Katarzyna Buszko

Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial

Abstract Aims The currently available data indicate a drug–drug interaction between morphine and oral P2Y12 receptor inhibitors, when administered together. The aim of this trial was to assess the influence of infused morphine on pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite (AR-C124910XX) in patients with acute myocardial infarction. Methods and results In a single-centre, randomized, double-blind trial, patients were assigned in a 1:1 ratio to receive intravenously either morphine (5 mg) or placebo, followed by a 180 mg loading dose of ticagrelor. Pharmacokinetics was determined with liquid chromatography tandem mass spectrometry and ticagrelor antiplatelet effects were measured with up to three different platelet function tests: vasodilator-stimulated phosphoprotein phosphorylation assay, multiple electrode aggregometry and VerifyNow. The pharmacokinetic and pharmacodynamic assessment was performed in 70 patients (35 in each study group). Morphine lowered the total exposure to ticagrelor and its active metabolite by 36% (AUC(0–12): 6307 vs. 9791 ng h/mL; P = 0.003), and 37% (AUC(0–12): 1503 vs. 2388 ng h/mL; P = 0.008), respectively, with a concomitant delay in maximal plasma concentration of ticagrelor (4 vs. 2 h; P = 0.004). Multiple regression analysis showed that lower AUC(0–12) values for ticagrelor were independently associated with the administration of morphine (P = 0.004) and the presence of ST-segment elevation myocardial infarction (P = 0.014). All three methods of platelet reactivity assessment showed a stronger antiplatelet effect in the placebo group and a greater prevalence of high platelet reactivity in patients receiving morphine. Conclusions Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction. ClinicalTrials.gov Identifier: NCT02217878.

Comparison of Ticagrelor Pharmacokinetics and Pharmacodynamics in STEMI and NSTEMI Patients (PINPOINT): protocol for a prospective, observational, single-centre study

Introduction The most common classification of acute myocardial infarction (AMI) is based on electrocardiographic findings and distinguishes ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI). Both types of AMI differ concerning their epidemiology, clinical approach and early outcomes. Ticagrelor is a P2Y12 receptor inhibitor, constituting the first-line treatment for STEMI and NSTEMI. According to available data, STEMI may be associated with lower plasma concentration of ticagrelor in the first hours of AMI, but currently there are no studies directly comparing ticagrelor pharmacokinetics or antiplatelet effect in patients with STEMI versus NSTEMI. Methods and analysis The PINPOINT study is a phase IV, single-centre, investigator-initiated, prospective, observational study designed to compare the pharmacokinetics and pharmacodynamics of ticagrelor in patients with STEMI and NSTEMI assigned to the invasive strategy of treatment. Based on an internal pilot study, the trial is expected to include at least 23 patients with each AMI type. All subjects will receive a 180 mg loading dose of ticagrelor. The primary end point of the study is the area under the plasma concentration-time curve (AUC(0–6)) for ticagrelor during the first 6 hours after the loading dose. Secondary end points include various pharmacokinetic features of ticagrelor and its active metabolite (AR-C124910XX), and evaluation of platelet reactivity by the vasodilator-stimulated phosphoprotein assay and multiple electrode aggregometry. Blood samples for the pharmacokinetic and pharmacodynamic assessment will be obtained at pretreatment, 30 min, 1, 2, 3, 4, 6 and 12 hours post-ticagrelor loading dose. Ethics and dissemination The study received approval from the Local Ethics Committee (Komisja Bioetyczna Uniwersytetu Mikołaja Kopernika w Toruniu przy Collegium Medicum im. Ludwika Rydygiera w Bydgoszczy; approval reference number KB 617/2015). The study results will be disseminated through conference presentations and peer-reviewed journals. Trial registration number NCT02602444; Pre-results.

Rationale and Design of the Effectiveness of LowEr maintenanCe dose of TicagRelor early After myocardial infarction (ELECTRA) pilot study

Aims The degree and time course of platelet inhibition using ticagrelor can vary during the acute phase and the following stable period after acute myocardial infarction (AMI). The optimal level of platelet inhibition during the various stages of AMI remains an open question. The aim of the current study is to compare the antiplatelet efficacy of two ticagrelor maintenance dose regimens (60 mg b.i.d. vs. 90 mg b.i.d.) in stable patients following an initial strategy with ticagrelor 90 mg b.i.d. during the first month after AMI. Methods and results The Effectiveness of LowEr maintenanCe dose of TicagRelor early After myocardial infarction (ELECTRA) pilot study is a phase III, single-centre, randomized, open-label, pharmacokinetic/pharmacodynamic trial. The study population will include 50 patients with AMI treated with percutaneous coronary intervention. At Day 30 post-AMI, all trial participants will be randomly assigned in 1:1 ratio to receive either reduced (60 mg b.i.d.) or standard (90 mg b.i.d.) maintenance ticagrelor dose until Day 45 post-AMI. Platelet function testing in each patient will be performed using up to two different methods (the VASP assay and multiple electrode aggregometry). Pharmacokinetics of ticagrelor and its active metabolite (AR-C124910XX) will be assessed by liquid chromatography mass spectrometry. Conclusion A de-escalation strategy with reduced dose of ticagrelor (60 mg b.i.d.) following an initial standard dose (90 mg b.i.d.) during the first month after AMI may provide equally effective platelet inhibition as compared to maintenance with the standard ticagrelor dose. ClinicalTrials. gov Identifier NCT03251859.

