losartan-potassium and Cerebrovascular-Disorders

Global and focal cerebral ischemia is followed by a secondary damage characterized by oxidative stress, excitotoxicity, inflammation and apoptosis. Erythropoietin (EPO) exerts antiapoptotic, anti-inflammatory, antioxidative, angiogenetic and neurotrophic properties. Its potential therapeutic role has been demonstrated in several animal models of cerebral ischemia and also in a clinical trial of ischemic stroke, so it could be considered an ideal compound for neuroprotection in ischemic stroke and in cardiac arrest. Intracerebral hemorrhage (ICH) is the least treatable form of stroke; the mechanisms involved in the secondary brain injury include hematoma mass effect, neuronal apoptosis and necrosis, inflammation. It has been demonstrated in an experimental ICH that EPO intervenes in the inflammatory process, reduces brain water content, hemorrhage volume and hemispheric atrophy, promotes cell survival, preserves cerebral blood flow, has antiapoptotic protective function against oxidative stress and excitotoxic damage. EPO can attenuate acute vasoconstriction and prevent brain ischemic damage in subarachnoid hemorrhage. The neuroprotective function of EPO has been studied also in traumatic brain injury: it reduces the inflammation and improves cognitive and motor deficits. The authors review some of the physiological actions of EPO in the physiopathology of ischemic and hemorrhagic stroke, subarachnoid hemorrhage and brain trauma, and its potential usefulness in the brain injured patient management.

Topics: Brain Diseases; Cerebrovascular Disorders; Erythropoietin; Humans; Neuroprotective Agents

Topics: Animals; Apoptosis; Brain Diseases; Brain Ischemia; Cerebral Hemorrhage; Cerebrovascular Disorders; Erythropoietin; Humans; Ischemia; Neurons; Neuroprotective Agents; Stroke

Cerebral vasospasm and the resulting cerebral ischemia occurring after subarachnoid hemorrhage (SAH) are still responsible for the considerable morbidity and mortality in patients affected by cerebral aneurysms. Mechanisms contributing to the development of vasospasm, abnormal reactivity of cerebral arteries and cerebral ischemia after SAH have been intensively investigated in recent years. It has been suggested that the pathogenesis of vasospasm is related to a number of pathological processes, including endothelial damage, smooth muscle cell contraction resulting from spasmogenic substances generated during lyses of subarachnoid blood clots, changes in vascular responsiveness and inflammatory or immunological reactions of the vascular wall. A great deal of experimental and clinical research has been conducted in an effort to find ways to prevent these complications. However, to date, the main therapeutic interventions remain elusive and are limited to the manipulation of systemic blood pressure, alteration of blood volume or viscosity, and control of arterial dioxide tension. Even though no single pharmacological agent or treatment protocol has been identified which could prevent or reverse these deadly complications, a number of promising drugs have been investigated. Among these is the hormone erythropoietin (EPO), the main regulator of erythropoiesis. It has recently been found that EPO produces a neuroprotective action during experimental SAH when its recombinant form (rHuEPO) is systemically administered. This topic review collects the relevant literature on the main investigative therapies for cerebrovascular dysfunction after aneurysmal SAH. In addition, it points out rHuEPO, which may hold promise in future clinical trials to prevent the occurrence of vasospasm and cerebral ischemia after SAH.

Topics: Animals; Cerebrovascular Disorders; Endothelins; Erythropoietin; Humans; Nitric Oxide Donors; Potassium Channels; Recombinant Proteins; Subarachnoid Hemorrhage

