losartan-potassium and Intracranial-Hemorrhages

Treatments for spontaneous intracerebral, thrombolytic-induced and intraventricular hemorrhages (IVH) are still at the preclinical or early clinical investigational stages. There has been some renewed interest in the use of surgical evacuation surgery or thrombolytics to remove hematomas, but these techniques can be used only for specific types of brain bleeding. The STICH (Surgical Trial in Intracerebral Haemorrhage) clinical trials should provide some insight into the potential for such techniques to counteract hematoma-induced damage and subsequently, morbidity and mortality. More recently, clinical trials (ATACH [Antihypertensive Treatment in Acute Cerebral Hemorrhage] and INTERACT [Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial]) have begun testing whether or not regulating blood pressure affects the well-being of hemorrhage patients, but the findings thus far have not conclusively demonstrated a positive result. More promising trials, such as the early stage CHANT (Cerebral Hemorrhagic And NXY-059 Treatment) and the late stage FAST (Factor VIIa for Acute Hemorrhagic Stroke Treatment), have addressed whether or not manipulating oxidative stress and components of the blood coagulation cascade can achieve an improved prognosis following spontaneous hemorrhages. However, CHANT was halted prematurely because although it showed that the spin trap agent NXY-059 was safe, it also demonstrated that the drug was ineffective in treating acute ischemic stroke. In addition, the recombinant activated factor VII FAST trial recently concluded with only modestly positive results. Despite a beneficial effect on the primary end point of reducing hemorrhage volume, controlling the coagulation cascade with recombinant factor VIIa did not decrease the mortality rate. Consequently, Novo Nordisk has abandoned further development of the drug for the treatment of intracerebral hemorrhaging. Even though progress in hemorrhage therapy that successfully reduces the escalating morbidity and mortality rate associated with brain bleeding is slow, perseverance and applied translational drug development will eventually be productive. The urgent need for such therapy becomes more evident in light of concerns related to uncontrolled high blood pressure in the general population, increased use of blood thinners by the elderly (e.g., warfarin) and thrombolytics by acute ischemic stroke patients, respectively. The future of drug development for hemorrhage may requi

Topics: Animals; Antihypertensive Agents; Antioxidants; Benzenesulfonates; Blood Pressure; Cardiovascular Agents; Coagulants; Disease Models, Animal; Drug Design; Enzyme Inhibitors; Erythropoietin; Excitatory Amino Acid Antagonists; Factor VIIa; Hemostasis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intracranial Hemorrhages; Oxidative Stress; Signal Transduction; Stroke; Treatment Outcome

To investigate the safety and short term outcome of high dose recombinant human erythropoietin (rhEpo) given shortly after birth and subsequently over the first 2 days for neuroprotection to very preterm infants.. Randomized, double masked phase II trial. Preterm infants (gestational age 26 0/7-31 6/7 weeks) were given rhEpo (nt = 229; 3000 U/kg body weight) or NaCl 0.9% (nc = 214) intravenously at 3, 12-18, and 36-42 hours after birth.. There were no relevant differences between the groups for short-term outcomes such as mortality, retinopathy of prematurity, intraventricular hemorrhage, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. At day 7-10, we found significantly higher hematocrit values, reticulocyte, and white blood cell counts, and a lower platelet count in the rhEpo group.. Early high-dose rhEpo administration to very premature infants is safe and causes no excess in mortality or major adverse events.. ClinicalTrials.gov: NCT00413946.

Topics: Bronchopulmonary Dysplasia; Developmental Disabilities; Dose-Response Relationship, Drug; Double-Blind Method; Enterocolitis, Necrotizing; Erythropoietin; Europe; Hematocrit; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Infant, Premature; Intracranial Hemorrhages; Leukocyte Count; Leukomalacia, Periventricular; Neuroprotective Agents; Platelet Count; Recombinant Proteins; Reticulocyte Count; Retinopathy of Prematurity; Sepsis

We previously reported that erythropoietin (Epo) is present in human cerebrospinal fluid (CSF). It is not known whether CSF Epo concentrations change under conditions of CNS injury or, if so, whether this change reflects loss of blood-brain barrier integrity or increased CNS Epo synthesis. We hypothesized that CSF Epo increases in conditions of neural injury including hypoxia, meningitis, and intraventricular hemorrhage (IVH) and that CSF Epo concentrations are independent of plasma Epo concentrations. To test these hypotheses, Epo concentrations were measured in 122 paired CSF and blood samples obtained from neonates and children categorized as follows: 16, asphyxia; 31, meningitis; 11, IVH; 41, controls. Twelve infants treated with recombinant Epo (rEpo) and 11 additional samples from children with miscellaneous neurologic problems were also evaluated. CSF and plasma Epo concentrations were significantly higher in asphyxiated infants than in controls (225.0+/-155.0 versus 4.5+/-0.5 mU/mL; mean +/- SEM, p < 0.05, respectively, in CSF; 1806.7+/-1254 versus 5.2+/-0.5, p < 0.05 in plasma). Neonates with IVH had higher CSF Epo concentrations than controls (p < 0.01) but did not have higher plasma Epo concentrations than controls. Patients with meningitis did not have elevated CSF or plasma Epo concentrations. There was no correlation between CSF and plasma Epo concentrations in infants treated with rEpo. We conclude that Epo is selectively increased in the CSF by hypoxia, less so by IVH, and not at all by meningitis. rEpo treatment does not elevate CSF Epo. These findings suggest that rEpo does not cross the blood-brain barrier and that hypoxia induces increased CNS synthesis of Epo.

