Volume 43, No. 6/2005(June)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Pharmacogenetics
P-selectin (CD62p) and P-selectin glycoprotein ligand-1 (PSGL-1) polymorphisms: minor phenotypic differences in the formation of platelet-leukocyte aggregates and response to clopidogrel
U. Klinkhardt, I. Dragutinovic and S. Harder
Abstract
U. Klinkhardt, I. Dragutinovic and S. Harder
pharmazentrum frankfurt, Institute for Clinical Pharmacology,
University Hospital Frankfurt, Frankfurt/Main, Germany
Introduction: Formation of platelet-leukocyte aggregates (PLA) via the CD62p-ligand PSGL-1 represents an important mechanism by which leukocytes contribute to thrombotic and inflammatory events. Deficient variants (namely the Thr715Pro-SNP for CD62p and a VNTR-polymorphism for PSGL-1) might affect PLA formation and probably the response to clopidogrel (which is known to reduce PLA-formation). Methods: CD62p-expression, PLA-formation and the up-regulation of CD11b before (V1) and 24 hours after (V2) a loading dose of clopidogrel 225 mg were investigated in ten wild-type controls, ten heterozygote carriers of the Thr715Pro-allele and five carriers of the rare PSGL-1 B-allele (2 A/B and 3 B/B). Results: CD62p-expression before application of clopidogrel and under clopidogrel treatment in Pro715-haplotype samples did not differ from that in wild-type subjects. The response to clopidogrel was similar in all subjects. Pro715-carriers exhibited a significantly lower percentage of monocytes with platelets attached prior to clopidogrel treatment (ADP: median 22 (1st ? 3rd quartile 20 ? 23), TRAP: 27 (25 ? 38)) compared to the wild-type (ADP: 37 (31 ? 44), TRAP: 55 (37 ? 63)). These differences were not present under clopidogrel, and CD11b-expression was significantly reduced in both groups (controls: median 150 (quartile range 121 ? 230) to 113 (121 ? 230), Pro715-carriers: 147 (139 ? 221) to 126 (109 ? 170); all values refer to mean fluorescence intensity). Statistical analysis was not done in the case of PSGL-1 B-allele carriers, but PLA-formation before and under clopidogrel was always at the bottom end of the range seen in the control group and the Pro715-carriers or even below this range. Conclusion: Minor phenotypic differences in the CD62p-PSGL-1 axis could be demonstrated in this study. Carriers of these polymorphisms showed a full response to clopidogrel comparable to that in control subjects.Correspondence to:
Prof. Dr. S. Harder
pharmazentrum frankfurt
Institute for Clinical Pharmacology
University Hospital Frankfurt
Theodor-Stern-Kai 7
60590 Frankfurt/Main, Germany
Email: harder@em.uni-frankfurt.de
Drug Interactions
Lack of pharmacokinetic drug-drug interaction between ciclesonide and erythromycin
R. Nave, A. Drollmann, V.W. Steinijans, K. Zech and T.D. Bethke
Abstract
R. Nave, A. Drollmann, V.W. Steinijans, K. Zech and T.D. Bethke
ALTANA Pharma AG, Konstanz, Germany
Objective: To investigate whether systemic exposure to desisobutyryl-ciclesonide (des-CIC) (the pharmacologically active metabolite of ciclesonide) and erythromycin are affected by combined administration of ciclesonide and erythromycin. Methods: 18 healthy subjects were enrolled in a Phase 1, open-label, randomized, three-period crossover study. Each subject received ciclesonide (640 Correspondence to:
R. Nave, PhD
ALTANA Pharma AG
Byk-Gulden-Stra
Email: ruediger.nave@altanapharma.com
Pharmacodynamic Modeling
Improved glycemic control with decreased hypoglycemia prevents long-term complications in type 2 diabetes patients: long-term simulation analysis using the ?Diabetes Mellitus Model?
S. Maxion-Bergemann, E. Huppertz, L.-D. Jacobs, E. M
Abstract
S. Maxion-Bergemann, E. Huppertz, L.-D. Jacobs, E. M
1Analytica International GmbH, L
Objective: The purpose of this study was to compare the effect of insulin glargine (glargine) and NPH insulin (NPH) on long-term outcomes in type 2 diabetes patients using the Diabetes Mellitus Model (DMM). Methods: The DMM predicts short- and long-term complications over ten years using data in studies published previously. The main effect on outcome is the influence of the treatment on the HbA1c level which is simulated over time. The simulation was based on a cohort size of 10,000 type 2 diabetes patients taking either glargine or NPH. The best scenario, baseline scenario and worst case scenario were simulated based on differences of 0.13%, 0.44% and 0.85%, respectively, in HbA1c values and corresponding to potentially attainable improvements with comparable or lower hypoglycemia rates in glargine-treated patients and NPH-treated patients. Assumptions for scenarios 1, 2 and 3 were based on a regression analysis of clinical trial data (pooled data clinical trials comparing glargine and NPH) in which the effect of glargine on the HbA1c/hypoglycemia incidence ratio was superior to that of NPH. Results: The relative risks (RR, glargine/NPH) obtained for scenarios 1, 2 and 3 were 0.97, 0.89 and 0.81, respectively, for long-term microvascular complications and 0.99, 0.95 and 0.91, respectively, for long-term macrovascular complications. RR reductions ranged from 1% in the less optimistic scenario to > 20% in the ?best case? scenario. Sensitivity analyses showed that variations in the mean baseline HbA1c values and duration of the diabetes were without effect on these outcomes. Conclusions: Although there is a need to corroborate the results of these simulations with real, long-term clinical data, they have demonstrated that, assuming comparable or lower rates of hypoglycemia, a better glycemic control (HbA1c reduction) can be expected with glargine when compared to NPH together with a reduction in long-term complications, mortality and associated costs.Correspondence to:
