Eva-Luise Hobl

Morphine Decreases Clopidogrel Concentrations and Effects A Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVES This study sought to examine the possible drug-drug interactions between clopidogrel and morphine. BACKGROUND Because morphine-the recommended treatment for pain of myocardial infarction-is associated with poor clinical outcome, we hypothesized that morphine lowers the plasma levels of clopidogrel active metabolite as well as its effects on platelets. METHODS Twenty-four healthy subjects received a loading dose of 600 mg clopidogrel together with placebo or 5 mg morphine intravenously in a randomized, double-blind, placebo-controlled, cross-over trial. Pharmacokinetics was determined by liquid chromatography tandem mass spectrometry, and clopidogrel effects were measured by platelet function tests. RESULTS Morphine injection delayed clopidogrel absorption (p = 0.025) and reduced the area under the curve levels of its active metabolite by 34% (p = 0.001). Morphine delayed the maximal inhibition of platelet aggregation on average by 2 h (n = 24; p < 0.001). Residual platelet aggregation was higher 1 to 4 h after morphine injection (n = 24; p < 0.005). Furthermore, morphine delayed the inhibition of platelet plug formation under high shear rates (P2Y-Innovance; n = 21; p < 0.004) and abolished the 3-fold prolongation in collagen adenosine diphosphate-induced closure times seen in extensive and rapid metabolizers (n = 16; p = 0.001). CONCLUSIONS Morphine delays clopidogrel absorption, decreases plasma levels of clopidogrel active metabolite, and retards and diminishes its effects, which can lead to treatment failure in susceptible individuals. (Drug/Drug Interactions of Aspirin and P2Y12-inhibitors; NCT01369186).

Clinical ResearchAntithrombotic TherapyMorphine Decreases Clopidogrel Concentrations and Effects: A Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVES This study sought to examine the possible drug-drug interactions between clopidogrel and morphine. BACKGROUND Because morphine-the recommended treatment for pain of myocardial infarction-is associated with poor clinical outcome, we hypothesized that morphine lowers the plasma levels of clopidogrel active metabolite as well as its effects on platelets. METHODS Twenty-four healthy subjects received a loading dose of 600 mg clopidogrel together with placebo or 5 mg morphine intravenously in a randomized, double-blind, placebo-controlled, cross-over trial. Pharmacokinetics was determined by liquid chromatography tandem mass spectrometry, and clopidogrel effects were measured by platelet function tests. RESULTS Morphine injection delayed clopidogrel absorption (p = 0.025) and reduced the area under the curve levels of its active metabolite by 34% (p = 0.001). Morphine delayed the maximal inhibition of platelet aggregation on average by 2 h (n = 24; p < 0.001). Residual platelet aggregation was higher 1 to 4 h after morphine injection (n = 24; p < 0.005). Furthermore, morphine delayed the inhibition of platelet plug formation under high shear rates (P2Y-Innovance; n = 21; p < 0.004) and abolished the 3-fold prolongation in collagen adenosine diphosphate-induced closure times seen in extensive and rapid metabolizers (n = 16; p = 0.001). CONCLUSIONS Morphine delays clopidogrel absorption, decreases plasma levels of clopidogrel active metabolite, and retards and diminishes its effects, which can lead to treatment failure in susceptible individuals. (Drug/Drug Interactions of Aspirin and P2Y12-inhibitors; NCT01369186).

Morphine decreases ticagrelor concentrations but not its antiplatelet effects: a randomized trial in healthy volunteers

Our recent drug interaction trial with clopidogrel shows that morphine decreases the concentrations and pharmacodynamic effects of clopidogrel, which could lead to treatment failure in susceptible individuals.

Reversal strategy in antagonizing the P2Y12 -inhibitor ticagrelor.

Patients on antiplatelet therapy have a higher incidence of bleeding complications. Reversal of antiplatelet drug effects is an important issue at trauma or emergency departments. For old and conventional anticoagulants, reversal strategies are established. While the effects of ticagrelor are reversible, developing a method to restore platelet function in patients is of importance due to its longer half‐life (approximately 8 h), compared with other P2Y12‐inhibitors.

A randomized, double-blind, parallel, single-site pilot trial to compare two different starting doses of methotrexate in methotrexate-naïve adult patients with rheumatoid arthritis.