Topics: Asphyxia Neonatorum; Brain Injuries; Cerebral Ventricles; Erythropoietin; Female; Humans; Infant, Newborn; Intracranial Hemorrhages; Linear Models; Meningitis; Postpartum Hemorrhage; Pregnancy

Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is associated with increased risks of all cause and cardiovascular mortality in patients undergoing hemodialysis (HD). However, the impact of the hematopoietic response to ESAs on the development of stroke, including brain hemorrhage and infarction, remains unclear.. In total, 2886 patients undergoing maintenance HD registered in the Q-Cohort Study who were treated with ESAs were prospectively followed up for 4 years. The hematopoietic response to ESAs was evaluated by the erythropoietin resistance index (ERI), calculated by dividing the weekly dose of ESA by post-HD weight and hemoglobin (U/kg/week/g/dL). The primary outcomes were the incidences of brain hemorrhage and infarction. Patients were divided into quartiles based on their ERI at baseline (Q1, ≤ 4.1; Q2, 4.2-7.0; Q3, 7.1-11.2; and Q4, ≥ 11.3). The risks of brain hemorrhage and infarction were estimated using Cox proportional hazards models, adjusting for potential confounders.. During the 4 year follow-up period, 71 patients developed brain hemorrhage and 116 developed brain infarction. In the multivariable analysis, the incidence of brain hemorrhage in the highest quartile (Q4) was significantly higher than that in the lowest quartile (Q1) (hazard ratio [95% confidence interval], 2.18 [1.08-4.42]). However, the association between the ERI and the incidence of brain infarction was not significant.. A higher ERI was associated with an increased risk of brain hemorrhage, but not brain infarction, in patients undergoing maintenance HD. A high ERI is thus an important risk factor for brain hemorrhage in these patients.

Topics: Anemia; Cohort Studies; Erythropoiesis; Erythropoietin; Hematinics; Humans; Intracranial Hemorrhages; Kidney Failure, Chronic; Renal Dialysis

This study aims to investigate the incidence and the relative risk factors of retinopathy of prematurity (ROP) and posterior-ROP (P-ROP): ROP in Zone I and posterior Zone II, as well as to analyze the occurrence of surgical treatment of ROP and to evaluate the short term outcome of the disease in Italy.. It is a prospective multicenter observational study; all infants with a birth weight (BW) ≤ 750 g and/or a gestational age (GA) ≤27 weeks born between January 1st 2008 and December 31st 2009 in 25 III level Italian neonatal intensive care units were eligible for the study.. 421 infants were examined: 265 (62.9%) developed ROP and 102 (24.2%) P-ROP.. P-ROP is the most aggressive type of ROP. It associates with lower GA and sepsis. Obstetricians and Neonatologists must focus on the reduction of severe preterm births and on the prevention of neonatal early and late onset sepsis in order to reduce the incidence of P-ROP.

Topics: Birth Weight; Erythropoietin; Female; Gestational Age; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Intracranial Hemorrhages; Italy; Laser Therapy; Male; Multivariate Analysis; Prospective Studies; Retinopathy of Prematurity; Sepsis

Our patient is a 26-week-old preterm female infant delivered by caesarean section secondary to severe maternal preeclampsia who had been receiving subcutaneous recombinant erythropoietin (r-EPO) for anemia of prematurity. At 8 weeks of age after 8 doses of r-EPO, the infant developed numerous non-blanching erythematous macules and patches located on the back, posterior shoulder, and posterior arms, concerning for late-onset blueberry muffin lesions. Biopsy of the lesions confirmed dermal hematopoiesis. After r-EPO was discontinued all skin lesions gradually resolved over a period of 2 weeks and never recurred.