S. Maxion-Bergemann
Analytica International GmbH
Untere Herrenstra
Email: smaxion-bergemann@de.analyticaintl.com
Drug Profile
Safety, tolerability and pharmacokinetics of oral S-3304, a novel matrix metalloproteinase inhibitor, in single and multiple dose escalation studies in healthy volunteers
S. van Marle, A. van Vliet, F. Sollie, Y. Kambayashi and T. Yamada-Sawada
Abstract
S. van Marle, A. van Vliet, F. Sollie, Y. Kambayashi and T. Yamada-Sawada
1Pharma Bio-Research Group B.V. Science Park, Zuidlaren, The Netherlands, and 2Shionogi & Co., Ltd., Osaka, Japan
Objective: A novel sulfonamide derivative, S-3304, was discovered as a potent matrix metalloproteinase (MMP) inhibitor. It is a more specific inhibitor to MMP-2 and MMP-9 (in vitro) than to MMP-1, and may therefore lack the musculoskeletal side effects seen with non-specific inhibitors. The aim of the present study was to investigate the safety, tolerability and pharmacokinetics of S-3304 when administered as single and multiple oral doses to healthy male volunteers. Materials and methods: 48 male volunteers received single oral doses ranging from 10 ? 800 mg S-3304 or placebo under fasting conditions. At the 200 mg dose level, effects of high-fat diets were studied in a crossover design. In the multiple dose design, 24 male subjects were administered 200 mg, 400 mg or 800 mg S-3304 or placebo b.i.d. after meals for 10 ? 17 days. Studies were conducted in a randomized double-blind fashion. Safety assessment was conducted based on blood chemistry, hematology, urinalysis, electrocardiogram and physical examination. Pharmacokinetic parameters were determined for S-3304 and its metabolites. All subjects were enrolled in the studies after obtaining informed consent. Results: Adverse events reported after single dose administration of S-3304 or placebo were all of mild severity. Adverse events reported in the multiple dose treatment with S-3304 or placebo were mostly of mild severity, except for two episodes of moderate headache and two episodes of moderate myalgia. Most commonly reported adverse events in the multiple treatments with S-3304 were headache and somnolence. No clinically significant changes were observed in the clinical laboratory tests, except for reversible elevation of alanine aminotransferase of one subject at 800 mg S-3304 b.i.d. In the single dose administration, Cmax and mean AUC0?Correspondence to:
Y. Kambayashi, PhD
Shionogi & Co., Ltd.
12-4, Sagisu 5-chome, Fukushima-ku
Osaka 553-0002, Japan
Email: yoshikazu.kambayashi@shionogi.co.jp
Drug Utilization
An evaluation of prescribing errors in primary care in Bahrain
K.A.J. Al Khaja, T.M. Al-Ansari and R.P. Sequeira
Abstract
K.A.J. Al Khaja, T.M. Al-Ansari and R.P. Sequeira
1College of Medicine and Medical Sciences, Arabian Gulf University, and 2Ministry of Health, Kingdom of Bahrain
Objectives: Prescribing errors are preventable and are considered an important target for improving healthcare. The aim of this study was to identify prescribing errors and their determinants in a primary care setting. Methods: Prescriptions with errors were collected on a daily basis by the pharmacy staff during the first two weeks of September 2003 in 18 out of 20 primary care health centers in Bahrain. Prescribing errors were classified as omission (minor and major), commission and integration errors. Results: Out of 77,511 prescriptions dispensed, 5,959 (7.7%) were identified to contain errors. The frequency of prescribed medication items in 5,959 prescriptions was 16,091. Of these medications, 13,630 (84.7%) were with errors and only 13.2% were written using generic names. Minor errors of omission such as absence of physician?s stamp (34.4%), date (9.8%), and information about patients? address (3.8%), age (3.5%) and sex (0.5%) were not specified. Major errors of omission accounted for 93.6% and were as follows: strength/dose (31.0%), length of therapy/ quantity (29.5%), dosage form (19.7%), and frequency of dosing (13.4%). In 6.3% errors of commission (incorrect information) the most common was strength/dose (3.3%), followed by frequency of dosing (2.6%), dosage form (0.3%), and length of therapy/quantity (0.1%). Major errors of omission associated with topical preparations were significantly higher than those with systemic preparations. However, prescriptions with systemic preparations had a higher rate of commission errors. Significant differences in errors were found in prescriptions ordered by family physicians and general practitioners. In 9.2% of prescriptions with errors, potential drug-drug interactions were expected. Conclusions: This nationwide survey revealed that in primary care, a considerable proportion of prescriptions contained errors. Strategies to minimize medication errors by improving the prescribing skills, adherence to essential drugs list, and use of National Formulary are needed.
*The abstract of this paper was presented at the ISoP Annual Conference ?Pharmacovigilance ? Current and Future Challenges?
Correspondence to:
Dr. K.A.J. Al Khaja
Department of Pharmacology and Therapeutics
College of Medicine and Medical Sciences
Arabian Gulf University
P.O. Box 22979, Kingdom of Bahrain
Email: khlidj@agu.edu.bh
Letter to the Editor
Quality of prescribing for drugs affecting the nervous system: comparison between Croatia (Zagreb) and Finland
D. Erceg, I. Vuku?ic, E. Palva, T. Voipio, M. Polic-Vi?intin and J. Culig
Abstract
D. Erceg, I. Vuku?ic, E. Palva, T. Voipio, M. Polic-Vi?intin and J. Culig
Book Review
Drug Metabolism and Transport
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