CYP2C19 and CYP3A4 activity and ADP-induced platelet reactivity in prasugrel- or ticagrelor-treated STEMI patients: monocentric study in PRAGUE-18 trial participants.

We assessed the contribution of CYP2C19 and CYP3A4 metabolic activity to the ADP-induced platelet aggregation 1h and 24h after a loading dose of 60 mg prasugrel or 180 mg ticagrelor in patients with ST-elevation myocardial infarction (STEMI). Further, we assessed the contribution of CYP2C19 polymorphisms and medication to the CYP enzymatic activity.Patients with STEMI were randomly assigned to the treatment with prasugrel (n = 51) or ticagrelor (n = 46). Metabolic activity of CYP2C19 and CYP3A4 was assessed by the rate of 5-hydroxylation and sulfoxidation of lansoprazole. Further, patients were genotyped for CYP2C19 *2 and *17 alleles.In prasugrel-treated patients, high ADP-induced platelet reactivity 1h after the loading dose positively correlated with 5OH-lansoprazole/lansoprazole ratio (r = 0.44, p = 0.002), a marker of CYP2C19 metabolic activity, and negatively with lansoprazole-sulfone/lansoprazole ratio, which reflects CYP3A4 metabolic activity (r = -0.35, p = 0.018).CYP2C19 poor metabolizers had lower 5OH-lansoprazole/lansoprazole ratio and higher lansoprazole-sulfone/lansoprazole ratio, but without any effect on the ADP-induced platelet reactivity. The treatment with amiodarone, a CYP3A4 inhibitor, influenced neither the metabolic ratios nor the ADP-induced platelet reactivity.The CYP3A4 and CYP2C19 metabolic activity is associated with ADP-induced platelet reactivity in prasugrel-treated, but not ticagrelor-treated patients with STEMI.

Early Inflammatory Response in the Brain and Anesthesia Recovery Time Evaluation After Experimental Subarachnoid Hemorrhage.

The main objective was to evaluate, whether the subarachnoid hemorrhage (SAH)-associated early inflammatory response has focal or global character, i.e., whether areas distant to hematoma may be affected by an early inflammatory response. The second objective was to evaluate the association of anesthesia recovery time for basic reflexes/neurological functions with severity of SAH. SAH was induced in rats using an endovascular perforation model. Anesthesia recovery time was evaluated for pain reaction recovery time (spinal level), spontaneous ventilation recovery time (brain stem level), and consciousness recovery time (neocortical level). mRNA expressions of TNFα, IL-1ß, IL-6, ICAM-1, and VCAM-1 in areas adjacent and distant to hematoma were evaluated between 2 and 8 h after SAH. Serum levels of TNFα, IL-1ß, and IL-6 were assessed at 4 and 8 h after SAH. Anesthesia recovery time of all selected parameters was associated with severity of SAH. The consciousness recovery time test had the best predictive value, while the spontaneous ventilation recovery time test was able to bring information in the shortest time. The mRNA expressions of pro-inflammatory cytokines were significantly increased in severe SAH groups in both adjacent and distant areas. The inflammatory response in mild/moderate SAH groups was less strong, peaking at 4 h after SAH. Serum levels of pro-inflammatory cytokines were ambiguous. Anesthesia recovery time may be useful for bleeding severity prediction in the SAH model; however, further validation is needed. Severe subarachnoid hemorrhage is associated with the strong early inflammatory response, which has a global character, while mild subarachnoid hemorrhage is accompanied by a weaker inflammation.

The Role of Inflammatory Response in Stroke Associated Programmed Cell Death.

Stroke represents devastating pathology which is associated with a high morbidity and mortality. Initial damage caused directly by the onset of stroke, primary injury, may be eclipsed by secondary injury which may have a much more devastating effect on the brain. Primary injury is predominantly associated with necrotic cell death due to fatal insufficiency of oxygen and glucose. Secondary injury may on the contrary, lead apoptotic cell death due to structural damage which is not compatible with cellular functions or which may even represent the danger of malign transformation. The immune system is responsible for surveillance, defense and healing processes and the immune system plays a major role in triggering programmed cell death. Severe pathologies, such as stroke, are often associated with deregulation of the immune system, resulting in aggravation of secondary brain injury. The goal of this article is to overview the current knowledge about the role of immune system in the pathophysiology of stroke with respect to programmed neuronal cell death as well as to discuss current therapeutic strategies targeting inflammation after stroke.

Brain-derived neurotrophic factor and ciliary neurotrophic factor in maternal plasma and umbilical cord blood from pre-eclamptic and physiological pregnancies.

The aim of the study was to investigate the circulating levels of ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) in maternal serum and umbilical cord blood from respective pregnancies in pre-eclampsia (PE) cases and a control cohort. A total of 12 pre-eclampsia cases and 34 healthy controls were enrolled and the maternal peripheral blood - umbilical cord blood duos, were examined for BDNF and CNTF levels. BNDF levels were significantly higher in umbilical cord blood from pre-eclamptic pregnancies; there was also significant difference between maternal plasma and umbilical cord blood levels of BDNF (p < 0.001) in the controls. The CNTF levels in umbilical cord blood (CNTF-UCB) were significantly higher in PE cases than in the controls (p = 0.03). Significant differences were observed in expression of BDNF and CNTF proteins in maternal peripheral blood and umbilical cord blood between pre-eclampsia cases and healthy controls.

Circulating levels of B-cell activating factor in paediatric patients with malignancy with or without cancer-related cachexia.

BACKGROUND: Cancer-related cachexia is a multifactorial syndrome characterised by progressive loss of body weight and it affects a large proportion of patients with advanced cancer. Cachexia is associated with reduced treatment tolerance, response to therapy, quality of life and duration of survival, whereas some of its mechanisms are shared across the whole continuum of diseases in the population, either cancer-related or non-cancer related e.g. systemic inflammation, increased lipolysis, insulin resistance and reduced physical performance. However, so far there has been only little effort to utilise the integrative physiology of adipose tissue to achieve therapeutic gain. B cell-activating factor (BAFF) is a novel member of the TNF ligand superfamily, is mainly produced by myeloid cells and has recently been shown to participate in B-cell survival and B- and T-cell maturation, but also in adipogenesis. Therefore, it represents an elegant candidate molecule linking the immune system and adipose tissue metabolism, both being involved deeply in the pathogenesis of cachexia. Moreover, it has been described very recently that BAFF directly influences secretion of IL-6 and IL-10. MATERIAL AND METHODS: In this study, pre-treatment circulating levels of BAFF were investigated in a cohort of 83 paediatric patients with malignancy (0-18 y) with or without cancer-related cachexia using ELISA-based methodology. RESULTS: Apart from logical significant associations of BAFF circulating levels with disease severity in B-lineage malignancies (ALL or B-cell lymphomas), we observed significant elevation of BAFF in adolescent patients with Ewing sarcoma and rhabdomyosarcoma, compared to the circulating levels appropriate for given age. CONCLUSION: To the best of our knowledge, this is so far the first study focusing on BAFF in paediatric malignancies with or without cancer-related cachexia. More research into whether BAFF can represent a useful circulating biomarker for detection and monitoring of the cancer-related cachexia is imperative.