Topics: Anemia; Dermis; Erythroblasts; Erythropoietin; Female; Fetal Growth Retardation; Hematopoiesis, Extramedullary; Humans; Infant; Infant, Premature; Infant, Premature, Diseases; Intracranial Hemorrhages; Recombinant Proteins; Respiratory Distress Syndrome, Newborn; Skin Diseases

To evaluate cord blood erythropoietin (EPO) and interleukin-6 (IL-6) levels to predict preterm infants at risk of developing intraventricular hemorrhage (IVH).. Levels of umbilical cord EPO, acid-base status and IL-6 were analyzed in 116 consecutive, preterm newborns (GA at delivery: 29 [23-34 ] weeks) born to mothers who had a clinically indicated amniocentesis to rule out infection. Early-onset neonatal sepsis (EONS) was diagnosed using symptoms, hematological criteria and blood cultures.. IVH was diagnosed by cranial ultrasounds. The prevalence of IVH in our population was 25% (29/116). There was a direct relationship between cord blood EPO and cord blood IL-6 concentration (r = 0.225, p = 0.014), independent of GA at birth. Elevated cord blood EPO levels (r = 0.182, p = 0.016) and GA at birth (r =  -0.236, p = 0.004) remained significant independent factors associated with the risk of IVH, when evaluated with stepwise logistic regression analyses. Cord blood IL-6, pH, and EONS were not associated with IVH. These relationships remained following correction for GA at birth (p = 0.027).. Our results suggest that elevation in cord blood EPO may predict newborns at risk for IVH, independent of fetal inflammatory status. Further studies are warranted to confirm this association.

Topics: Adult; Biomarkers; Chorioamnionitis; Erythropoietin; Female; Fetal Blood; Humans; Infant, Newborn; Infant, Premature, Diseases; Interleukin-6; Intracranial Hemorrhages; Pregnancy; Premature Birth; Prospective Studies; Sepsis; Young Adult

Erythropoietin (EPO), a hematopoietic cytokine, exerts neuroprotective effects in experimental stroke. In the present study, we investigated the effect of recombinant human EPO (rhEPO) in combination with tissue plasminogen activator (tPA) on embolic stroke.. Rats subjected to embolic middle cerebral artery occlusion (MCAO) were treated with rhEPO (5000 U/kg) in combination with tPA (10 mg/kg) at 2 or 6 hours after MCAO. Control groups consisted of ischemic rats treated with rhEPO (5000 U/kg) alone, tPA (10 mg/kg) alone, or saline at 2 or 6 hours after MCAO.. The combination therapy of rhEPO and tPA initiated 6 hours after MCAO did not reduce the ischemic lesion volume and significantly (P<0.05) increased the incidence of brain hemorrhage measured by frequency of gross hemorrhage and a quantitative spectrophotometric hemoglobin assay compared with rats treated with rhEPO alone and tPA alone. However, when the combination therapy was initiated 2 hours after MCAO, the treatment significantly (P<0.05) reduced the lesion volume and did not substantially increase the incidence of hemorrhagic transformation compared with saline-treated rats. Immunostaining analysis revealed that the combination therapy of rhEPO and tPA at 6 hours significantly (P<0.05) increased matrix metalloproteinase-9, NF-kappaB, and interleukin-1 receptor-associated kinase-1 immunoreactive cerebral vessels compared with rats treated with rhEPO alone and saline.. EPO exacerbates tPA-induced brain hemorrhage without reduction of ischemic brain damage when administered 6 hours after stroke in a rat model of embolic MCAO and that matrix metalloproteinase-9, NF-kappaB, and interleukin-1 receptor-associated kinase-1 upregulated by the delayed combination therapy may contribute to augmentation of brain hemorrhage.

Topics: Analysis of Variance; Animals; Blotting, Western; Brain; Chi-Square Distribution; Drug Therapy, Combination; Erythropoietin; Immunohistochemistry; Interleukin-1 Receptor-Associated Kinases; Intracranial Hemorrhages; Male; Matrix Metalloproteinase 9; NF-kappa B; Rats; Rats, Wistar; Stroke; Time Factors; Tissue Plasminogen Activator; Treatment Outcome

A 58 year old male heavy smoker presented with intracranial haemorrhage and erythrocytosis. Four aetiologies of polycythaemia--polycythaemia rubra vera (PRV), renal cell carcinoma, sleep apnoea syndrome, and relative polycythaemia--were found to be associated with the underlying causes of erythrocytosis. He did not fulfill the diagnostic criteria for PRV at initial presentation, but an erythropoietin independent erythroid progenitor assay identified the masked PRV, and the low post-phlebotomy erythropoietin concentration also suggested the likelihood of PRV evolution. This case demonstrates that a search for all the possible causes of erythrocytosis is warranted in patients who already have one aetiology of polycythaemia.

Topics: Carcinoma, Renal Cell; Erythroid Precursor Cells; Erythropoietin; Humans; Intracranial Hemorrhages; Kidney Neoplasms; Male; Middle Aged; Polycythemia; Polycythemia Vera; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sleep Apnea Syndromes; Smoking