losartan-potassium and Intracranial-Aneurysm

Erythropoietin (EPO) is neuroprotective in experimental models of stroke and subarachnoid haemorrhage (SAH) and possibly in patients with thromboembolic stroke. We studied the efficacy and safety of EPO in patients with SAH.. A larger scale clinical trial was planned but preliminarily terminated because of a lower than expected inclusion rate. However, 73 patients were randomised to treatment with EPO (500 IU/kg/day for three days) or placebo. The primary endpoint was Glasgow Outcome Score at six months. We further studied surrogate measures of secondary ischaemia, i.e. transcranial Doppler (TCD) flow velocity, symptomatic vasospasm, cerebral metabolism (microdialysis) and jugular venous oximetry, biochemical markers of brain damage (S-100beta and neuron specific enolase) and blood-brain barrier integrity.. The limited sample size precluded our primary hypotheses being verified and refuted. However, data from this study are important for any other study of SAH and as much raw data as possible are presented and can be included in future meta analyses. On admission the proportion of patients in a poor condition was higher in the EPO group compared with the placebo group but the difference was statistically insignificant. In the EPO-treated patients the CSF concentration of EPO increased 600-fold. Except for a higher extracelullar concentration of glycerol in the EPO group probably caused by the poorer clinical condition of these patients, there were no statistically significant group differences in the primary or secondary outcome measures. EPO was well tolerated.. Beneficial effects of EPO in patients with SAH cannot be excluded or concluded on the basis of this study and larger scale trials are warranted.

Topics: Adult; Aged; Blood Flow Velocity; Brain; Brain Damage, Chronic; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Glasgow Outcome Scale; Hematinics; Hospital Mortality; Humans; Intracranial Aneurysm; Magnetic Resonance Imaging; Male; Microdialysis; Microsurgery; Middle Aged; Neuroprotective Agents; Oxygen Consumption; Premedication; Recombinant Proteins; Subarachnoid Hemorrhage; Tomography, X-Ray Computed; Ultrasonography, Doppler, Transcranial

: This study explored a new approach to enhance aneurysm (AN) neck endothelialization via erythropoietin (EPO)-induced endothelial progenitor cell (EPC) stimulation. Results suggest that EPO enhanced the endothelialization of a coiled embolization AN neck by stimulating EPCs via vascular endothelial growth factor modulation. Thus, the promotion of endothelialization with EPO provides an additional therapeutic option for preventing the recurrence of ANs. Endovascular coil embolization is an attractive therapy for cerebral ANs, but recurrence is a main problem affecting long-term outcomes. In this study, we explored a new approach to enhance AN neck endothelialization via EPO-induced EPC stimulation. Ninety adult male Sprague-Dawley rats were selected for an in vivo assay, and 60 of them underwent microsurgery to create a coiled embolization AN model. The animals were treated with EPO, and endothelial repair was assessed via flow cytometry, immunofluorescence, electronic microscopy, cytokine detection, and routine blood work. EPO improved the viability, migration, cytokine modulation, and gene expression of bone marrow-derived EPCs and the results showed that EPO increased the number of circulating EPCs and improved endothelialization compared with untreated rats (p < .05). EPO had no significant effect on the routine blood work parameters. In addition, the immunofluorescence analysis showed that the number of KDR(+) cells in the AN neck was elevated in the EPO-treated group (p < .05). Further study demonstrated that EPO promoted EPC viability and migration in vitro. The effects of EPO may be attributed to the modulation of vascular endothelial growth factor (VEGF). In particular, EPO enhanced the endothelialization of a coiled embolization AN neck by stimulating EPCs via VEGF modulation. Thus, the promotion of endothelialization with EPO provides an additional therapeutic option for preventing the recurrence of ANs.. Erythropoietin (EPO) is involved in erythropoiesis and related conditions and is reported to enhance stem-cell mobilization from bone marrow while elevating stem-cell viability and function. In this study, EPO was also found to stimulate endothelial progenitor cells to induce the endothelialization of a coiled embolic aneurysm neck via vascular endothelial growth factor modulation. Endothelialization induction provides an additional therapeutic opportunity during vascular inner layer repair and remodeling. The results provide important information on the unique role EPO plays during vascular repair and remodeling.

