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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

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Volume 43 p. 255 - 263

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: [email protected]

Therapeutics

Monitoring effects of direct FXa-inhibitors with a new one-step prothrombinase-induced clotting time (PiCT) assay: comparative in vitro investigation with heparin, enoxaparin, fondaparinux and DX 9065a

J. Graff, B. Picard-Willems and S. Harder

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Volume 45 p. 237 - 243

Abstract

J. Graff, B. Picard-Willems and S. Harder

J. Graff, B. Picard-Willems and S. Harder
Selective, direct factor Xa-inhibitors are an emerging new class of antithrombotic drugs but their application in therapy may require adequate laboratory monitoring. A recently introduced assay for monitoring anti-FXa-activity using Russell’s viper venom is based on the prothrombinase-induced clotting time (PiCT). In this study comparative data on the performance of PiCT using direct and indirect FXa-inhibitors and measurements of FXa-activity and aPTT are reported. Methods: Whole citrated blood samples from six healthy volunteers were pre-incubated with UFH (0 – 1.0 IU/ml), enoxaparin (0 – 10 µg/ml), fondaparinux (0 – 1.0 µg/ ml) and DX 9065a (0 – 10 µg/ml). PTT, FXa-activity and PiCT in plasma were determined on an ACL coagulation analyzer. PiCT was done with both a 180-sec incubation period before recalcification (2-step), and without (1-step). FXa-activity was based on a chromogenic assay (S2222). Results: FXa-activity was reduced 10 – 40% by the lowest concentration and by 80 – 95% by the highest concentration of all agents. At the highest concentration the maximum prolongation in aPTT exceeded 120 sec with UFH, enoxaparin and DX 9065a but was only marginally prolonged (increase 39 ± 3 sec) by fondaparinux. Prolongation in PiCT was significantly different when the two PiCT-methods were compared e.g. at 1.0 IU/ml UFH, 137 ± 25 (1-step) vs. 187 ± 32 sec (2-step) (p < 0.001); at 10 mg/ml enoxaparin 83 ± 9 sec vs. 130 ± 15 (p < 0.001); at 1.0 µg/ml fondaparinux 48 ± 5 sec vs. 73 ± 9 sec (p < 0.001); at 10 µg/ml DX 9065a 28 ± 3 vs. 25 ± 2 (p < 0.01), respectively. The 2-step method was unable to detect a prolongation in the effects of DX 9065a, and at concentrations < 5 mg/ml clotting times were even shorter (e.g. 13 ± 1 sec at 1.0 µg/ml DX 9065a) than the baseline readings (20 ± 2 sec). Conclusions: Only the 1-step method (i.e. without pre-incubation) seems suitable for the monitoring of new, direct selective FXa-inhibitors.Correspondence to:
Prof. Dr. S. Harder
Institute for Clinical Pharmacology at the Pharmazentrum
Frankfurt
University Hospital Frankfurt/Main
Theodor-Stern-Kai 7
60590 Frankfurt am Main, Germany
Email: [email protected]

Drug Utilization

Appropriateness and surveillance of medication in a cohort of diabetic patients on polypharmacy

