Danuta Rość

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.

Minimally Invasive Methods for the Treatment of Lymphocele After Kidney Transplantation

BACKGROUND One common complication after kidney transplantation is a lymphocele. The aim of our work was an analysis of incidence of lymphocele and the effectiveness of minimal invasive methods in the management of this complication. MATERIALS AND METHODS The examined group was consisted of 158 patients (68 female and 90 male) with end-stage renal disease who underwent kidney transplantation. RESULTS Twenty-one patients (13%) developed symptoms of lymphocele after transplantation procedure within an average time of 34 weeks. The clinical symptoms included a decrease in 24-hour urine collection, an increase in plasma creatinine concentration, abdominal discomfort, lymphorrhea with a surgical wound dehiscence, voiding problems of urgency or vesical tenesmus, febrile states, or symptoms of deep vein thrombosis. The following methods were applied with variable efficacy: aspiration with recurrence 75%; percutaneous drainage with 55%, effectiveness; laparoscopic fenestration with 72% satisfactory outcomes (1 patient presented an excessive bleeding after the procedure), and classic surgery with favorable results. CONCLUSION Percutaneous drainage guided by ultrasonic imaging should be recommended as the first attempt to cure a lymphocele. Laparoscopy is a feasible, safe technique that should be used after unsuccessful percutaneous drainage. A larger series of patients is required to confirm the superiority of minimal invasive methods to the classical approach.

Triglycerides as an early pathophysiological marker of endothelial dysfunction in nondiabetic women with a previous history of gestational diabetes.

Abstract  Objective. To investigate whether baseline triglyceride levels are associated with early glucose dysregulation and/or cardiovascular risk in women with a previous history of gestational diabetes. Design. Prospective postpregnancy cohort study. Setting. Polish university hospitals. Sample. Participants included 125 women with previous gestational diabetes and 40 women with normal glucose regulation during pregnancy. Methods. All women were studied 2–24months (mean 12±10months) after the index pregnancy. Women with previous gestational diabetes were divided into tertiles in accordance with baseline triglyceride levels. Main Outcome Measures. We assessed glucose regulation (oral glucose tolerance test), insulin resistance (homeostasis model assessment), markers of endothelial dysfunction (soluble: intercellular adhesion molecule‐1, vascular cell adhesion molecule‐1, E‐selectin, tissue plasminogen activator antigen, von Willebrand factor antigen), fibrinolysis (plasminogen activator inhibitor antigen), inflammation (high‐sensitivity C‐reactive protein) and lipid levels. Results. Women with previous gestational diabetes (78% normal glucose regulation, 22% impaired glucose tolerance) had a high cardiometabolic risk profile compared with control women (100% normal glucose regulation). Baseline triglycerides >0.83mmol/l were associated with a higher prevalence of impaired glucose tolerance, higher high‐sensitivity C‐reactive protein and triglyceride/high‐density lipoprotein‐cholesterol ratio. Triglycerides >1.22mmol/l were associated with higher body fat indexes, higher insulin resistance, higher levels of endothelial dysfunction biomarkers, higher plasminogen activator inhibitor antigen and dyslipidemia. Only E‐selectin was independently associated with triglyceride levels. Conclusions. Baseline triglyceride levels are a cardiovascular risk marker as well as a pathophysiological parameter independently associated with endothelial dysfunction in nondiabetic women with previous gestational diabetes at 2–24months after an index pregnancy. Normalization of triglycerides should be included in preventive therapy after a pregnancy complicated by gestational diabetes.

A preliminary evaluation of VEGF-A, VEGFR1 and VEGFR2 in patients with well-controlled type 2 diabetes mellitus

