that this procedure should be performed with caution in patients at risk of autoimmune diseases.Correspondence to:
Dr. E. Malecka-Tendera

Department of Pediatrics, Endocrinology and Diabetes

Silesian University School of Medicine

ul. Medykow 16

40752 Katowice, Poland
Email: etendera@slam.katowice.pl

Abstract

J. Darimont, S. Grösch, C. Skarke, G. Geisslinger and J. Lötsch

pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology,
Johann Wolfgang Goethe-University, Frankfurt/Main, Germany
Two genetic screening methods, the fluorescence resonance energy transfer (FRET) technique on the LightCyclerä and the real-time pyrophosphate detection technique on the Pyrosequencerä have been compared with regard to their usefulness as screening methods for subject recruitment in clinical studies in pharmacology units. Two SNPs of possible clinical relevance were selected, namely the 118A>G SNP of the OPRM1 gene and the 3435C>T SNP of the ABCB1 gene. Genotypes diagnosed using conventional sequencing served as control. The allelic frequency of the mutated 118G allele of the OPRM1 gene was 12.7% and that of the mutated 3435T allele of the ABCB1 gene was 50.7%. All results obtained with the PyrosequencerTM were in accord with those obtained using conventional sequencing. With the LightCyclerTM, an incorrect genotype was assigned to 1 of the 130 DNA samples corresponding to an error rate of 0.8%. Although both methods were found suitable for rapid SNP detection, PyrosequencingTM was the preferred method since it provides the nucleotide sequence directly thus facilitating interpretation.Correspondence to:
J. Lötsch MD, PhD
pharmazentrum frankfurt/ZAFES
Institute of Clinical Pharmacology,
Johann Wolfgang Goethe-University
Theodor-Stern-Kai 7
60590 Frankfurt/Main, Germany
Email: j.loetsch@em.uni-frankfurt.de

Abstract

T.J. Cleophas

European Interuniversity College of Pharmaceutical Medicine, Lyon, France, Albert Schweitzer Hospital, Dordrecht, Netherlands
Background: Data modeling can be applied to improving the precision of clinical studies and multiple regression modeling is increasingly used for this purpose. Objective: To assess the uncertainties and risks of misinterpretations commonly encountered in regression analyses and rarely communicated in research papers. Results: Regression analyses add uncertainties to the data in the form of subjective judgments and uncertainty about the appropriate transformation of the data. Additional flaws include; the assumption that baseline characteristics are independent of treatment efficacies; the loss of sensitivity of testing if the models do not fit the data well enough; the risk that clinical phenomena like toxicity effects and complete remissions go unobserved; the risk of clinically unrealistic results if multiple variables are included. Conclusion: Regression analyses, although a very good tool for exploratory research, are not sufficiently reliable for randomized clinical trials.
Correspondence to:
Dr. T.J. Cleophas European Interuniversity College of Pharmaceutical Medicine, Lyon, France c/o Albert Schweitzer Hospital PO Box 306 3300 AH, Dordrecht, Netherlands
Email: ajm.cleophas@wxs.nl

Abstract

S. Hirata, S. Izumi, T. Furukubo, M. Ota, M. Fujita,

¹Department of Pharmacy Service and ²Department of Medicine, Shirasagi Hospital, Osaka, ³Department of Pharmacy, Chubu-Rosai Hospital, Nagoya, and ⁴Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
Objective: To report a significant increase in the serum levels of digoxin associated with the use of clarithromycin in six patients undergoing renal replacement therapy. Case summary: All six patients were males with end-stage renal disease and in need of renal replacement therapy. Four patients were anuric. The mean age was 78.8 ± 5.8 (66–83) years. All patients except one, who was treated by hemofiltration, were treated by hemodialysis. All patients except one, who had been treated with metildigoxin (0.35 mg/week), were also taking digoxin (0.375 mg/week). Clarithromycin was administered at a dose of 200 – 400 mg/day for the treatment of bronchitis in all patients. The concomitant administration of clarithromycin increased serum digoxin levels from 1.8 – 4.0-fold in all cases. In two of six cases, a high probability of digoxin intoxication and suspicion of digoxin intoxication was evident. In three of six cases, serum digoxin levels increased within 12 days after the co-administration of clarithromycin, while in the other three cases, serum digoxin levels were increased 53 – 190 days after the administration of clarithromycin. Conclusion: The simultaneous administration of clarithromycin caused an increase in digoxin levels in six patients undergoing renal replacement therapy. The increase in the serum digoxin can be attributed to the inhibition of P-glycoprotein in the intestine and/or bile capillary rather than the kidney by clarithromycin since renal function was dramatically impaired, and four of the patients were anuric. The issue of why serum digoxin levels were increased so late in three patients undergoing renal replacement is unclear. However, this interaction seemed to be clinically significant even in ESRD patients, whose renal function was highly impaired. The simultaneous use of digoxin and clarithromycin should be avoided even in patients undergoing renal replacement therapy whose renal function is impaired, since digoxin levels may increase unexpectedly.Correspondence to:
Dr. S. Hirata
Department of Pharmacy Service
Shirasagi Hospital
7-11-23 Kumata
Higashisumiyoshi-Ku, Osaka 546-0002, Japan
Email: hirata@shirasagi-hp.or.jp

