Katarzyna Stankowska

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.

Prasugrel overcomes high on-clopidogrel platelet reactivity in the acute phase of acute coronary syndrome and maintains its antiplatelet potency at 30-day follow-up

BACKGROUND The aim of this study was to assess antiplatelet effect of prasugrel in acute coronary syndrome (ACS) patients with high on-treatment platelet reactivity (HTPR) on clopidogrel, undergoing percutaneous coronary intervention (PCI). METHODS A prospective, platelet reactivity-guided, parallel-group, open-label study including 71 patients pretreated with clopidogrel 600 mg and assigned either to prasugrel (30 mg loading dose, 10 mg maintenance dose; n = 46) or clopidogrel (150 mg maintenance dose for 6 days and thereafter 75 mg maintenance dose; n = 25) regimen, based on vasodilator-stimulated phosphoprotein (VASP)-assessed platelet reactivity index (PRI; > 50% vs. ≤ 50%) measured next morning post-PCI. RESULTS Median PRI value after switch to prasugrel sharply declined at 24 h (70.0 [61.3-75.6] vs. 11.9 [6.8-25.7]%; p < 0.000001) and slightly but significantly rose between 24 h and 30 days (27.9 [15.5-46.8]%; p < 0.0006). In contrast, median PRI values in the clopidogrel group were similar at baseline and at 24 h (25.1 [13.7-40.2] vs. 22.0 [18.4-36.8]%; p = NS) and then modestly rose at 30 days (30.3 [20.4-45.7]%; p < 0.03). The prevalence of HTPR decreased in the prasugrel group between baseline and 24 h measurements (100.0 vs. 4.3%; p < 0.0001). Rates of patients with HTPR at 24 h and 30 days were similar in both groups, so were the tendencies in patterns of platelet inhibition evaluated with multiple electrode aggregometry as compared with the VASP assay. CONCLUSIONS Our study indicates that prasugrel overcomes HTPR on clopidogrel in the acute phase of interventionally treated ACS and maintains its antiplatelet potency in 30-day follow-up. Potential clinical benefits of personalized antiplatelet prasugrel-based therapy warrant further investigation in clinical ACS trials.

Impact of type 2 diabetes on the plasma levels of vascular endothelial growth factor and its soluble receptors type 1 and type 2 in patients with peripheral arterial disease

ObjectiveType 2 diabetes coexistent with lower extremity artery disease (peripheral arterial disease (PAD)) can be observed in numerous patients. The mechanism compensating for ischemia and contributing to healing is angiogenesis—the process of forming new blood vessels. The purpose of this study was to assess the likely impact of type 2 diabetes on the plasma levels of proangiogenic factor (vascular endothelial growth factor A (VEGF-A)) and angiogenesis inhibitors (soluble VEGF receptors type 1 and type 2 (sVEGFR-1 and sVEGFR-2)) in patients with PAD.MethodAmong 46 patients with PAD under pharmacological therapy (non-invasive), we identified, based on medical history, a subgroup with coexistent type 2 diabetes (PAD-DM2+, n=15) and without diabetes (PAD-DM2−, n=31). The control group consisted of 30 healthy subjects. Plasma levels of VEGF-A, sVEGFR-1, and sVEGFR-2 were measured using the enzyme-linked immunosorbent assay (ELISA) method.ResultsThe subgroups of PAD-DM2+ and PAD-DM2−revealed significantly higher concentrations of VEGF-A (P=0.000 007 and P=0.000 000 1, respectively) and significantly lower sVEGFR-2 levels (P=0.02 and P=0.000 01, respectively), when compared with the control group. Patients with PAD and coexistent diabetes tended to have a lower level of VEGF-A and higher levels of sVEGFR-1 and sVEGFR-2 comparable with non-diabetic patients.ConclusionsThe coexistence of type 2 diabetes and PAD is demonstrated by a tendency to a lower plasma level of proangiogenic factor (VEGF-A) and higher levels of angiogenesis inhibitors (sVEGFR-1 and sVEGFR-2) at the same time. Regardless of the coexistence of type 2 diabetes, hypoxia appears to be a crucial factor stimulating the processes of angiogenesis in PAD patients comparable with healthy individuals, whereas hyperglycemia may have a negative impact on angiogenesis in lower limbs.中文概要目 的研究2 型糖尿病对外周动脉疾病患者血浆内的血管内皮生长因子(VEGF-A)及其水溶性受体(sVEGFR-1 和sVEGFR-2)浓度的影响。创新点首次研究了2 型糖尿病对外周动脉疾病患者血浆内sVEGFR-1 和sVEGFR-2 浓度的影响。方 法选取46 个外周动脉疾病患者, 根据有无2 型糖尿病分为糖尿病组(15 例)和无糖尿病组(31 例), 另选30 个健康志愿者为正常对照组。采用酶联免疫吸附法(ELISA)检测他们血浆中VEGF-A及sVEGFR-1 和sVEGFR-2 的浓度, 然后通过对比各组浓度研究2 型糖尿病的影响。结 论与正常对照组相比, 外周动脉疾病患者具有较高的VEGF-A 浓度(2 型糖尿病组 P=0.000 007, 非糖尿病组 P=0.000 000 1)以及较低的sVEGFR-2浓度(2 型糖尿病组 P=0.02, 非糖尿病组 P=0.000 01)。同时, 2 型糖尿病组比非糖尿病组具有较低的VEGF-A 浓度及较高的sVEGFR-1 和sVEGFR-2 浓度。研究结果表明: 无论2 型糖尿病是否共存, 缺氧是导致血管生成的一个关键的刺激因素; 同时, 高血糖状态对下肢的血管生成有抑制作用。