Objective: Decompensated chronic hyperglycemia often leads to late microvascular complications such as retinopathy, diabetic foot syndrome, and diabetic kidney disease. The aim of this study was to determine the concentration of vascular endothelial growth factor A (VEGF-A) and its receptors in patients with well-controlled diabetes. Methods: The study was conducted on 31 patients with well-controlled type 2 diabetes without micro-or macroangiopathy. Thirty healthy volunteers were enrolled in a control group. Serum concentrations of VEGF-A, VEGF receptors 1 and 2 (VEGFR1 and VEGFR2), fasting glucose, and lipid profiles were measured, and the plasma concentration of glycated hemoglobin (HbA1c) was determined. Results: No significant differences were observed between the concentration of VEGF-A, VEGFR1 or VEGFR2 in the subject group and that in the control group. Positive correlations were noted between the levels of VEGF-A, VEGFR2, and triglyceride, and there was a negative correlation between the levels of VEGFR2 and high-density lipoprotein (HDL)-cholesterol in the study group. Conclusions: The concentrations of VEGF-A and its receptors 1 and 2 in patients with well-controlled diabetes are comparable to those of healthy individuals, which may indicate that appropriate control of glucose levels delays the occurrence of vascular complications. A negative correlation between VEGFR2 and HDL-cholesterol levels, and positive correlations between VEGF-A, VEGFR2, and triglyceride levels, suggest that lipid abnormalities occurring in diabetes may be involved in the modulation of angiogenesis.

Elevation of sE-Selectin Levels 2–24 Months following Gestational Diabetes Is Associated with Early Cardiometabolic Risk in Nondiabetic Women

Objective. We hypothesised that the endothelial dysfunction is associated with early glucose dysregulation and/or atherosclerosis risk factors in nondiabetic women with a previous history of gestational diabetes (pGDM). Material/Methods. Anthropometric parameters, glucose regulation (OGTT), insulin resistance (HOMA), lipids, biomarkers of endothelial dysfunction, and inflammation were evaluated in 85 women with pGDM and in 40 controls 2–24 months postpartum. Results. The pGDM group consisted of 67% normoglycemic women (pGDM-N) and 33% with prediabetic state (pGDM-P). The BMI, waist circumference, fasting and 2 h glucose (OGTT), soluble adhesion molecules, tissue plasminogen activator antigen, high sensitivity C-reactive protein, total-, LDL-cholesterol, and triglycerides/HDL-cholesterol ratio were higher in the pGDM women compared with the controls. After adjustment for BMI and fasting glucose, only higher triglycerides, higher TG/HDL and lower HDL-cholesterol were associated with pGDM. The pGDM-P differed from pGDM-N for only higher triglycerides and TG/HDL. The plasma level of sE-selectin was not independently associated with glucose concentration in pGDM group. sE-selectin level correlated with triglycerides, TG/HDL, plasminogen activator inhibitor-1 antigen, and sICAM-1. Conclusions. sE-selectin level correlated with components of metabolic syndrome, but only the atherogenic lipid profile was independently associated with a previous history of GDM in nondiabetic women 2–24 months postpartum.

Risk of venous thromboembolic disease in postmenopausal women taking oral or transdermal hormone replacement therapy.

ObjectiveThe influence of hormone replacement therapy (HRT) on hemostasis processes depends on the type of hormone, the combination of doses, the time of taking HRT, and the route of administration (oral, transdermal, implanted). The aim of the current study was to assess some parameters of coagulation, especially tissue factor pathway inhibitor (TFPI) and tissue factor (TF) in postmenopausal women using oral or transdermal HRT.MethodsThe study was conducted on 76 healthy women, including 46 women aged 44–58 years who were taking oral (26) or transdermal (20) HRT, and 30 women aged 44–54 years who did not take HRT as the control group. Plasma concentrations of TF, TFPI, thrombin-antithrombin complex (TAT), and D-dimer were performed by enzyme-linked immunosorbent assay (ELISA). Moreover, the concentration of fibrinogen and activity of protein C were measured by chromogenic and chronometric methods.ResultsWe observed a significantly higher concentration of TF and a significantly lower concentration of TFPI in women taking oral and transdermal HRT in comparison with the control group. We also found a significantly lower concentration of fibrinogen in women taking oral HRT vs. the control group. Moreover, no statistically significant changes in concentrations of TAT and D-dimer, or activity of protein C were noted.ConclusionsIn this study, the occurrence of an increased TF concentration simultaneously with a decreased concentration of TFPI in women taking HRT indicates hypercoagulability. No significant modification of TAT or D-dimer occurred, and thus there may not be increased risk of thrombosis.