Comparison of bioavailability and antiplatelet action of ticagrelor in patients with ST-elevation myocardial infarction and non-ST-elevation myocardial infarction: A prospective, observational, single-centre study

Background Data from available studies suggest that the presence of ST-elevation myocardial infarction (STEMI) may be associated with delayed and attenuated ticagrelor bioavailability and effect compared with non-ST-elevation myocardial infarction (NSTEMI). Methods In a single-center, prospective, observational trial 73 patients with myocardial infarction (STEMI n = 49, NSTEMI n = 24) underwent a pharmacokinetic and pharmacodynamic assessment after a 180 mg ticagrelor loading dose (LD). Ticagrelor and its active metabolite (AR-C124910XX) plasma concentrations were determined with liquid chromatography tandem mass spectrometry, and their antiplatelet effect was measured with the VASP assay and multiple electrode aggregometry. Results During the first six hours after ticagrelor LD, STEMI patients had 38% and 34% lower plasma concentration of ticagrelor and AR-C124910XX, respectively, than NSTEMI (ticagrelor AUC(0–6): 2491 [344–5587] vs. 3991 [1406–9284] ng*h/mL; p = 0.038; AR-C124910XX AUC(0–6): 473 [0–924] vs. 712 [346–1616] ng*h/mL; p = 0.027). STEMI patients also required more time to achieve maximal concentration of ticagrelor (tmax: 4.0 [3.0–12.0] vs. 2.5 [2.0–6.0] h; p = 0.012). Impaired bioavailability of ticagrelor and AR-C124910XX seen in STEMI subjects was associated with diminished platelet inhibition in this group, which was most pronounced during the initial hours of treatment. Conclusions Plasma concentrations of ticagrelor and AR-C124910XX during the first hours after ticagrelor LD were one third lower in STEMI than in NSTEMI patients. This reduced and delayed ticagrelor bioavailability was associated with weaker antiplatelet effect in STEMI. Clinical trial registration ClinicalTrials.gov identifier: NCT02602444 (November 09, 2015)

Transient Dynamics Inside Periodic Windows and in Their Vicinity I. Logistic Maps

The paper contains results of numerical experiments on evolution generated by logistic maps inside periodic windows and in their vicinity. We study properties of dynamics in terms of rambling time inside periodic windows and duration of the non-laminar phase in their proximity, showing that a close relation between these two notions exists. We also give results of numerical experiments on map-generated evolution of measure on the unit interval.

Bone morphogenetic protein 6—a possible new player in pathophysiology of heart failure

Derangement of bone morphogenetic protein (BMP) signalling was observed in cardiovascular disorders. The present study assesses the diagnostic and prognostic value of BMP6 plasma concentration in chronic heart failure (CHF). 130 CHF patients and 32 controls participated in the study. BMP6 plasma level was measured at baseline. During 12‐month follow‐up death and hospitalisation with CHF exacerbation were recorded. BMP6 was significantly increased in CHF patients with highest concentration in most advanced disease. Individuals with pulmonary congestion or peripheral oedema had higher levels of BMP6 than isovolemic patients. BMP6 was not a predictor of all‐cause mortality or CHF hospitalisation. BMP6 may be involved in pathophysiology of systolic CHF. BMP6 plasma level is related to the disease severity and signs of exacerbation.

Melanoma cell adhesion molecule as an emerging biomarker with prognostic significance in systolic heart failure

BACKGROUND Melanoma cell adhesion molecule (MCAM) is a marker of endothelial damage. MCAM diagnostic and prognostic value was assessed in chronic heart failure (CHF). MATERIALS & METHODS 130 CHF patients and 32 controls were included in the study. Telephone follow-up lasted one year. End points were: death from all causes, and hospitalization with CHF exacerbation. RESULTS MCAM was higher in patients than in controls (p = 0.01). Receiver operator curve analysis revealed that MCAM may serve as a predictor of death (area under the curve: 0.8404; p < 0.002). Patients with MCAM above 500 ng/ml had worse prognosis (p = 0.03). NT-proBNP and age were independent predictors of death in multivariate analysis. CONCLUSION The increased MCAM indicates endothelial damage in CHF and may serve as a marker of worse prognosis in these patients.

The Adherence Scale in Chronic Diseases (ASCD). The power of knowledge: the key to successful patient — health care provider cooperation

Introduction. Autotransfusions of ozonised blood or infusions of gaseous ozone into blood vessels andbody cavities are believed to exert therapeutic effects in some pathological states. Investigations on thereaction of ozone with biological molecules and membrane structures are a subject of crucial importance. The present study aimed to yield more precise data about the alterations, which occur in different erythrocytemembrane regions subjected to medical ozone. This could provide some additional informationabout the structural changes in the membrane at a molecular level. Material and methods. Blood was obtained from 22 healthy volunteers (aged 21 to 63) by vein puncture andmixed with 1/10 volume of 0.13 M trisodium citrate. Erythrocytes were isolated from fresh blood by centrifugationat 4°C, at 1,500 × g and purified by three cycles of resuspension and washing with PBS. Ozone was generatedby passing pure gaseous oxygen at 30 l/h through an apparatus producing silent electric discharges. EPRspectra were obtained at X-band (9.4 GHz), at modulation frequency of 100 kHz. The scan time was 4 min, and the time constant 0.3 s. Since biological membranes are heterogeneous systems composed of severalcoexisting domains, EPR spectra are superimpositions of several spectra with different fluidity parameters. Results. The effects of ozone at two concentrations (10 and 45 g/m3) on fluidity and phospholipid domainstructure of erythrocyte membranes were investigated by electron paramagnetic resonance (EPR). Atincreased ozone concentration (45 g/m3), the portion of the least ordered domains (WLO) increased, witha corresponding decrease of ordered (WMO, WO), more rigid regions. The order of lipid acyl chains of twoordered (MO and O) as well as the least ordered (LO) domains diminished, as expressed by smaller orderparameters. For ozone concentration of 10 g/m3 values of order parameter were slightly increased, whichindicates a tendency to rigidisation of lipid bilayer at this ozone concentration. This change was, however,statistically insignificant. There were no statistically significant differences in the thermotropic behaviour ofweight factor of ordered domains (WMO, WO) between ozonised and control red cells. Conclusion. The obtained data shows that ozonation of erythrocytes results in cell membrane fluidisationand an increase in red cell deformability. On the other hand, these results could suggest that ozonationof erythrocytes leads to structural changes in the membranes, especially in cytoskeletal proteins, but thiseffect is probably dose-dependent.

The impact of laser irradiation on global stability in patients with vertebrobasilar insufficiency: A clinical report

Summary Background The purpose of our experiment was to determine whether laser stimulation can improve microcirculation in the posterior regions of the brain in patients with vertebrobasilar insufficiency (VBI). Material/Methods We studied 25 patients (20 female, 5 male, mean age 64) diagnosed with chronic VBI. All were evaluated using the De Klyn test, followed by qualitative assessment of stability using a Berg Balance Scale and evaluation of global stability using an electronic balance platform. A CTL-1100 low power laser was used with standard parameters. We established a protocol for laser irradiation at 5 points along the vertebral artery in the cervical region bilaterally. Irradiation was performed 10 times over two weeks. Results Significant improvement occurred after therapy in headache (p=0.0005), vertigo (p<0.0000), and tinnitus (p=0.0387). No significant differences were observed in nausea or nystagmus caused by head rotation. The Berg Balance Scale results showed significant differences in almost all features. There was a tendency towards improved stability in all parameters, and statistically significant differences in the total surface of support and the spread surface of support for the left foot. Conclusions Laser stimulation as applied in this study can be useful in the treatment of patients with VBI. The main reason for improvement in global stability, balance, and other VBI symptoms is better blood perfusion.

Metabolism of ticagrelor in patients with acute coronary syndromes

Ticagrelor is a state-of-the-art antiplatelet agent used for the treatment of patients with acute coronary syndromes (ACS). Unlike remaining oral P2Y12 receptor inhibitors ticagrelor does not require metabolic activation to exert its antiplatelet action. Still, ticagrelor is extensively metabolized by hepatic CYP3A enzymes, and AR-C124910XX is its only active metabolite. A post hoc analysis of patient-level (n = 117) pharmacokinetic data pooled from two prospective studies was performed to identify clinical characteristics affecting the degree of AR-C124910XX formation during the first six hours after 180 mg ticagrelor loading dose in the setting of ACS. Both linear and multiple regression analyses indicated that ACS patients presenting with ST-elevation myocardial infarction or suffering from diabetes mellitus are more likely to have decreased rate of ticagrelor metabolism during the acute phase of ACS. Administration of morphine during ACS was found to negatively influence transformation of ticagrelor into AR-C124910XX when assessed with linear regression analysis, but not with multiple regression analysis. On the other hand, smoking appears to increase the degree of ticagrelor transformation in ACS patients. Mechanisms underlying our findings and their clinical significance warrant further research.