CRP, but not TNF-α or IL-6, decreases after weight loss in patients with morbid obesity exposed to intensive weight reduction and balneological treatment.

ObjectiveThe aim of this study was to evaluate the concentrations of C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and the degree of homeostasis model assessment-insulin resistance (HOMA-IR) in patients with morbid obesity exposed to a three-week low-calorie diet and balneotherapy.MethodsThe study included 33 patients (25 females and 8 males; mean age 46 years) with body mass index (BMI) values of >40 kg/m2. Evaluations of CRP, IL-6, TNF-α, lipid profile, HOMA-IR, and fasting glucose were carried out before (baseline data) and three weeks after the treatment. The control group consisted of 20 healthy volunteers (15 females and 5 males) with a mean age of 39 years and BMI values of ≤24.9 kg/m2.ResultsIn the blood of patients with morbid obesity we found significantly elevated levels of CRP, TNF-α, triglycerides, HOMA-IR and fasting glucose, but a decreased level of high density lipoprotein (HDL)-cholesterol, compared with the healthy individuals. The treatment resulted in about a 9.4% reduction in body weight from 122.5 to 111.0 kg and a significant decrease in the concentration of CRP, but no change in TNF-α or IL-6. HOMA-IR was significantly reduced.ConclusionThe decrease in CRP level without changes in TNF-α or IL-6 concentrations after the low-calorie diet and balneological treatment, suggests that an essential amount of adipose tissue must be removed before proper adipocyte function is restored. The decrease in HOMA-IR indicates an improvement in insulin sensitivity, which is beneficial in obese patients.概要目的评估病态肥胖患者在低热量饮食和浸浴治疗前后, C 反应蛋白 (CRP)、肿瘤坏死因子α (TNF-α)、白细胞介素-6 ( IL-6) 以及胰岛素抵抗指数 (HOMA-IR) 的水平变化。创新点研究炎症反应对病态肥胖的影响。方法本研究包括33 个病例和20 个正常对照, 对治疗前后的CRP、IL-6、TNF-α、血脂谱、HOMA-IR以及空腹血糖水平进行评估。结论与对照组相比, 低热量饮食和浸浴治疗后, 病态肥胖患者的CRP水平显著降低, 而TNF-α 和IL-6的水平却没有显著变化, 这表明脂肪细胞的正常功能恢复之前必须先去除一定量的脂肪组织。HOMA-IR 水平的降低说明对胰岛素的敏感性有所提高, 这有利于肥胖患者的治疗。

Selected parameters of hemostasis in patients with myeloproliferative neoplasms.

Hemostatic disorders are a major clinical problem in patients with myeloproliferative neoplasms (MPNs) and they are the second most common cause of death in MPN patients, after infections. The aim of this study was to assess the fibrinolytic potential of the blood of patients with MPNs. The study involved 112 patients with MPNs diagnosed at the Hematology Clinic Dr J. Biziel University Hospital No. 2 in Bydgoszcz, Poland. The study group included 63 patients with essential thrombocythemia, 29 with polycythemia vera, 11 with chronic myelogenous leukemia (CML) and nine with primary myelofibrosis. The control group consisted of 25 healthy volunteers who were age and sex-matched. The following parameters were determined: concentration of tissue plasminogen activator antigen (t-PA:Ag), plasminogen activator inhibitor type 1 antigen concentration (PAI-1:Ag), D-dimer, thrombin–antithrombin complexes, fibrinogen, activated partial thromboplastin time and international normalized ratio. The study showed significantly increased t-PA:Ag, PAI-1:Ag and D-dimer levels in patients with MPNs. Moreover, we found increased concentrations of thrombin–antithrombin complexes and fibrinogen, as well as elevated platelet counts. Detailed analysis revealed that t-PA:Ag concentration was elevated in patients with essential thrombocythemia, CML and polycythemia vera. Concentration of PAI-1:Ag was increased in patients with essential thrombocythemia and polycythemia vera; D-dimer was significantly higher in essential thrombocythemia, polycythemia vera, CML and primary myelofibrosis patients. Increased concentrations of t-PA:Ag and D-dimer indicate secondary activation of the fibrinolytic system in patients with MPNs. Elevated levels of PAI-1 in MPN patients may result from its increased production by elevated number of activated platelets and vascular endothelial damage. PAI-1 by having an inhibitory effect on fibrinolysis manifests its procoagulant activity.