S. Harder, K. Saal, E. Blauth, M. Beyer and F.M. Gerlach

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Volume 47 p. 104 - 110

Abstract

S. Harder¹, K. Saal², E. Blauth², M. Beyer² and F.M. Gerlach²

¹Institute for Clinical Pharmacology, ²Institute for General Practice, University Hospital Frankfurt am Main, Germany
Context: It is assumed that with increasing polypharmacy, medication surveillance by the General Practitioner (GP) and adherence to the therapy regimen by the patient will both decline. Aim of the study: We evaluated clinical and medication records taken from GP documentations in a cohort of 102 diabetic patients (48 f, 54 m, median age 70, range 39 – 81) with 3 or more chronic prescriptions. Patients were asked about their current medication and its tolerability by means of a structured telephone interview. Results: 45% of the patients received up to 6 medications, 36% 7 – 9 and 19% > 10. The main comorbidity was hypertension (93%) and symptomatic CAD (39%). The use of established medications (beta-blockers and ACE inhibitors) for these comorbidities was appropriate. Although 76% were eligible for a statin therapy, only 51% actually took a statin, and 28% had a dose lower than the defined daily dose. 68% of the patients had no prescriptions other than those recorded in the GP documentation, but 8% of the total number of medicines taken by the patients were not recorded in the GP’s database. 62% of patients took all the medication prescribed by the GP, while 7% of all medicines recorded in the GP’s database were not taken by the patients. In 10% of cases, an incompatible medication (defined in accordance with a consented list) was taken by the patient. 81% of patients regularly (twice per year) had their HbA1c checked, but only 62% had their potassium levels checked, despite the use of ACI and diuretics. Most patients knew the reason for taking at least one medication, but 18% knew this for less than half of their (multiple) medications. 70% of the patients said they had been informed about the possible risks of their medication by the GP, and 7% knew the risks for only one medication. Conclusion: In this cohort of patients on polypharmacy and with a high risk profile for adverse drug reactions, we found a mismatch between GPs’ documentation of prescriptions and the medication taken by the patient. Patients had no detailed knowledge about indications and almost no knowledge about risks. Although the overall performance of therapy (appropriateness) was deemed sufficient, there would appear to be room for improvement in order to fill information gaps and strive for stricter surveillance.Correspondence to:
Prof. Dr. med. S. Harder; Institute for Clinical Pharmacology, Pharmazentrum Frankfurt, University Hospital Frankfurt/Main, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany
Email: [email protected]

Antiplatelet agents

Effects of antiplatelet agents on platelet-induced thrombin generation

W. Wegert, J. Graff, D. Kaiser, H.K. Breddin, U. Klinkhardt and S. Harder

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Volume 40 p. 135 - 141

Abstract

W. Wegert¹, J. Graff¹, D. Kaiser¹, H.K. Breddin², U. Klinkhardt¹ and S. Harder¹

¹Institute for Clinical Pharmacology, University Hospital, Frankfurt am Main and ²International Institute for Thrombosis and Vascular Diseases, Frankfurt am Main, Germany
Objectives: The influence of antiplatelet agents on platelet-induced thrombin generation may increase the risk of bleeding. Assessment of the endogenous thrombin potential (ETP), is therefore a parameter deserving attention in early pharmacodynamic studies with antiplatelet drugs. The aim of this study was to assess whether an automated ETP-assay can be used to determine possible inhibitory effects of antiplatelet drugs on platelet-associated thrombin generation. Methods: We first characterized the in vitro dose-response relationship of several platelet agonists (ADP, collagen, U46619, TRAP (amino acid sequence: SFLLRNP) and tissue factor (TF) using the generation of ETP. One submaximal concentration of each agonist was then used to assess the influence of in vivo treatment with aspirin (single oral dose of 500 mg as inhibitor of thromboxane synthesis) and clopidogrel (given orally for 6 days, as an inhibitor of the purinergic P2Y12-receptor on platelets) and in vitro treatment with abciximab (which inhibits the platelet glycoprotein IIb/IIIa-receptor for fibrinogen), on the ETP. Results: The effect of TF and the other platelet inducers on thrombin generation was dose-dependent. Repeat measurements on samples from the same subject, with the same inducer concentration on 2 different occasions showed a variability of approx. 22% (absolute difference between 2 measurements as % of mean). The coefficient on variation of repeat measurements of one sample varied between 7% and 17%, depending on the inducer. After a single dose of aspirin, ETP was reduced by 25 – 40%, depending on the platelet activating agent used. The reduction in ETP with abciximab in vitro was more pronounced. In contrast, TF-induced ETP was not influenced by aspirin or abciximab. Clopidogrel, administered for 6 days, reduced the ETP by 60% when platelets were stimulated using 20 mM ADP, whereas collagen-induced ETP and TF-induced ETP remained unchanged. Conclusions: The ETP-method is a sensitive and reproducible method for the detection of drug effects on platelet-induced thrombin generation of high throughput, and can be recommended for studies on the pharmacodynamic profile of drugs interfering with platelet function.Correspondence to:
Prof. Dr. S. Harder; Institute for Clinical Pharmacology at the Pharmazentrum Frankfurt, University Hospital, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany
Email: [email protected]