If one reviews the literature with zeal, it is increasingly apparent that few organs escape recruitment when IBD is chronic or progressive. Insights into mucosal pathophysiology have helped with understanding the more frequent extraintestinal manifestations, but the mechanisms attendant to the development of less common events (e.g. acute pancreatitis, concurrent gluten sensitive enteropathy, or active pulmonary disease) remain either poorly studied or obscure. It is particularly interesting, however, to read reports of abnormal pulmonary function, generally of the obstructive type, correlated to measurements of abnormal intestinal permeability in patients with either active pulmonary sarcoid or pulmonary involvement in Crohn's disease. It has been further speculated that similarities in the mucosal immune system of the lung and intestine are responsible for evidence of bronchial hyperreactivity in patients with active IBD. Finally, it is important to recognize that extensions of the inflammatory process are not restricted to the development of organ-based events but may be responsible for some of the most frequent systemic abnormalities detected in IBD patients. It is now also well confirmed that the cytokine environment in IBD can support activated coagulation and, in some clinical situations, overt vascular thrombosis. The cerebrovascular complications of IBD are well recognized and range from peripheral venous thrombosis to central stroke syndromes and pseudotumor cerebri. Reports of focal white matter lesions in the brains of patients with IBD or an increased incidence of polyneuropathy may be other clinical examples of regional microvascular clotting. Microvascular injury appears to be more ubiquitously present, with reports ranging from a speculated primary causative role (e.g., granulomatous vasculitis in the mesenteric circulation) to the utility of nailbed vasospasm, in Crohn's disease, as a clinical marker for disease activity. It is also reported that IL-6 suppression of erythropoietin production is a major feature of the chronic anemia seen in active IBD. Moreover, the capacity of peripheral monocytes from active IBD patients to secrete TNF and IL-8 is reported predictive for the degree of therapeutic response from recombinant erythropoietin. These collected observations constitute another excellent example of the symmetry between basic science and clinical utility. It is from the context of applied basic science that many future therapies wi

Topics: Anemia; Animals; Brain Diseases; Bronchial Hyperreactivity; Cerebrovascular Disorders; Crohn Disease; Cytokines; Disease Models, Animal; Erythropoietin; Humans; Inflammatory Bowel Diseases; Interleukin-6; Lung Diseases; Lung Diseases, Obstructive; Sarcoidosis; Thrombosis

The Final Rule regulations were developed to allow exception from informed consent (EFIC) to enable clinical trial research in emergency settings where major barriers exist for informed consent. There is little known evidence of the effect of the Final Rule in minority enrollment in clinical trials, particularly in traumatic brain injury (TBI) trials. A clinical trial funded by the National Institute of Neurological Disorders and Stroke was conducted to study the effects of erythropoietin on cerebral vascular dysfunction and anemia in subjects with TBI. There were periods of time when EFIC was and was not available for enrollment into the study.. To explore the effect of EFIC availability on TBI trial enrollment of minority versus non-minority subjects.. Minority status of screened (n = 289) and enrolled (n = 191) TBI subjects was determined for this study. We tested for the presence of a minority and EFIC availability interaction in a multiple logistic regression model after controlling for EFIC and minority group main effects and other covariates.. An interaction between the availability of EFIC minority and non-minority enrollment was not detected (odds ratio = 1.22; 95% confidence interval (CI) = 0.29-5.16).. Our study was conducted at a single site, and the CI for the EFIC and minority interaction term was wide. Therefore, a small interaction effect cannot be ruled out.. EFIC increased the odds of being enrolled regardless of minority status.

Topics: Adult; Anemia; Asian; Black or African American; Brain Injuries; Cerebrovascular Disorders; Clinical Trials as Topic; Cultural Diversity; Erythropoietin; Ethnicity; Female; Hematinics; Hispanic or Latino; Humans; Informed Consent; Logistic Models; Male; Middle Aged; Minority Groups; Odds Ratio; Patient Selection; United States; White People

Vascular dementia is the second most common cause of dementia in older people and is characterized by the sudden onset of impairments in thinking skills and behavior, which generally occur following a stroke. Unfortunately, effective therapy for vascular dementia remains inadequate. Erythropoietin (EPO) is a glycoprotein hormone that controls erythropoiesis, or red blood cell production. Recently, a prominent role for EPO has been defined in the nervous system, and there is growing interest in the potential therapeutic use of EPO for neuroprotection. However, whether it is protective from memory impairments and the underlying mechanisms of vascular dementia (VD) remains unknown. In the current study, we reported that supplements with exogenous erythropoietin (EPO) for 4 weeks could restore impaired memory in 2-vessel occlusion (2VO) rats, a well-established vascular dementia animal model. EPO also rescued impairments in dendritic spines and cholinergic dysfunctions in the hippocampus. Moreover, EPO suppressed the overactivation of GSK-3β in the hippocampus by stimulating the JAK2/STAT5/PI3K/Akt signal pathway. Furthermore, we found that genetic knockdown of the EPO receptor (EPO-R) by shRNA blocks the neuroprotection conferred by EPO on memory in VD. We hypothesized that EPO treatment is able to rescue the memory impairments in VD by stimulating the EPO-R/JAK2/STAT5/PI3K/Akt/GSK-3β pathway and suggest the potential usage of EPO in the therapy for VD.

