losartan-potassium and Brain-Damage--Chronic

The scarcity of pharmacological neuroprotective treatments for traumatic brain injury is a concern being targeted on various fronts. This review examines the latest treatments under investigation.. In the last 12-18 months, no drug has completed phase III clinical trials as a clearly proven method to treat traumatic brain injury. While the drugs work in rodents, when they make it to clinical trial they have failed primarily due to negative side-effects. Those still in trial show promise, and even those rejected have undergone modifications and now show potential, e.g. second-generation N-methyl-D-aspartic acid and alpha-amino-3-hydroxy-methyl-4-isoxazolyl-propionic acid receptor antagonists, calpain inhibitors, and cyclosporine A analogues. Also, several drugs not previously given much attention, such as the antibiotic minocycline, estrogen and progesterone, and a drug already approved for other diseases, erythropoietin, are being examined. Finally, a treatment generating some controversy, but showing potential, is the application of hypothermia to the patients.. Clearly, finding treatments for traumatic brain injury is not going to be easy and is evidently going to require numerous trials. The good news is that we are closer to finding one or more methods for treating traumatic brain injury patients.

Topics: Animals; Brain; Brain Damage, Chronic; Brain Injuries; Enzyme Inhibitors; Erythropoietin; Excitatory Amino Acid Antagonists; Gonadal Steroid Hormones; Humans; Hypothermia, Induced; Neuroprotective Agents

The purpose of this study was to evaluate the efficacy and safety of erythropoietin in neonatal hypoxic-ischemic encephalopathy (HIE), by using a randomized, prospective study design.. A total of 167 term infants with moderate/severe HIE were assigned randomly to receive either erythropoietin (N = 83) or conventional treatment (N = 84). Recombinant human erythropoietin, at either 300 U/kg (N = 52) or 500 U/kg (N = 31), was administered every other day for 2 weeks, starting <48 hours after birth. The primary outcome was death or disability. Neurodevelopmental outcomes were assessed at 18 months of age.. Complete outcome data were available for 153 infants. Nine patients dropped out during treatment, and 5 patients were lost to follow-up monitoring. Death or moderate/severe disability occurred for 35 (43.8%) of 80 infants in the control group and 18 (24.6%) of 73 infants in the erythropoietin group (P = .017) at 18 months. The primary outcomes were not different between the 2 erythropoietin doses. Subgroup analyses indicated that erythropoietin improved long-term outcomes only for infants with moderate HIE (P = .001) and not those with severe HIE (P = .227). No negative hematopoietic side effects were observed.. Repeated, low-dose, recombinant human erythropoietin treatment reduced the risk of disability for infants with moderate HIE, without apparent side effects.

Topics: Asphyxia Neonatorum; Brain Damage, Chronic; China; Developmental Disabilities; Disability Evaluation; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Follow-Up Studies; Humans; Hypoxia-Ischemia, Brain; Infant; Infant, Newborn; Infusions, Intravenous; Injections, Subcutaneous; Intensive Care Units, Neonatal; Male; Neurologic Examination; Prospective Studies; Psychomotor Disorders; Recombinant Proteins

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

Intrauterine infection and inflammation have been linked to preterm birth and brain damage. We hypothesized that recombinant human erythropoietin (rhEPO) would ameliorate brain damage in anovine model of fetal inflammation. At 107 +/- 1 day of gestational age (DGA), chronically catheterized fetal sheep received on 3 consecutive days 1) an intravenous bolus dose of lipopolysaccharide ([LPS] approximately 0.9 microg/kg; n = 8); 2) an intravenous bolus dose of LPS, followed at 1 hour by 5,000 IU/kg of rhEPO (LPS + rhEPO, n = 8); or 3) rhEPO (n = 5). Untreated fetuses (n = 8) served as controls. Fetal physiological parameters were monitored, and fetal brains and optic nerves were histologically examined at 116 +/- 1 DGA. Exposure to LPS, but not to rhEPO alone or saline, resulted in fetal hypoxemia, hypotension (p < 0.05), brain damage, including white matter injury, and reductions in numbers of myelinating oligodendrocytes in the corticospinal tract and myelinated axons in the optic nerve (p < 0.05 for both). Treatment of LPS-exposed fetuses with rhEPO did not alter the physiological effects of LPS but reduced brain injury and was beneficial to myelination in the corticospinal tract and the optic nerve. This is the first study in a long-gestation species to demonstrate the neuroprotective potential of rhEPO in reducing fetal brain and optic nerve injury after LPS exposure.