Review

Pharmacokinetics of pravastatin in heart-transplant patients taking cyclosporin A*

J.-W. Park, R. Siekmeier, M. Merz, B. Krell, S. Harder, W. März, D. Seidel, S. Schüler and W. Groß

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Volume 40 p. 439 - 450

Abstract

J.-W. Park¹, R. Siekmeier²,³, M. Merz⁴, B. Krell⁴, S. Harder⁵, W. März⁶, D. Seidel⁷, S. Schüler⁸ and W. Groß⁹

¹Medizinische Klinik I, Krankenhaus Hoyerswerda, Hoyerswerda, ²Institut für Klinische Chemie und Laboratoriumsmedizin, Klinikum Carl-Gustav-Carus der Technischen Universität, Dresden, ³Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), Bonn, ⁴Herzzentrum Duisburg, Kaiser-Wilhelm-Krankenhaus, Duisburg, ⁵Institut für Klinische Pharmakologie, Klinikum der Johann-Wolfgang-Goethe-Universität, Frankfurt/Main, ⁶Institut für Klinische Chemie – Zentrallabor, Medizinische Klinik der Albert-Ludwigs-Universität, Freiburg, ⁷Institut für Klinische Chemie, Klinikum Großhadern der Universität, München, ⁸Herzzentrum der Universitätsklinik Dresden e.V., Dresden, and ⁹Labor für Angewandte Biochemie, Gustav-Embden-Zentrum für Biologische Chemie der Johann-Wolfgang-Goethe-Universität, Frankfurt am Main
Background: Heart transplantation is an established tool for the treatment of terminal heart failure. Hyperlipidemia is a common problem following heart transplantation and has been implicated as an additional risk factor in the development of transplant coronary artery disease (TxCAD). Therefore, heart recipients are commonly treated with inhibitors of cholesterol synthesis (HMG-CoA reductase inhibitors). However, these patients have an increased risk of developing rhabdomyolysis due to elevated concentrations of HMG-CoA reductase inhibitors under co-administration with the immunosuppressive cyclosporin A (CsA). Aim of the study: Aim of our study was to obtain pharmacokinetic data on pravastatin whilst monitoring the safety and efficiency of the lipid lowering therapy in heart-transplant recipients under immunosuppression with CsA and to compare these data to those of a healthy control group. Subjects, materials and methods: Eleven patients (30.2 ± 12.3 months after transplantation) receiving immunosuppressive therapy consisting of cyclosporin A, prednisone and azathioprine with LDL cholesterol (LDL-C) concentrations exceeding 3.9 mmol/l and 8 control subjects were included into the study. In addition to the immunosuppressive therapy, the patients received a daily dose of 40 mg/day pravastatin for the first 8 days which was then reduced to 10 mg/day administered until Day 29. Blood was sampled for pharmacokinetic profiling (maximum concentration of the drug (Cmax), time to reach Cmax (tmax), area under the concentration vs. time curve (AUC0-24h), elimination half-life time (tel)) and measurement of the parameters of clinical chemistry on Days 1, 8 and 29. The control group received a single dose of 60 mg pravastatin and the values of Cmax and AUC0-24h were normalized for a dose of 10 mg. Results: Pravastatin 40 mg/day for 1 week in the patient group caused a significant reduction in total cholesterol (C) and LDL-C from 8.11 ± 1.20 mmol/l and 5.88 ± 1.15 mmol/l to 6.91 ± 1.01 mmol/l and 4.72 ± 1.05 mmol/l, respectively (p = 0.005 and p = 0.003). Triglycerides and HDL cholesterol (HDL-C) concentrations did not change significantly. Mean values for Cmax of pravastatin were 384.2 ng/ml, 392.0 ng/ml and 115.1 ng/ml in patients on Days 1, 8 and 29, respectively. After normalization for a dose of 10 mg, the corresponding values of Cmax-DN10mg and Cmax were 96.0 ng/ml, 98.0 ng/ml and 115.1 ng/ml on study Days 1, 8 and 29. These values were 7 – 8 times higher than the normalized value of Cmax-DN10mg for the control group (13.7 ng/ml). The corresponding values of AUC0-24h were 1228.2 ng/ml´h, 1214.1 ng/ml´h and 345.9 ng/ml´h in the patient group on study Days 1, 8 and 29 as well as 157.5 ng/ml´h in the control group prior to normalization. After normalization for a dose of 10 mg, the values of AUC0-24h-DN10mg in the patient group were approximately 12 times higher than those of the control group. However, no significant differences between the 2 groups were observed in tmax and tel. Within the patient group, no significant increase in Cmax or AUC was found on Day 1 to Day 8. The results of creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) showed also no significant increase during the observation period. Conclusion: Heart-transplant recipients treated with the HMG-CoA reductase inhibitor pravastatin generally show higher plasma concentrations of this drug than control subjects. However, our data suggest that the HMG-CoA reductase inhibitor pravastatin can be used effectively in these patients receiving the immunosuppressive cyclosporin A. The pharmacokinetic data obtained indicate that there is no significant cumulation of the drug following multiple dosages in spite of increased drug concentrations after a single oral dosage.Correspondence to:
Dr. R. Siekmeier; Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), Kurt-Georg-Kiesinger-Allee 3, D-53175 Bonn
Email: [email protected]