Deep venous thrombosis in patients with chronic spinal cord injury

Context/Objective: Deep venous thrombosis (DVT) is a well-known complication of an acute spinal cord injury (SCI). However, the prevalence of DVT in patients with chronic SCI has only been reported in a limited number of studies. The aim of our study was to examine the prevalence of DVT in patients with SCI beyond three months after injury. Design: Cross-sectional study. Setting: Rehabilitation Department at the Bydgoszcz University Hospital in Poland. Participants: Sixty-three patients with SCI that were more than 3 months post injury. The patients, ranging in age from 13 to 65 years, consisted of 15 women and 48 men; the mean age of the patients was 32.1 years. The time from injury varied from 4 to 124 months. Outcome measures: Clinical assessment, D-dimer and venous duplex scan. Results: The venous duplex scan revealed DVT in 5 of the 63 patients. The post-injury time in four of the patients varied between 4 and 5 months; one patient was 42 months post-injury. Conclusion: DVT occurred in patients with chronic SCI, mainly by the 6th post injury month.

Effect of uncontrolled hyperglycemia on levels of adhesion molecules in patients with diabetes mellitus type 2.

ObjectiveUncontrolled diabetes has become a major cause of mortality and morbidity by reason of vascular angiopathy. The aim of this study was to evaluate the concentrations of soluble forms of vascular adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), E-selectin, and thrombomodulin in patients with well-controlled and uncontrolled diabetes type 2.MethodsThe study was conducted on 62 patients with diabetes. Group I consisted of 35 patients with well-controlled diabetes. The second group included 27 patients with uncontrolled diabetes with micro-albuminuria. A control group was made up of 25 healthy volunteers. The concentrations of sVCAM-1, sICAM-1, sE-selectin, and soluble thrombomodulin were assayed in plasma. Serum concentration of creatinine was measured and the plasma concentrations of fasting glucose and glycated hemoglobin (HbA1c) determined.ResultsLower concentrations of ICAM-1 were found in the group of uncontrolled diabetes patients compared with those with well-controlled disease. In patients with uncontrolled diabetes, VCAM-1 levels were significantly higher compared with the group with well-controlled diabetes. In patients with uncontrolled diabetes a positive correlation was obtained between glomerular filtration rate and sE-selectin and a negative correlation between the levels of creatinine and ICAM-1, although there was a positive correlation between (HbA1c) and ICAM-1.ConclusionThe study confirmed the participation of the inflammatory process associated with impaired vascular endothelial function in the pathogenesis of type 2 diabetes. The opposite effect of uncontrolled hyperglycemia on adhesion molecules suggests different functions of VCAM-1 and ICAM-1 in complications of diabetes.概要目的评估可溶性血管细胞间黏附分子 (sVCAM-1)、可溶性细胞间黏附分子 (sICAM-1)、可溶性选择素E 和可溶性血栓调节蛋白在血糖控制良好和不受控制的2 型糖尿病患者中的水平。创新点对2 型糖尿病患者的血管内皮炎症标记物进行评估。方法62 例糖尿病患者分成两组: 第一组包括35 个血糖控制良好的糖尿病患者, 第二组包括27 个未控制血糖并伴有微蛋白尿的糖尿病患者。对照组由25 名健康志愿者组成。测定血浆中sVCAM-1、sICAM-1、可溶性选择素E 和可溶性血栓调节蛋白的浓度, 同时测定血清肌酐及血浆中空腹血糖和糖化血红蛋白 (HbA1c) 的浓度。结论与血糖控制良好的糖尿病组相比, 未控制血糖组具有相对低的ICAM-1 水平和更高的VCAM-1 水平。未控制血糖组中患者的糖化血红蛋白和ICAM-1 之间呈正相关, 肾小球滤过率和可溶性选择素E 之间呈正相关, 而肌酐和ICAM-1 之间呈负相关。研究证实2 型糖尿病的发病机理中炎症过程的出现与血管内皮功能受损有关。未受控制的高血糖对粘附分子的反向作用表明, 在糖尿病的并发症中VCAM-1和ICAM-1具有不同功能。

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。