Topics: Animals; Brain; Brain Damage, Chronic; Demyelinating Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis; Endotoxins; Erythropoietin; Female; Fetal Diseases; Fetal Hypoxia; Injections, Intravenous; Lipopolysaccharides; Nerve Fibers, Myelinated; Neuroprotective Agents; Optic Nerve; Pregnancy; Sheep, Domestic; Treatment Outcome

Results of recent studies indicate that erythropoietin (EPO) produces a neuroprotective effect on experimental subarachnoid hemorrhage (SAH). It has been reported that S-100 protein levels increase in cerebrospinal fluid (CSF) after SAH, providing a highly prognostic indication of unfavorable outcome. This study was conducted to validate further the findings of S-100 protein as an index of brain damage and to assess whether treatment with recombinant human EPO (rhEPO) would limit the increase of S-100 protein level in CSF following experimental SAH.. Thirty-two rabbits were each assigned to one of four groups: Group 1, control; Group 2, SAH; Group 3, SAH plus placebo; and Group 4, SAH plus rhEPO (each group consisted of eight rabbits). The rhEPO and placebo were administered to the rabbits after SAH had been induced, and S-100 protein levels in the CSF of these animals were measured at 24, 48, and 72 hours after the experimental procedure. In each group of animals levels of S-100 protein were compared with the mortality rate, neurological outcome, and neuronal ischemic damage. High S-100 protein levels were found in rabbits in Groups 2 and 3, which exhibited poor neurological status and harbored a high number of damaged cortical neurons. Favorable neurological outcome and significant reductions in total numbers of damaged neurons were observed in animals in Group 4 in which there were significantly lower S-100 protein concentrations compared with animals in Groups 2 and 3 (p < 0.001).. The results of this study support the concept that determination of the S-100 protein level in CSF has prognostic value after SAH. The findings also confirm that rhEPO acts as a neuroprotective agent during experimental SAH.

Topics: Animals; Brain; Brain Damage, Chronic; Erythropoietin; Humans; Male; Neurologic Examination; Neurons; Neuroprotective Agents; Rabbits; Recombinant Proteins; S100 Proteins; Subarachnoid Hemorrhage

For an assessment of whether cord plasma arginine vasopressin, erythropoietin, and hypoxanthine concentrations are predictors of perinatal brain damage, these concentrations were measured in 62 infants born after preeclampsia of pregnancy, 31 acutely asphyxiated infants, and 38 control infants. Follow-up at 2 years included neurologic examination and the determination of a Bayley mental score. Clear abnormality (death, cerebral palsy, or developmental delay) was found in four infants in the preeclampsia group and five in the asphyxia group; slight abnormality was found in 12 and 6 infants, respectively; and no abnormality was found in the remainder. Neither arginine vasopressin values nor hypoxanthine values predicted adverse outcome in either study group. A high erythropoietin level was found in infants born after preeclampsia regardless of outcome: normal outcome (geometric mean (GM), 102; 95% confidence interval [CI], 69 to 153 mU/ml), slightly abnormal outcome (GM, 100; 95% CI, 37 to 270 mU/ml) or clearly abnormal outcome (GM, 84; 95% CI, 19 to 378 mU/ml). However, asphyxiated infants with clearly abnormal outcome had higher erythropoietin values (GM, 67; 95% CI, 33 to 137 mU/ml; p less than 0.05) than the normal infants (GM, 37; 95% CI, 23 to 59 mU/ml). We conclude that a high erythropoietin level after normal pregnancy, but not after preeclampsia, indicates an increased risk for cerebral palsy or death.

Topics: Arginine Vasopressin; Asphyxia Neonatorum; Brain Damage, Chronic; Cerebral Palsy; Erythropoietin; Female; Fetal Blood; Humans; Hypoxanthine; Hypoxanthines; Infant, Newborn; Male; Pre-Eclampsia; Pregnancy; Prognosis