Drug utilization

Lipid-lowering treatment in coronary artery disease: a survey in an ambulatory outpatient clinic

S. Harder, O. Mohr and H. Klepzig

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Volume 39 p. 534 - 538

Abstract

S. Harder¹, O. Mohr¹ and H. Klepzig²

¹Institute of Clinical Pharmacology, University Hospital, Frankfurt/Main, and ²Städtische Kliniken Offenbach, Germany
Objectives: In controlled trials, HMG-CoA reductase inhibitors (statins) effectively reduced cardiovascular events in patients with coronary artery disease (CAD). However, recent pharmacoepidemiological studies indicate an underuse of statins in the target population. The objective of this study was to examine the extent to which CAD patients in Germany actually received statins under field conditions. Methods: We evaluated the medical records of 296 patients referred to the cardiology outpatient clinic of the Frankfurt University Hospital by their general practitioner (GP) in the period 1995 to 1998. All patients had symptomatic, angiographically proven CAD, 142 had previous myocardial infarction. A diagnosis of dyslipidemia was taken from the records. Most patients were visited on more than 1 occasion. In all, we were able to access 296 records for a 1st visit, 76 records for a 2nd visit and 29 records for a 3rd visit and 16 records for > 3 visits. Results: According to the entry criteria of the 4S Trial (total cholesterol 5.5 – 8.0 mmol/l or 212 – 311 mg/dl), 108 patients were deemed as eligible for lipid-lowering treatment, criteria of the LIPID Trial (4.0 – 7.0 mmol/l or 154 – 270 mg/dl) gave a yield of 190 patients. The actual treatment rate with a statin at the 1st visit was 34% (LIPID Group) and 40% (4S Group). At later visits, the treatment rates with statins increased to 63% (LIPID Group) and 79% (4S Group), due to advice given to the GP by the outpatient clinic. When the observation period was devided into 2 periods (04/95 – 01/97; 02/97 – 09/98), actual treatment rates (all visits) for the 4S Group were 43% and 38%, respectively, indicating no further “penetration” of the 4S Study in the therapy decision-making of the GPs. Conclusions: The data indicate that necessary treatment with a HMG-CoA reductase inhibitor is often withheld in the ambulatory setting.Correspondence to:
PD Dr. S. Harder; Institute of Clinical Pharmacology at the Pharmazentrum Frankfurt, University Hospital, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany
Email: [email protected]

Original Research

Appropriate dosing in patients with impaired renal function on medical wards before and after an educational intervention