Abstract

T. Setoyama, A. Laurent, T. Humphries and J. Hasegawa

¹Project Coordination, Eisai Research Institute of Boston Inc., Andover, MA, ²PPD Development, Austin, TX, ³Ferring Pharmaceuticals, Suffern, NY, USA, and ⁴Eisai Company Ltd., Tokyo, Japan
The study was designed to determine the absolute bioavailability of 20 mg rabeprazole tablets in normal, healthy subjects in comparison with intravenous administration of 20 mg rabeprazole. Twenty-eight healthy subjects were enrolled in this study. The study was a randomized, balanced, open-label, 2-period crossover study. Each subject was randomized at the beginning of the study to receive either a single 20 mg dose of rabeprazole intravenously or orally during Period 1. Following a 7-day washout period, all subjects received the alternate formulation during Period 2. Intravenous dose was given in constant infusion over five minutes. The absolute bioavailability of rabeprazole was 51.8%. The elimination half-life of rabeprazole sodium (1.47 ± 0.82 h) after oral administration was significantly longer than the elimination half-life after intravenous administration (1.02 ± 0.63 h), probably due to slower rate of absorption than that of elimination. The mean total body clearance was 283 ± 98 ml/minutes following a 20 mg intravenous dose. The administration of rabeprazole sodium was safe as evidenced by the lack of serious adverse events and the rapid resolution of the mostly mild adverse events that occurred during the study. Both treatments were well-tolerated throughout the study. Rabeprazole was well-absorbed after oral administration.Correspondence to:
T. Setoyama
Project Coordination, Eisai Research Institute of Boston, Inc.
1 Corporate Drive
Andover, MA 01810, USA
Email: tsutomu_setoyama@eisai.com

Abstract

Z.S. Herman

Chair of Clinical Pharmacology, Department of Clinical Pharmacology, Silesian University School of Medicine, Katowice, Poland
Owing to the great progress in clinical chemistry connected with utilization of applied mathematics, pharmacokinetics came into being. The unknown objective methods of research of drugs in human were discovered, among them controlled clinical trials (CCT). These new methodologies generated a new clinical discipline called clinical pharmacology (CPH) which has its roots in basic pharmacology but was applied in clinical specialties. This field is very young, recognized by World Health organization in 1970. Up to the 90s several enthusiasts developed quickly CPH. The scope and development of this discipline is presented in the ferst part of this article. At the end of the 20th century the science on drugs performed in humans was in the center of interest of the public as well as an object of great pressure of pharmaceutical industry, politicians, and the public. These phenomena started to influence CPH, practiced and taught in medical university faculties and patients care, unfavourably. Government, university authorities, non-profit organizations are not interested in supporting objective research in CPH on the highest academic level. The industry considers the mentioned studies as a threat for its profit. CCT was elaborated for objective comparison of effectiveness and efficacy of old (standard) drugs with the new approved substance. The main purpose of this type of study is a rejection of null hypothesis. Since 1990, these trials caused a strong movement toward evidence-based medicine. A few years ago trials were performed in independent academic centers. These studies were in experienced hands of the teams consistent of highly competents specialists of several fields of medicine. These centers contributed to the quality, intellectual rigor and impact of such clinical trials. But as economic pressure increases, this may belong to the past. Actually pharmaceutical companies curtailed the participation of academic centers in CCT to 40%. According to EU Parliament decision the pharmaceutical industry adopted the whole control of CCT. Politicians and society demand the instant application of new observations and discoveries into practice. Then new drugs approved in 2003 are mentioned. At the end, the general proposition to improve the Status of academic CPH and creditability of CCT is suggested: to develop essential studies on mechanisms of drugs on human being. The highest academic authorities, who understand the importance of CPH, have to discuss the necessity of funding of this type of research with university authorities, non-profit organizations and the Ministry of Health. To soften unavoidable conflict of interests, laborious discussions between academic scientists, pharmaceutic company authorities and governmental authorities are necessary. There is also an urgent necessity of new legislative acts. These proposals are very general and deficient. They were presented here to conclude this article on the present status of clinical pharmacology with the statement that the real threat for this discipline exists.Correspondence to:
Z.S. Herman
Chair of Clinical Pharmacology
Department of Clinical Pharmacology
Silesian University School of Medicine
Medyków 18
40-752 Katowice, Poland
Email: zbiklin@slam.katowice.pl