Topics: Animals; Brain; Cerebrovascular Disorders; Cholinergic Neurons; Chronic Disease; Dendritic Spines; Disease Models, Animal; Erythropoietin; Fear; Gene Knockout Techniques; Glycogen Synthase Kinase 3 beta; Janus Kinase 2; Male; Memory Disorders; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats, Wistar; Receptors, Erythropoietin; Signal Transduction; Spatial Memory; STAT5 Transcription Factor

Erythropoietin (EPO) has been well known as a hematopoietic cytokine over the past decades. However, recent reports have demonstrated that EPO plays a neuroprotective role in the central nervous system, and EPO has been considered as a therapeutic target in neurodegenerative diseases such as ischemic stroke. Despite the neuroprotective effect of EPO, clinical trials have shown its unexpected side effects, including undesirable proliferative effects such as erythropoiesis and tumor growth. Therefore, the development of EPO analogs that would confer neuroprotection without adverse effects has been attempted. In this study, we examined the potential of a novel EPO-based short peptide, MK-X, as a novel drug for stroke treatment in comparison with EPO. We found that MK-X administration with reperfusion dramatically reduced brain injury in an in vivo mouse model of ischemic stroke induced by middle cerebral artery occlusion, whereas EPO had little effect. Similar to EPO, MK-X efficiently ameliorated mitochondrial dysfunction followed by neuronal death caused by glutamate-induced oxidative stress in cultured neurons. Consistent with this effect, MK-X significantly decreased caspase-3 cleavage and nuclear translocation of apoptosis-inducing factor induced by glutamate. MK-X completely mimicked the effect of EPO on multiple activation of JAK2 and its downstream PI3K/AKT and ERK1/2 signaling pathways, and this signaling process was involved in the neuroprotective effect of MK-X. Furthermore, MK-X and EPO induced similar changes in the gene expression patterns under glutamate-induced excitotoxicity. Interestingly, the most significant difference between MK-X and EPO was that MK-X better penetrated into the brain across the brain-blood barrier than did EPO. In conclusion, we suggest that MK-X might be used as a novel drug for protection from brain injury caused by ischemic stroke, which penetrates into the brain faster in comparison with EPO, even though MK-X and EPO have similar protective effects against excitotoxicity.

Topics: Animals; Blood-Brain Barrier; Brain Ischemia; Caspase 3; Cell Death; Cerebral Cortex; Cerebrovascular Disorders; Embryo, Mammalian; Erythropoietin; Gene Expression Regulation; Glutamic Acid; Janus Kinase 2; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Middle Cerebral Artery; Mitochondria; Neurons; Neuroprotective Agents; Peptides; Permeability; Phosphatidylinositol 3-Kinases; Primary Cell Culture; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Stroke

To investigate the role of erythropoietin (EPO) in the central nervous systems, we assayed EPO concentrations in the cerebrospinal fluid (CSF) of patients with depression or old cerebrovascular injuries and controls. Concentrations of EPO in the CSF were significantly higher in 13 patients with depression (3.21+/-0.46 mU/mL) than in 10 patients with old cerebrovascular diseases (1.80+/-0.32 mU/mL, P < 0.01), and in 10 healthy controls (0.98+/-0.26 mU/mL, P < 0.01). Serum EPO concentrations did not differ among these three groups. In the patients with depression, 5 months of treatment with imipramine and/or nortriptyline significantly reduced EPO concentrations in the CSF (1.56+/-0.34 mU/ mL, P < 0.01). Results suggest that the brain of patients with depression may be in an hypoxic state, and that the increased EPO in the CSF may act to limit hypoxia-induced damage to neurons in these patients.