S. Baum and S. Harder

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Volume 48 p. 29 - 35

Abstract

S. Baum and S. Harder

Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology at the Johann Wolfgang Goethe University Frankfurt, Frankfurt, Germany
Context: Whereas in larger hospitals individualized dose adjustment in renal insufficiency can be provided by expert systems and pharmacists, these options are often not available in smaller hospitals. Aims: We evaluated whether one short educational session for the medical staff of internal wards of a community hospital, focusing on creatinine clearance and dosing in renal insufficiency, and providing a list of frequently used drugs and their dosing schedule does reduce the rate of patients with unadjusted doses. Material and methods: In patients with a creatinine clearance < 60 ml/min, dosing schedules for 92 drugs were determined. After a 6-month observation period (Cohort 1), an educational intervention and the abovementioned list were delivered to the medical staff. This intervention was followed by a further 6-months observation period (Cohort 2). Results: In Cohort 1, 55/85 patients (median age 79 y) had at least one initially inappropriately adjusted medication, and 47/85 remained so at discharge, whereas in Cohort 2 (median age 77 y), 28/85 patients had at least one initially inappropriately adjusted medication (p = 0.014 compared to Cohort 1) and 27/85 remained so at discharge (p = 0.05). In Cohort 1, 46.0% of all prescriptions with drugs which need dose adjustment (n = 220) were not adjusted. After the intervention (Cohort 2), 25.6% of all prescriptions (n = 176) followed an unadjusted dosage (p < 0.001). Conclusion: This intervention was on a “low key”-level, and no further support e.g. academic detailing was effected. Despite this, we found a considerable reduction in the number of inappropriate doses in patients with impaired renal function.Correspondence to:
Prof. Dr. S. Harder
Institute for Clinical Pharmacology at the Pharmazentrum Frankfurt
University Hospital
Theodor-Stern-Kai 7
60590 Frankfurt am Main, Germany
Email: [email protected]

Original

Medication review of community-dwelling seniors using intensified home-care service

M. Ermer and S. Harder

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Volume 49 p. 179 - 184

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 3/2011 (179-184)

Medication review of community-dwelling seniors using intensified home-care service

M. Ermer and S. Harder

Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology at the Johann Wolfgang Goethe University Frankfurt, Frankfurt, Germany
Investigations on medication burden, falling, and inappropriate dosing in renal impairment have been obtained in patients living in nursing homes. Data from home-dwelling patients in intensified ambulatory care, especially from Germany are scant. Material and method: We evaluated patients daily visited by an ambulatory care service (Cohort 1, n = 102, median age 80 y) or had care given by relatives only (cohort 2, n = 101, median age 76 y) at baseline (V1), 6 (V2) and 12 months (V3). Results: At V1 patients in Cohort 1 had 5 (median, range 3 – 15) and at V3 6 (3 – 17) medications. No differences could be observed between cohorts regarding number and pattern of medications. At V1, 30/102 patients of Cohort 1 had creatinine measured within the last 6 months, 13/30 patients had an eGFR < 50 ml/min. 6/34 medications which need dose-adjustment were unadjusted. Low surveillance of renal function and unadjusted dosing were also observed at other visits and also in Cohort 2. Within 1 year, 29/75 mobile patients in cohort 1 had a fall, 18/29 patients had a benzodiazepine prescribed regularly, whereas a benzodiazepine was prescribed in 6/46 patients which did not fall (chi² p = 0.004). In Cohort 2, the number of falling patients was lower (19/84 mobile patients, p = 0.028). 11/19 patients had a benzodiazepine prescribed, in contrast to 5/65 patients which did not fall (chi² p = 0.001). Conclusions: It needs to be elucidated whether a care service can contribute to medication safety in patients e.g. by reviewing medication charts and organizing for controls of ancillary laboratory values.Correspondence to:
Prof. Dr. med. S. Harder
Institute for Clinical Pharmacology at the Pharmazentrum Frankfurt
University Hospital Frankfurt/Main
Theodor Stern Kai 7
60590 Frankfurt am Main, Germany
Email: [email protected]

Guideline for General Practitioners

Recommendations for Treating Adult and Geriatric Patients on Multimedication

F.W. Bergert, M. Braun, K. Ehrenthal, J. Feßler, J. Gross, U. Hüttner, B. Kluthe, A. Liesenfeld, J. Seffrin, G. Vetter, M. Beyer, C. Muth, U. Popert, S. Harder, H. Kirchner and I. Schubert

Volume 52 p. 1 - 64

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