Overweight and obesity versus concentrations of VEGF-A, sVEGFR-1, and sVEGFR-2 in plasma of patients with lower limb chronic ischemia

ObjectiveBeing overweight or obese comprises a significant risk factor for atherosclerosis. Fat tissue also generates factors stimulating angiogenesis, the process by which new blood vessels form. The purpose of this paper is to assess concentrations of the vascular endothelial growth factor A (VEGF-A) and its soluble type-1 and type-2 receptors (sVEGFR-1 and sVEGFR-2) in plasma of patients with peripheral arterial disease (PAD) depending on the level of nutrition according to body mass index (BMI).MethodsThe study group included patients suffering from symptomatic PAD (n=46) in Fontaine classes IIa–IV without any history of neoplastic disease and who have a normal BMI (n=15), are overweight (n=21) or are obese (n=10). The control group (n=30) consisted of healthy non-smoking volunteers who were neither overweight nor obese. Venous blood plasma samples were collected from both groups at rest in the morning to determine plasma concentrations of VEGF-A, sVEGFR-1, and sVEGFR-2 using the enzymelinked immunosorbent assay (ELISA) method.ResultsThe group of patients with PAD co-existent with being overweight or obese tended to have higher mean concentration levels of VEGF-A and sVEGFR-2 when compared with patients suffering from PAD with normal BMI. A statistically significant positive correlation was obtained between BMI and average plasma concentrations of sVEGFR-2 (R=0.37, P=0.0103). However, no significant correlation was noticed between BMI and VEGF-A or sVEGFR-1 concentrations.ConclusionsA positive correlation determined between the level of antiangiogenic factor and BMI value may be indicative of the linearly growing prevalence of some antiangiogenic factors in patients with metabolic disorders, which may be one of numerous factors contributing to incomplete efficiency of collateral circulation development in patients with PAD.中文概要目 的研究外周动脉疾病(PAD) 患者血浆中血管内皮 生长因子A(VEGF-A) 和它的可溶性1 型和2 型受体(sVEGFR-1 和sVEGFR-2) 的浓度与营 养水平的关系, 同时根据身体质量指数(BMI) 来评估营养水平。创新点将血管生成与超重和肥胖及下肢局部缺血联系起 来, 并根据BMI 评估了它们之间的关系。方 法研究组包括46 名Fontaine 等级IIa 至IV 且没有 任何肿瘤疾病史的PAD 症状患者, 其中15 名 BMI 正常, 21 名超重, 10 名肥胖。对照组由30 名不超重且不肥胖的健康非吸烟志愿者组成。试 验在上午休息时间采集两组静脉血的血浆标本, 用酶联免疫吸附(ELISA) 方法确定血浆中的 VEGF-A、sVEGFR-1 和sVEGFR-2 浓度。结 论如果PAD 患者同时伴随着超重或者肥胖, 会影 响血管再生的过程。sVEGFR-2 水平和BMI 值之 间有正相关关系, 这说明代谢紊乱患者中的一些 抗血管生成因子患病率的线性增长的原因, 同时 这可能是导致PAD 患者侧支循环发展效率不完 全的众多因素之一。

Activation of the tissue factor-dependent extrinsic pathway and its relation to JAK2 V617F mutation status in patients with essential thrombocythemia.