BACKGROUND Methotrexate (MTX) is a cornerstone in the treatment of rheumatoid arthritis. Despite its widespread use, expert opinions differ about the optimal MTX starting dosage to achieve rapid onset of action while averting increased occurrence of adverse effects. Plasma concentrations have not been assessed in previous studies that monitored clinical efficacy. OBJECTIVE This study was performed to compare the pharmacokinetic parameters and clinical response of a standard (15 mg) and an accelerated (25 mg) dosing regimen, each administered orally once a week. METHODS This randomized, controlled, double-blind, parallel, single-site study included 19 MTX-naïve patients older than 18 years with rheumatoid arthritis. Patients participated for 16 weeks. Disease activity was assessed using the Disease Activity Score in 28 joints (DAS-28) as the primary outcome parameter. Plasma MTX concentrations were measured using HPLC at weeks 1, 5, 10, and 16. Tolerability was assessed via routine blood analysis (hematology and clinical chemistry) and a patient questionnaire to monitor adverse events. Reported or observed adverse events were recorded along with information about their severity and causal relationship to the study medication. RESULTS Nineteen white patients (13 women and 6 men; mean age, 56 years; and mean weight, 74 kg) participated. At study entry, mean (SD) DAS-28-4v (erythrocyte sedimentation rate) was 4.73 (1.02). Health Assessment Questionnaire scores were 1.45 (0.85); for C-reactive protein, 11.45 (10.04) mg/dL; for alkaline phosphatase, 73.58 (19.91) U/L; for aspartate aminotransferase, 23.32 (7.13) U/L; and for creatinine, 0.87 (0.22) mg/dL. Although pharmacokinetic parameters such as AUC and C(max) were significantly higher after the accelerated dosing regimen, clinical activity scores (DAS-28) and inflammation parameters (C-reactive protein) did not indicate a significant benefit of an accelerated starting regimen. Considering toxicity, no elevation in liver function enzymes and no decrease in renal function were observed using the accelerated dosing (statistical significance set at P ≤ 0.05). No serious adverse events were noted. All observed adverse events were classified as study related. Overall, adverse events were noted in 58% of patients. Comparison of the two doses revealed that 60% of patients receiving the standard dosing regimen and 56% of patients receiving the accelerated dosing regimen reported adverse events, the most frequent being gastrointestinal. These events were generally self-limiting. CONCLUSIONS Differences in clinical response between these two small selected patient groups who received an initial oral dose of either 15 or 25 mg MTX per week did not reach the level of statistical significance. The overall incidence of adverse effects, all classified as study related, was 58%, with 60% of patients receiving the standard dosage and 56% of patients receiving the accelerated dosing regimen reporting adverse effects. However, because of the small sample size, this study was not powered to detect differences in the incidence of adverse events between the two dosing groups. ClinicalTrials.gov identifier: NCT00695188.

Simultaneous determination of acetylsalicylic acid and salicylic acid in human plasma by isocratic high-pressure liquid chromatography with post-column hydrolysis and fluorescence detection

A selective, sensitive and rapid high-performance liquid chromatography method with post-column hydrolysis and fluorescence detection was developed for the simultaneous quantification of acetylsalicylic acid and its metabolite salicylic acid in human plasma. Following the addition of 2-hydroxy-3-methoxybenzoic acid as internal standard and simple protein precipitation with acetonitrile, the analytes were separated on a ProntoSIL 120 C18 ace-EPS column (150 × 2 mm, 3 µm) protected by a C8 guard column (5 µm). The mobile phase, 10 mm formic acid in water (pH 2.9) and acetonitrile (70:30, v/v), was used at a flow rate of 0.35 mL/min. After on-line post-column hydrolysis of acetylsalicylic acid (ASA) to salicylic acid (SA) by addition of alkaline solution, the analytes were measured at 290 nm (λex ) and 400 nm (λem ). The method was linear in the concentration ranges between 0.05 and 20 ng/μL for both ASA and SA with a lower limit of quantification of 25 pg/μL for SA and 50 pg/μL for ASA. The limit of detection was 15 pg/μL for SA and 32.5 pg/μL for ASA. The analysis of ASA and SA can be carried out within 8 min; therefore this method is suitable for measuring plasma concentrations of salicylates in clinical routine.

Absorption kinetics of low-dose chewable aspirin – implications for acute coronary syndromes

This study describes the implications of the pharmacokinetics of low‐dose chewable aspirin for acute coronary syndromes. Current guidelines recommend the administration of 162–325 mg aspirin chewing tablets for the treatment of acute myocardial infarction. Although aspirin is widely used and a cornerstone in myocardial infarction, there is no information available on the pharmacokinetics of low doses of chewable aspirin.

Comparison of a new ELISA‐based with the flow cytometric assay for vasodilator‐associated stimulated phosphoprotein phosphorylation to assess P2Y12‐inhibition after ticagrelor intake

Ticagrelor is a P2Y12 receptor antagonist, with superior effects but also ensuing enhanced bleeding risk as compared to clopidogrel. Determination of platelet inhibition may be useful to confirm efficient platelet inhibition on an individual patient level and to identify patients at risk for bleeding. The vasodilator‐associated stimulated phosphoprotein (VASP) phosphorylation assay specifically measures platelet P2Y12 inhibition, but has so far required individual sample processing. A new ELISA‐based VASP assay has been developed, which allows batch analysis after initial platelet activation. Because of the reversible binding of ticagrelor it is unclear if the ELISA and flow cytometric assays provide comparable results; several washing steps of the ELISA may potentially result in false low results through dilution.

Towards the development of specific antidotes: Idarucizumab for reversal of dabigatran effects

Towards the development of specific antidotes: Idarucizumab for reversal of dabigatran effects -

Clopidogrel in Critically Ill Patients

Only limited data are available regarding the treatment of critically ill patients with clopidogrel. This trial investigated the effects and the drug concentrations of the cytochrome P450 (CYP450) activated prodrug clopidogrel (n = 43) and the half‐life of the similarly metabolized pantoprazole (n = 16) in critically ill patients. ADP‐induced aggregometry in whole blood classified 74% (95% confidence intervals 59–87%) of critically ill patients as poor responders (n = 43), and 65% (49–79%) responded poorly according to the vasodilator‐stimulated phosphoprotein phosphorylation (VASP‐P) assay. Although the plasma levels of clopidogrel active metabolite normally exceed the inactive prodrug ∼30‐fold, the parent drug levels even exceeded those of the metabolite 2‐fold in critically ill patients. The half‐life of pantoprazole was several‐fold longer in these patients compared with reference populations. The inverse ratio of prodrug/active metabolite indicates insufficient metabolization of clopidogrel, which is independently confirmed by the ∼5‐fold increase in half‐life of pantoprazole. Thus, high‐risk patients may benefit from treatment with alternative platelet inhibitors.