Topics: Antidepressive Agents, Tricyclic; Cerebrovascular Disorders; Depression; Erythropoietin; Female; Humans; Imipramine; Male; Middle Aged; Nortriptyline

To investigate the influence of functioning on unexplained senile anemia, we measured commonly used hematological parameters (serum iron, transferrin, iron saturation and ferritin) in addition to specific erythropoietic factors, such as interleukin-3 (IL-3), interleukin-6 (IL-6), and erythropoietin (EPO) in 48 elderly subjects aged 65-90 years. The subjects were divided into 3 groups: 1) 17 patients with unexplained mild anemia; 2) 17 non-anemic patients with newly acquired stroke and who previously were functionally active; 3) 14 functionally active patients with no major disease who served as controls. Anemia was defined as hemoglobin (Hb) values under 12.0 g/dL. The degree of functional ability was defined and scored by the "functional independence measure" (FIM) test. Data are presented as mean values +/- SD. The results revealed a correlation between the functional state and levels of Hb, iron and transferrin with unchanged iron saturation. Patients in the mild anemia group were found to be functionally declined (FIM = 57 +/- 19.4) with the relatively lowest mean iron (75.1 +/- 17 micrograms/dL) and transferrin levels (243 +/- 42.6 micrograms/dL). The stroke group (FIM = 62 +/- 17.7) had intermediate levels of iron (85.4 +/- 20.3 micrograms/dL) and transferrin (245 +/- 45.2), and with the continuation of the declined functional state the Hb level decreased significantly (13.7 +/- 0.9 to 12.0 +/- 1.0 g/dL, p < 0.001). The highest mean values of iron (102 +/- 27.9 micrograms/dL) and transferrin (322 +/- 42.7 micrograms/dL) were found in the control group (FIM = 122.7 +/- 5.8). The ferritin levels showed an opposite trend. IL-3 values were undetectable in the anemic and control groups, and were elevated in some patients in the stroke group. The lowest IL-6 level was observed in the anemic group, and the highest in the control group. Serial IL-6 assays in the stroke group showed an upward trend. Erythropoietin levels in all groups showed no difference.

Topics: Activities of Daily Living; Aged; Aging; Anemia; Cerebrovascular Disorders; Erythropoietin; Ferritins; Hemoglobins; Humans; Interleukin-3; Interleukin-6; Iron; Reference Values

Children with sickle-cell anaemia are predisposed to thrombotic strokes, the aetiology of which is unclear. We propose that erythropoietin, produced in response to chronic anaemia, is responsible for changes in platelet reactivity with a resulting increase in thromboses. This hypothesis is based on reports of enhanced aggregability of erythropoietin-driven platelets and an increased rate of thrombosis in patients receiving large doses of recombinant erythropoietin. Experiments in animals have shown that erythropoietin stimulates synthesis of platelets, that erythropoietin-driven platelets are hyper-reactive compared with age-matched control platelets, and that erythropoietin is pro-thrombotic. These data suggest that erythropoietin-dependent changes in platelet reactivity may potentiate thrombosis in sickle-cell anaemia, particularly in children who, compared with adults, have markedly higher erythropoietin concentrations and incidence of strokes.

Topics: Adult; Anemia, Sickle Cell; Animals; Case-Control Studies; Cerebrovascular Disorders; Child; Erythropoietin; Humans; Platelet Activation; Platelet Aggregation; Recombinant Proteins; Thrombosis

Erythropoietin (EPO) prevents the ischemia-induced delayed neuronal death in the hippocampal CA1 field in gerbils. EPO receptor (EPOR) is also expressed in the cerebral cortex but its function is not known. To examine whether EPO has a neuroprotective action in the cortex, EPO was infused into the cerebroventricles of stroke-prone spontaneously hypertensive rats with permanent occlusion of the left middle cerebral artery. Morris water maze test indicated that EPO infusion alleviated the ischemia-induced place navigation disability. The left (ischemic)-to-right (contralateral nonischemic) (L/R) ratio of cerebrocortical area in the EPO-infused ischemic group was larger than that in the vehicle-infused ischemic group. The occlusion caused secondary thalamic degeneration but infusion of EPO prevented the decrease in the L/R ratio of thalamic area and supported neuron survival in the ventroposterior thalamic nucleus. In situ hybridization indicated that EPOR mRNA was upregulated in the periphery (ischemic penumbra) of a cerebrocortical infarct after occlusion of the middle cerebral artery, suggesting that an increased number of EPOR in neurons facilitates the EPO signal transmission, thereby preventing the damaged area from enlarging.