Thrombotic complications may occur in 7.6–29.4% of patients with essential thrombocythemia. According to the cellular theory, tissue factor (TF) activating extrinsic blood coagulation pathway is essential for the activation of blood clotting. The aim of the study was to evaluate the activation of the TF-dependent extrinsic pathway in patients with essential thrombocythemia, depending on the presence or absence of the Janus kinase 2 (JAK2) V617F mutation. The study included 74 newly diagnosed patients (F/M: 47/27; mean age 61 years) with essential thrombocythemia (Tefferi and Vardiman, Leukemia 2008; 22(1):14–22). Patients were diagnosed in the Department of Clinical Hematology and Hematological Malignancies University Hospital No. 2, Bydgoszcz, Poland. The control group consisted of 30 healthy volunteers (F/M: 17/13; mean age 49 years). The concentration and activity of TF and TF pathway inhibitor (TFPI) were measured using ELISA method. In patients with essential thrombocythemia, we observed a higher concentration of TF [median (Me) = 686.90 vs 164.28 pg/ml] and over 10-fold higher activity of TF (Me = 46.05 vs 4.01 pmol/l) when compared with the control group. We also reported significantly higher activity of TFPI compared with the control group (Me = 1.93 vs 1.78 U/ml). Moreover, a concentration of TFPI was significantly lower in patients with essential thrombocythemia with JAK2 V617F mutation as compared with patients without the mutation (Me = 1.90 vs 2.16 U/ml; P = 0.039639). Increased TF activity and concentration is responsible for higher procoagulant potential in patients with essential thrombocythemia. Reduced activity of TFPI in patients with essential thrombocythemia with JAK2 V617F mutation indicates an increased prothrombotic risk in this group of patients.

VEGF-A, sVEGFR-1, and sVEGFR-2 in BCR-ABL negative myeloproliferative neoplasms

BACKGROUND AND OBJECTIVE Data from the literature indicate the relationship between the bone marrow microvessel density and the blood parameters of angiogenesis. The aim of this study was to evaluate selected parameters of angiogenesis (VEGF-A, sVEGFR-1, and sVEGFR-2) and their correlations with white blood cells, platelets, and red blood cells. MATERIALS AND METHODS The study included 72 patients (mean age, 61.84 years) with myeloproliferative neoplasms (MPNs): essential thrombocythemia (ET) (n=46), polycythemia vera (PV) (n=19), and primary myelofibrosis (PMF) (n=7). Serum VEGF-A, sVEGFR-1, and sVEGFR-2 were determined using the ELISA assay. RESULTS We observed a significantly higher level of VEGF-A and reduced concentrations of sVEGFR-1 and sVEGFR-2 in the whole group of patients with MPNs as compared to controls. Detailed analysis confirmed significantly higher level of VEGF-A and lower concentration of sVEGFR-2 in each subgroups of MPNs patients. However, sVEGFR-1 concentrations were significantly lower only in PV and ET patients. CONCLUSIONS The study showed an increased level of VEGF-A, which may indicate the intensity of neoangiogenesis in the bone marrow. Decreased sVEGFR-1 and sVEGFR-2 in the blood of patients with MPNs may reflect consumption of these soluble receptors.

ENDOTHELIAL PROGENITOR CELLS IN MYELOPROLIFERATIVE NEOPLASMS – PRELIMINARY REPORT

Celem niniejszej pracy byla ocena liczby i funkcji komorek progenitorowych środblonka w przewleklej bialaczce szpikowej (PBS), czerwienicy prawdziwej (CzP), nadplytkowości samoistnej (NS). Badaniem objeto 21 pacjentow z nowotworami mieloproliferacyjnymi (średnia wieku 61,77), hospitalizowanych w Oddziale Klinicznym Hematologii i Chorob Rozrostowych Ukladu Krwiotworczego Szpitala Uniwersyteckiego nr 2 im. Jana Biziela w Bydgoszczy. M a t e r i a l i m e t o d y . Badania przeprowadzono u 12 chorych na ET, 4 chorych na CML i 5 chorych na PV. Grupe kontrolną stanowilo 25 zdrowych ochotnikow. Materialem do badan byla krew pobrana w godzinach porannych z naklucia zyly lokciowej do probowki zawierającej wersenian dwupotasowy (EDTA). Po inkubacji z odpowiednimi odczynnikami dokonana zostala analiza cytometryczna przy uzyciu cytometru przeplywowego FACS Calibur (Becton Dickinson, San Diego, USA) z zastosowaniem programu komputerowego CellQuest. Wy n i k i . U chorych na przewlekle nowotwory mieloproliferacyjne stwierdzono istotnie statystyczną zwiekszoną liczbe EPCs w porownaniu z grupą kontrolną. U chorych z PV i ET stwierdzono nieznacznie zwiekszoną liczbe EPCs w porownaniu do grupy kontrolnej, a roznica ta okazala sie nieistotna statystycznie. Najwyzszą liczbe EPCs stwierdzono u pacjentow z CML i roznica ta byla istotna statystycznie. Wn i o s k i . Zwiekszenie liczby EPCs w grupie chorych na przewlekle nowotwory mieloproliferacyjne świadczy o aktywacji procesow angiogenezy w tych nowotworach i prawdopodobnie czynnym udziale tych komorek w procesie nowotworzenia naczyn.