Abstract

S. Talpes, D. Knoerzer, R. Huber and B. Pfaffenberger

¹Str. Razbioieni Nr. ³⁸, Arad, Romania, and
²ALTANA Pharma AG, Konstanz, Germany
Objective: To investigate the bioequivalence of esomeprazole MUPS 40 mg tablets administered with and without a hard gelatine capsule. Material and methods: Bioequivalence of the esomeprazole MUPS 40 mg tablet administered without (Reference) and with a hard gelatine capsule (Test) was evaluated using a randomized, two-period crossover study. In each study period 49 healthy male Caucasian subjects received a single oral dose of 40 mg esomeprazole. Blood samples were collected at specified time intervals, and serum was separated and analyzed for esomeprazole concentrations using a validated HPLC-MS method. The primary parameters were AUC (extent of absorption) and Cmax (rate of absorption). The time-to-peak plasma concentration, tmax, and the elimination half-life, t1/2, were determined as secondary characteristics. Point estimates and 90%-confidence intervals were obtained for the ratio of the population medians of Test and Reference, using a multiplicative model and a parametric analysis except in the case of tmax, where an additive model and a non-parametric analysis was used. Bioequivalence of Test and Reference was concluded if the 90%-confidence intervals were entirely within the predefined equivalence ranges. Results: The AUC0-¥ and Cmax-ratios (Test/Reference) were 1.00 and 1.01, respectively. The 90%-confidence intervals for AUC0-¥ (0.94 – 1.06) and Cmax (0.93 – 1.09) of these ratios were within the predefined equivalence range of 0.80 – 1.25 and 0.75 – 1.33, respectively. The ratios and 90%-confidence intervals of the secondary characteristics t1/2 and tmax were also within the respective predefined equivalence ranges. Both esomeprazole formulations were well tolerated and safe. Conclusion: The encapsulation of esomeprazole MUPS 40 mg tablets does not influence the extent and rate of absorption assessed by using AUC0-¥ and Cmax. Thus, bioequivalence could be demonstrated.
Correspondence to:
B. Pfaffenberger
ALTANA Pharma AG
Byk-Gulden-Straße 2
78467 Konstanz, Germany
Email: bernd.pfaffenberger@altanapharma.com

Abstract

Y. Matsumoto, M. Shimizu and H. Ogata

¹Department of Clinical Pharmacology and Toxicology, Showa Pharmaceutical University, Machida, Tokyo, ²Department of Biopharmaceutics, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan
Objective: The aim of this study was to investigate whether the bioequivalence range applied world-wide, 80 – 120%, ensures the clinical equivalence. We investigated the relationship between variations of AUC and Cmax and those of AUEC based on a direct link model using a simulation technique. Methods: A one-compartment pharmacokinetic model and a sigmoid Emax pharmacodynamic model were used. Regarding the influence of AUC variation on AUEC variation, the total clearance value was changed from 80% to 120%. Regarding the influence of Cmax variation on AUEC variation, Cmax was changed from 80% to 120% under a constant AUC value estimated from zero to four elimination half-lives of a drug. Results: In the case that ¡, shape factor, is less than 1, irrespective of the ratio of EC50 to Cmax, AUEC is within the acceptable range as long as AUC and Cmax are within the acceptable range for bioequivalence, BE. In the case that ¡ is more than 1, and Cmax is lower than EC50, AUEC may fail within the acceptable range in the case that AUC and Cmax are within the acceptable range for BE. Conclusion: These results suggest that 20% difference for BE does not always ensure the clinical equivalence for all drugs.Correspondence to:
Y. Matsumoto, PhD
Department of Clinical Pharmacology and Toxicology
Showa Pharmaceutical University
3-3165 Higashitamagawagakuen
Machida, Tokyo 194-8543, Japan
Email: matsuy@ac.shoyaku.ac.jp

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Volume 43, No. 1/2005(January)