Topics: Animals; Arterial Occlusive Diseases; Cell Count; Cerebral Arteries; Cerebral Infarction; Cerebrovascular Disorders; Erythropoietin; Infusion Pumps, Implantable; Maze Learning; Nerve Degeneration; Neurons; Rats; Receptors, Erythropoietin; RNA, Messenger; Spatial Behavior; Thalamus

Recombinant human erythropoietin is widely used in chronic dialysis patients. However, the long-term effect, especially on the incidence of cardiovascular disease, has not been critically evaluated. We observed the annual incidence of stroke and acute myocardial infarction from April 1988 through March 1993 in Okinawa, Japan. Until April 1990, erythropoietin was not generally used. Therefore, we have two periods: pre-erythropoietin, April 1988 through March 1990, and post-erythropoietin, April 1990 through March 1993. Two thousand one hundred and sixteen patients (1,219 males and 897 females) were on chronic dialysis during the study period by March 31, 1993. Every case of stroke and acute myocardial infarction during the study period was registered. The odds ratio was calculated using the data of the general population in each sex and age class obtained in the same area. A total of 86 cases of stroke and 15 cases of acute myocardial infarction were registered during the study period. The annual incidence, per 1,000 patient-years, of stroke was 12.5 (1988), 10.5 (1989), 12.7 (1990), 14.0 (1991), and 17.5 (1992). The incidence of stroke was increased in the post-erythropoietin period compared to the pre-erythropoietin period, odds ratio 1.22 and 95% confidence interval (95% CI 1.06-1.41, p < 0.01). The annual incidence of acute myocardial infarction was 1.0 (1988), 1.8 (1989), 0.8 (1990), 2.9 (1991) and 4.7 (1992). The incidence of acute myocardial infarction was increased significantly in the post-erythropoietin period compared to the pre-erythropoietin period, odds ratio 1.87 (95% CI 1.66-2.10, p < 0.01). The odds ratio of stroke to the general population was 4.25 (95% CI 3.10-5.82) in the pre-erythropoietin and 4.58 (95% CI 2.14-9.80) in the post-erythropoietin period. In acute myocardial infarction, it was 2.98 (95% CI 2.84-3.12) and 3.81 (95% CI 3.18-4.56). The odds ratio of acute myocardial infarction was significantly increased (p < 0.01). The introduction of erythropoietin was associated with an increased risk of cardiovascular disease, especially acute myocardial infarction. Erythropoietin may unmask the sclerotic lesion in chronic dialysis patients.

Topics: Cardiovascular Diseases; Cerebrovascular Disorders; Diabetes Mellitus; Erythropoietin; Female; Humans; Japan; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Myocardial Infarction; Renal Dialysis; Risk Factors

Adverse hemorheologic effects induced by erythropoietin (EPO) treatment of renal anemia may pose a cerebrovascular risk. We therefore investigated the changes in cerebral perfusion, cerebral blood flow velocity (BFV) and neuropsychologic performance in 11 patients (mean age 37 years) receiving EPO. In response to EPO there was a significant (p less than 0.01) increase in hematocrit (35%), hemoglobin (43%) and whole-blood viscosity (50% at high and 90% at low shear rate). The initially increased blood flow velocity dropped significantly (p less than 0.05) and returned toward normal values in the middle cerebral arteries and the basilar artery (22 and 19% decrease, respectively). Global cerebral blood flow (CBF) decreased by 10% (not significant). The score of the Wechsler Adult Intelligence Scale digit symbol test improved significantly (p less than 0.01) after EPO treatment. None of the patients developed cerebrovascular symptoms or side effects. We conclude that the hematologic and rheologic changes following EPO treatment cause CBF and BFV to return toward normal and improve neuropsychologic performance in patients with end-stage renal disease.

Topics: Adult; Aged; Anemia; Blood Flow Velocity; Cerebrovascular Circulation; Cerebrovascular Disorders; Erythropoietin; Female; Hemodynamics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

Human recombinant erythropoietin (r-huEPO) is very effective in the treatment of anemia of hemodialyzed patients. We describe 4 patients who developed symptoms of central nervous dysfunction during r-huEPO therapy. Three exhibited typical hypertensive encephalopathy, whereas signs of cerebral ischemia were found in the fourth. The increase in blood viscosity with r-huEPO treatment, leading to a rise in peripheral vascular resistance and blood pressure especially in previously hypertensive patients, may be of importance in the pathogenesis of these cerebrovascular incidents; preexistent arteriosclerosis is an possible additional risk factor.

Topics: Adult; Aged; Anemia, Hemolytic; Blood Viscosity; Brain Edema; Brain Ischemia; Cerebrovascular Disorders; Erythropoietin; Female; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis