losartan-potassium and Vasospasm--Intracranial

Subarachnoid haemorrhage (SAH) caused by a ruptured aneurysm accounts for only 5 % of strokes, but occurs at a fairly young age and carries a poor prognosis. Delayed cerebral ischaemia (DCI) is an important cause of death and dependence after aneurysmal SAH. The current mainstay of preventing DCI is nimodipine and maintenance of normovolemia, but even with this strategy DCI occurs in a considerable proportion of patients.Several drugs have been developed that have the potential to limit cerebral vasospasm and delayed ischaemic neurologic deficit, thus improving outcome for patients. However, although numerous agents can prevent arterial narrowing and/or block the excitatory cascade of events leading to ischaemic neuronal death in experimental conditions, there is still no pharmacologic agent that has been shown conclusively to improve the outcome in clinical practice.Erythropoietin (EPO) is a well-known erythropoietic hormone recently found to exert neuroprotective properties and has been shown to reduce cerebral vasospasm and infarct volume after experimental SAH. In humans, although EPO treatment did not impact the overall incidence of vasospasm, it significantly reduced the incidence of severe vasospasm, the incidence of delayed ischaemic deficits with new cerebral infarcts, and the duration of impaired autoregulation. The current study provides new evidence for the potential benefit and relative safety of EPO for the treatment of SAH in humans. Future clinical trials will hopefully provide definite evidence whether EPO treatment is beneficial in SAH patients.

Topics: Animals; Brain Ischemia; Erythropoietin; Humans; Stroke; Subarachnoid Hemorrhage; Vasospasm, Intracranial

Anemia is common in patients with aneurysmal subarachnoid hemorrhage (SAH), but these patients have constituted only a small fraction of those studied in large trials of anemia and transfusion. Unlike other critically ill patients, those with SAH face a well-defined risk of vasospasm and cerebral ischemia in the weeks after their hemorrhage. The risk of ongoing ischemia may make them less able to tolerate anemia and more likely to benefit from blood transfusion. The available data show that anemia is associated with poor outcomes after SAH but that blood transfusion does not consistently improve physiological markers, and it may be associated with poor outcomes. Most of these data are observational in nature, although 1 recent study demonstrated the safety and feasibility of maintaining relatively high transfusion thresholds in patients with SAH. Larger, randomized trials are needed to determine at what levels of anemia patients with SAH might benefit from transfusion, the optimal timing of transfusion, and how to identify those patients who are most likely to benefit.

Topics: Anemia; Blood Transfusion; Erythrocyte Aging; Erythropoietin; Hemodilution; Humans; Intraoperative Care; Oxygen Consumption; Preoperative Care; Recombinant Proteins; Subarachnoid Hemorrhage; Vasospasm, Intracranial

Subarachnoid hemorrhage (SAH) has a worldwide incidence of approximately 10.5 cases per 100,000 person-years and constitutes 3% of all strokes. Erythropoietin (EPO) has recently been proposed for the treatment of a variety of brain diseases, including SAH, because of its neuroprotective effects. Hence, the current evidence in the published literature was reviewed to determine the potential utility of EPO in the treatment of SAH.. A careful retrospective review of the literature was performed to determine the potential benefit of employing EPO in the treatment of SAH and its sequelae.. Careful literature review revelaed that the use of EPO may not necessarily reduce the incidence of vasospasm after SAH, but it may reduce the severity and its eventual outcome.. Given the recent trial results, a dose-escalation study and subsequent randomized trial should be considered.

Topics: Erythropoietin; Humans; Neuroprotective Agents; Recombinant Proteins; Retrospective Studies; Stroke; Subarachnoid Hemorrhage; Treatment Outcome; Vasospasm, Intracranial

Cerebral vasospasm after subarachnoid hemorrhage (SAH) is a major clinical problem causing cerebral ischemia and infarction. The pathogenesis of vasospasm is related to a number of pathological processes including endothelial damage and alterations in vasomotor function leading to narrowing of arterial diameter and a subsequent decrease in cerebral blood flow. Discovery of the tissue protective effects of erythropoietin (EPO) stimulated the search for therapeutic application of EPO for the prevention and treatment of cerebrovascular disease. Recent studies have identified the role of EPO in vascular protection mediated by the preservation of endothelial cell integrity and stimulation of angiogenesis. In this review, we discuss the EPO-induced activation of endothelial nitric oxide (NO) synthase and its contribution to the prevention of cerebral vasospasm.

Topics: Animals; Cerebral Arteries; Erythropoietin; Humans; Janus Kinase 2; Nitric Oxide Synthase Type III; Phosphorylation; Protein Binding; Receptors, Erythropoietin; Recombinant Proteins; Vasospasm, Intracranial

Erythropoietin (EPO) was proven as a promising approach for experimental subarachnoid hemorrhage (SAH). Clinical data are, however, inconclusive so far. A detailed characterization of specific EPO effects could facilitate the design of trials. The aim of the present investigation was, therefore, to characterize these effects on prevention of delayed proximal cerebral vasospasm (CVS), impaired microcirculation and cerebral blood flow (CBF) after experimental SAH.. 27 male Sprague-Dawley rats were randomized in 3 groups: Sham, SAH control, and SAH EPO. SAH was induced by injection of 0.2ml autologous blood into the cisterna magna on days 1 and 2. Animals of the SAH EPO group received 5000iU rh EPO α 6h after the 2nd SAH intravenously. Surviving animals were examined on day 5 by MR perfusion weighted imaging (PWI). Cerebral blood flow (CBF) and volume (CBV) were determined by PWI, proximal CVS by basilar artery (BA) diameter, and neuroprotection by hippocampal cell count (CA1-CA4).. BA diameter was significantly reduced in both SAH groups, but improved significantly after EPO (Sham: 144±3μm, SAH control: 79±6μm, SAH EPO 109±4μm). The rrCBV ratio was 8.78±0.72 Sham, 5.14±1.73 SAH control, and 6.80±0.44 SAH EPO. The improvement by EPO did not reach statistical significance. RrCBF ratio was also significantly reduced in both SAH groups, but was significantly improved by EPO (Sham: 8.78±0.34, SAH control: 4.26±1.05, SAH EPO 5.85±0.46). Surviving neuronal cells were significantly reduced in SAH controls in all areas, but in SAH EPO only in CA1.. The present data suggest that an EPO application in a timely distance to the SAH is sufficient to prevent delayed proximal CVS, but that the doses were insufficient to improve microcirculation or to be directly neuroprotective.

Topics: Analysis of Variance; Animals; Basilar Artery; Brain; Cell Count; Cerebrovascular Circulation; Disease Models, Animal; Dose-Response Relationship, Drug; Erythropoietin; Hemodynamics; Magnetic Resonance Imaging; Male; Neurologic Examination; Rats; Rats, Sprague-Dawley; Subarachnoid Hemorrhage; Time Factors; Vasospasm, Intracranial

Vasospasm-related delayed cerebral ischemia (DCI) significantly impacts on outcome after aneurysmal subarachnoid hemorrhage (SAH). Erythropoietin (EPO) may reduce the severity of cerebral vasospasm and improve outcome, however, underlying mechanisms are incompletely understood. In this study, the authors aimed to investigate the effect of EPO on cerebral metabolism and brain tissue oxygen tension (PbtO2).. Seven consecutive poor grade SAH patients with multimodal neuromonitoring (MM) received systemic EPO therapy (30.000 IU per day for 3 consecutive days) for severe cerebral vasospasm. Cerebral perfusion pressure (CPP), mean arterial blood pressure (MAP), intracranial pressure (ICP), PbtO2 and brain metabolic changes were analyzed during the next 24 hours after each dose given. Statistical analysis was performed with a mixed effects model.. A total of 22 interventions were analyzed. Median age was 47 years (32-68) and 86 % were female. Three patients (38 %) developed DCI. MAP decreased 2 hours after intervention (P < 0.04) without significantly affecting CPP and ICP. PbtO2 significantly increased over time (P < 0.05) to a maximum of 7 ± 4 mmHg increase 16 hours after infusion. Brain metabolic parameters did not change over time.. EPO increases PbtO2 in poor grade SAH patients with severe cerebral vasospasm. The effect on outcome needs further investigation.

Topics: Adult; Aged; Brain; Dose-Response Relationship, Drug; Erythropoietin; Female; Humans; Male; Middle Aged; Oxygen; Oxygen Consumption; Subarachnoid Hemorrhage; Treatment Outcome; Vasospasm, Intracranial