Topics: Animals; Disease Models, Animal; Embolization, Therapeutic; Endothelial Progenitor Cells; Erythropoietin; Flow Cytometry; Fluorescent Antibody Technique; Intracranial Aneurysm; Male; Microscopy, Confocal; Rats; Rats, Sprague-Dawley; Vascular Endothelial Growth Factor A

Endothelial dysfunction triggers early pathological changes in vessel walls, potentially leading to the formation of cerebral aneurysm (CA). Endothelial progenitor cells (EPCs) are critical in repairing damaged endothelium and could prevent or slow CA formation. We hypothesize that erythropoietin (EPO) stimulates EPCs mobilization, could alter the rate of CA formation and progression. The hypothesis was tested in a rat model of CA. CAs were induced in male Sprague-Dawley rats and treated with s.c. administration of EPO. Circulating EPCs and serum vascular endothelial grow factor (VEGF) were measured be flow cytometry and ELISA, respectively. mRNAs for inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), matrix metalloproteinase-2 (MMP-2), and MMP-9 in aneurysm tissue were quantified by Real-time PCR. The size, internal elastic lamina (IEL), and media thickness of CAs were evaluated 1 and 3 months after aneurysm induction. Circulating EPCs were significantly lower in CA rats as compared to non-surgical controls. EPO increased levels of circulating EPCs and VEGF. It also decreased iNOS, MMP-2, and MMP-9 mRNA levels, while increased eNOS mRNA in aneurysm tissue. The changes in EPCs and biochemical markers are associated with suppression of new CA formation and prevention of preexisting CA progression. We have shown a close association among circulating EPCs, biochemical markers related to vascular remodeling, and the rate of CA formation and progression. Changes in patterns of cerebral blood flow and hypertension induced by surgical ligations of selected arteries exert significant hemodynamic stress to weaken vessel walls, primarily at sites of basilar bifurcation. The surgical stress also reduced circulating EPCs and slowed vascular repairs. EPO mobilizes EPCs from the bone marrow and promotes their homing. These results suggest that EPCs may serve as a marker for CA progression and EPO a promising candidate for the clinical management of CA.

Topics: Animals; Disease Models, Animal; Endothelial Cells; Erythropoietin; Intracranial Aneurysm; Male; Rats; Rats, Sprague-Dawley; Stem Cells

In a previous randomized controlled trial, the authors demonstrated that acute erythropoietin (EPO) therapy reduced severe vasospasm and delayed ischemic deficits (DIDs) following aneurysmal subarachnoid hemorrhage. In this study, the authors aimed to investigate the potential interaction of neurovascular protection by EPO with age, sepsis, and concurrent statin therapy.. The clinical events of 80 adults older than 18 years and with < 72 hours of aneurysmal subarachnoid hemorrhage, who were randomized to receive 30,000 U of intravenous EPO-beta or placebo every 48 hours for a total of 3 doses, were analyzed by stratification according to age (< or > or = 60 years), sepsis, or concomitant statin therapy. End points in the trial included cerebral vasospasm and impaired autoregulation on transcranial Doppler ultrasonography, DIDs, and unfavorable outcome at discharge and at 6 months measured with the modified Rankin Scale and Glasgow Outcome Scale. Analyses were performed using the t-test and/or ANOVA for repeated measurements.. Younger patients (< 60 years old) or those without sepsis obtained benefits from EPO by a reduction in vasospasm, impaired autoregulation, and unfavorable outcome at discharge. Compared with nonseptic patients taking EPO, those with sepsis taking EPO had a lower absolute reticulocyte count (nonsepsis vs sepsis, 143.5 vs. 105.8 x 10(9)/L on Day 6; p = 0.01), suggesting sepsis impaired both hematopoiesis and neurovascular protection by EPO. In the EPO group, none of the statin users suffered DIDs (p = 0.078), implying statins may potentiate neuroprotection by EPO.. Erythropoietin-related neurovascular protection appears to be attenuated by old age and sepsis and enhanced by statins, an important finding for designing Phase III trials.

Topics: Age Factors; Aneurysm, Ruptured; Clinical Trials, Phase II as Topic; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Erythropoietin; Glasgow Outcome Scale; Hematopoiesis; Homeostasis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperemia; Intracranial Aneurysm; Middle Aged; Neuroprotective Agents; Randomized Controlled Trials as Topic; Recombinant Proteins; Sepsis; Subarachnoid Hemorrhage; Ultrasonography, Doppler, Transcranial; Vasospasm, Intracranial