Delayed ischemic deficits (DIDs), a major source of disability following aneurysmal subarachnoid hemorrhage (aSAH), are usually associated with severe cerebral vasospasm and impaired autoregulation. Systemic erythropoietin (EPO) therapy has been demonstrated to have neuroprotective properties acting via EPO receptors on cerebrovascular endothelia and ischemic neurons. In this trial, the authors explored the potential neuroprotective effects of acute EPO therapy following aSAH.. Within 72 hours of aSAH, 80 patients (age range 24-82 years) were randomized to receive intravenous EPO (30,000 U) or placebo every 48 hours for a total of 90,000 U. Primary end points were the incidence, duration, and severity of vasospasm and impaired autoregulation on transcranial Doppler ultrasonography. Secondary end points were incidence of DIDs and outcome at discharge and at 6 months.. Randomization characteristics were balanced except for age, with the EPO group being older (mean age 59.6 vs 53.3 years, p=0.034). No differences were demonstrated in the incidence of vasospasm and adverse events; however, patients receiving EPO had a decreased incidence of severe vasospasm from 27.5 to 7.5% (p=0.037), reduced DIDs with new cerebral infarcts from 40.0 to 7.5% (p=0.001), a shortened duration of impaired autoregulation (ipsilateral side, p<0.001), and more favorable outcome at discharge (favorable Glasgow Outcome Scale score, p=0.039). Among the 71 survivors, the EPO group had fewer deficits measured with National Institutes of Health Stroke Scale (median Score 2 vs 6, p=0.008).. This preliminary study showed that EPO seemed to reduce delayed cerebral ischemia following aSAH via decreasing severity of vasospasm and shortening impaired autoregulation.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Blood Pressure; Blood Transfusion; Brain Ischemia; Double-Blind Method; Erythropoietin; Female; Follow-Up Studies; Homeostasis; Humans; Male; Middle Aged; Neuroprotective Agents; Placebos; Subarachnoid Hemorrhage; Treatment Outcome; Ultrasonography, Doppler, Transcranial; Vasospasm, Intracranial; Young Adult

Topics: Animals; Erythropoietin; Hemodynamics; Male; Subarachnoid Hemorrhage; Vasospasm, Intracranial

Darbepoetin alpha is a hypersialylated analogue of erythropoietin effective for activating erythropoietin-receptors. This study investigated the vasodilator and neuroprotective effects of darbepoetin alpha on an experimental subarachnoid hemorrhage model and compared it with erythropoietin.. Forty adult male New Zealand white rabbits were randomly divided into four groups of ten rabbits each: group 1 (control), group 2 (subarachnoid hemorrhage), group 3 (erythropoietin), and group 4 (darbepoetin alpha). Recombinant human erythropoietin was administered at a dose of 1,000 U/kg intraperitoneally after the induction of subarachnoid hemorrhage and continued every 8 h up to 72 h. Darbepoetin alpha was administered at a single intraperitoneal dose of 30 μg/kg. Animals were killed 72 h after subarachnoid hemorrhage. Basilar artery cross-sectional areas, arterial wall thicknesses, hippocampal degeneration scores and biochemical analyses were measured in all groups.. Both erythropoietin and darbepoetin alpha treatments were found to attenuate cerebral vasospasm and provide neuroprotection after subarachnoid hemorrhage in rabbits. Darbepoetin alpha revealed better morphometric and histopathological results than erythropoietin among experimental subarachnoid hemorrhage-induced vasospasm.. Our findings, for the first time, showed that darbepoetin alpha can prevent vasospasm and provides neuroprotection following experimental subarachnoid hemorrhage. Moreover, darbepoetin alpha showed better results when compared with erythropoietin.

Topics: Animals; Basilar Artery; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Hippocampus; Humans; Male; Neuroprotective Agents; Rabbits; Recombinant Proteins; Subarachnoid Hemorrhage; Vasoconstriction; Vasospasm, Intracranial

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

Cerebral vasospasm is the common cause of poor outcome after aneurysmal subarachnoid hemorrhage (aSAH). Although many agents are experimentally and clinicaly used to protect or recover from vasospasm, an effective neurotherapeutic drug is still missing. Erythropoietin (EPO) is recently a promising candidate. The aim of this study is to investigate the dose-dependent effects of recombinant human EPO (rhEPO) on arterial wall in a rat femoral artery vasospasm model.. Thirty two animals were divided into four groups: vasospasm without any treatment (group A), vasospasm +250 IU/kg rhEPO group (group B), vasospasm +500 IU/kg rhEPO group (group C), and control group (group D). Rat femoral artery vasospasm model was used. For groups B and C, 7 days of 250 IU/kg and 500 IU/kg intraperitoneal rhEPO in 0.3 ml saline were administered respectively; and for groups A and D, 0.3 ml saline were administered intraperitoneally without any treatment. After 7 days, histological and morphometric analyses were carried out.. Vasospasm alone group demonstrated the highest vessel wall thicknesses, comparing to other groups (p < 0.001). While for groups B and C, vessel wall thickness values were significantly higher than the control group (p < 0.001), between these two groups, there was no significant difference achieved (p > 0.05).. In our study, there was no significant difference between the two rhEPO treatment groups, but rhEPO treatment was shown to be histologically and morphometrically effective in vasospasm. However, if dosage of EPO treatment is augmented, successful results may be achieved.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelial Cells; Erythropoietin; Femoral Artery; Injections, Intraperitoneal; Male; Microscopy, Electron, Transmission; Rats; Rats, Sprague-Dawley; Tunica Intima; Tunica Media; Vasoconstriction; Vasospasm, Intracranial

Topics: Brain Ischemia; Erythropoietin; Humans; Neurosurgical Procedures; Recombinant Proteins; Subarachnoid Hemorrhage; Vasospasm, Intracranial

Previous studies have shown that recombinant human erythropoietin (rhEPO) can attenuate the degree of cerebral vasospasm following experimental subarachnoid hemorrhage (SAH). However, the mechanisms for this beneficial effect are still poorly understood. SAH-induced endothelial apoptosis may trigger, aggravate, and maintain cerebral vasospasm. We, therefore, tried to analyze whether rhEPO administration influenced the endothelial cell apoptosis in the basilar artery after SAH. Another aim of the current study was to investigate the modulation of rhEPO on the activity of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3), which played an important role in the signaling of apoptosis. A total of 48 rabbits were randomly divided into four groups; control group, SAH group, SAH+vehicle group, and SAH+rhEPO group. All SAH animals were subjected to injection of autologous blood into cisterna magna twice on day 0 and day 2. The rhEPO was administered i.p. starting 5 min after the induction of SAH on day 0 and repeated every 8 h for 120 h. The basilar arteries were extracted on day 5 after SAH. As a result, we found that administration of rhEPO could activate JAK2 and STAT3 in the basilar artery and decrease the apoptosis index of endothelial cells following SAH. Moreover, the anti-apoptotic genes such as bcl-2 and bcl-xL were up-regulated after the injections of rhEPO. In conclusion, the therapeutic effect of rhEPO on the subsequent vasospasm after SAH may relate to its inhibition on the endothelial apoptosis in the cerebral arteries, which may be mediated in part by JAK2/STAT3 signaling pathway.

Topics: Animals; Apoptosis; Basilar Artery; bcl-X Protein; Endothelium, Vascular; Erythropoietin; Humans; Janus Kinase 2; Male; Proto-Oncogene Proteins c-bcl-2; Rabbits; Random Allocation; Recombinant Proteins; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Subarachnoid Hemorrhage; Up-Regulation; Vasospasm, Intracranial

In the present study, the effect of subarachnoid hemorrhage (SAH) on the phosphorylation of endothelial NO synthase (eNOS) and the ability of recombinant erythropoietin (Epo) to augment this vasodilator mechanism in the spastic arteries were studied.. Recombinant adenoviral vectors (10(9) plaque-forming units per animal) encoding genes for human Epo (AdEpo), and beta-galactosidase were injected immediately after injection of autologous arterial blood into the cisterna magna (day 0) of rabbits. Cerebral angiography was performed on day 0 and day 2, and basilar arteries were harvested for Western blots, measurement of cGMP levels, and analysis of vasomotor functions.. Injection of autologous arterial blood into cisterna magna resulted in significant vasospasm of the basilar arteries. Despite the narrowing of arterial diameter and reduced expression of eNOS, expressions of phosphorylated protein kinase B (Akt) and phosphorylated eNOS were significantly increased in spastic arteries. Gene transfer of AdEpo reversed the vasospasm. AdEpo-transduced basilar arteries demonstrated significant augmentation of the endothelium-dependent relaxations to acetylcholine, whereas the relaxations to an NO donor, 2-(N,N-diethylamino)diazenolate-2-oxide sodium salt, were not affected. Transduction with AdEpo further increased the expression of phosphorylated Akt and eNOS and elevated basal levels of cGMP in the spastic arteries.. Phosphorylation of eNOS appears to be an adaptive mechanism activated during development of vasospasm. The vascular protective effect of Epo against cerebral vasospasm induced by SAH may be mediated in part by phosphorylation of Akt/eNOS.

Topics: Animals; Cerebral Angiography; Endothelium, Vascular; Erythropoietin; Gene Transfer Techniques; Male; Nitric Oxide Synthase; Phosphorylation; Rabbits; Recombinant Proteins; Subarachnoid Hemorrhage; Up-Regulation; Vasospasm, Intracranial