Pharmacological inhibition of lipid peroxidative damage by the 21-aminosteroid U-74389G improves cortical mitochondrial function following traumatic brain injury in young adult male rats.

The 21-aminosteroid ("lazaroid") U-74389G (U74), an inhibitor of lipid peroxidation (LP), was used to protect mitochondrial function following TBI in young adult male rats. The animals received a severe (2.2 mm) controlled cortical impact-TBI. U74 was administered intravenous at 15 min and 2 h post injury (hpi) followed by intraperitoneal dose at 8 hpi at the following doses (mg/kg): 0.3 (IV) + 1 (IP), 1 + 3, 3 + 10, 10 + 30. Total cortical mitochondria were isolated at 72 hpi and respiratory rates were measured. Mitochondrial 4-HNE and acrolein were evaluated as indicators of LP-mediated oxidative damage. At 72 h post-TBI injured animals had significantly lower mitochondrial respiration rates compared to sham. Administration of U74 at the 1 mg/kg dosing paradigm significantly improved mitochondrial respiration rates for States II, III, V(II) and RCR compared to vehicle-treated animals. At 72 h post-TBI injured animals administration of U74 also reduced reactive aldehydes levels compared to vehicle-treated animals. The aim of this study was to explore the hypothesis that interrupting secondary oxidative damage via acute pharmacological inhibition of LP by U74 following a CCI-TBI would provide mitochondrial neuroprotective effects in a dose-dependent manner. We found acute administration of U74 to injured rats resulted in improved mitochondrial function and lowered the levels of reactive aldehydes in the mitochondria. These results establish not only the most effective dose of U74 treatment to attenuate LP-mediated oxidative damage, but also set the foundation for further studies to explore additional neuroprotective effects following TBI.

Beneficial Effect of U-74389 G and Sildenafil in An Experimental Model of Flap Ischemia/Reperfusion Injury in Swine. Histological and Biochemical Evaluation of the Model.

Purpose of the study: Tissue reconstruction after burns, tumor excisions, infections or injuries is a frequent surgical challenge to avoid Ischemia-reperfusion injury. Lazaroids and sildenafil, through their mechanisms of action, have been studied for their protective effects on various organs subjected to IRI. In this study, we aimed to evaluate the therapeutic potential of U-74389G and sildenafil in a swine model of ischemia and reperfusion injury of latissimus dorsi flap. Materials and methods: Forty-two Landrace male pigs, weighing 28-35 kg, were equally (n = 6) randomized into the following groups: (a) Group I: control, (b) Group II: administration of U-74389G after ischemia, (c) Group III: administration of sildenafil after ischemia, (d) Group IV: administration of U-74389G and sildenafil after ischemia, (e) Group V: administration of U-74389G prior to ischemia, (f) Group VI: administration of sildenafil prior to ischemia, and (g) Group VII: administration of U-74389G and sildenafil prior to ischemia. Blood and tissue sampling was conducted before ischemia, 15 and 30 min after occlusion, 30, 60, 90, and 120 min after reperfusion. Results: Statistically significant reduction (p < 0.05) was detected in lymphocytes and polymorphonuclear leukocytes concentrations as well as in the appearance of edema after histopathologic evaluation of the ischemic tissue, especially in the groups of combined treatment. Measurements of malondialdeyde and tumour necrosis factor alpha in tissues revealed a significant decrease (p < 0.001) of these markers in the treatment groups when compared to the control, particularly in the latest estimated timepoints. Conclusions: The synergistic action of U-74389G and sildenafil seems protective and promising in cases of flap IRI during tissue reconstruction surgery.

Neurosurgeon academic impact is associated with clinical outcomes after clipping of ruptured intracranial aneurysms.

BACKGROUND: Surgeon-dependent factors such as experience and volume are associated with patient outcomes. However, it is unknown whether a surgeon's research productivity could be related to outcomes. The main aim of this study is to investigate the association between the surgeon's academic productivity and clinical outcomes following neurosurgical clipping of ruptured aneurysms. METHODS: We performed a post-hoc analysis of 3567 patients who underwent clipping of ruptured intracranial aneurysms in the randomized trials of tirilazad mesylate from 1990 to 1997. These trials included 162 centers and 156 surgeons from 21 countries. Primary and secondary outcomes were: Glasgow outcome scale score and mortality, respectively. Total publications, H-index, and graduate degrees were used as academic indicators for each surgeon. The association between outcomes and academic factors were assessed using a hierarchical logistic regression analysis, adjusting for patient covariates. RESULTS: Academic profiles were available for 147 surgeons, treating a total of 3307 patients. Most surgeons were from the USA (62, 42%), Canada (18, 12%), and Germany (15, 10%). On univariate analysis, the H-index correlated with better functional outcomes and lower mortality rates. In the multivariate model, patients under the care of surgeons with higher H-indices demonstrated improved neurological outcomes (p = 0.01) compared to surgeons with lower H-indices, without any significant difference in mortality. None of the other academic indicators were significantly associated with outcomes. CONCLUSION: Although prognostication following surgery for ruptured intracranial aneurysms primarily depends on clinical and radiological factors, the academic impact of the operating neurosurgeon may explain some heterogeneity in surgical outcomes.

Comparison of the Acute Hematopoietic Capacities of Erythropoietin and U-74389G Concerning Hematocrit Levels.

AIM: This study compared the hematopoietic capacities of erythropoietin (Epo) and antioxidant drug U-74389G, based on 2 preliminary studies. The provided results on hematocrit levels augmentation were co-evaluated in a hypoxia reoxygenation protocol of an animal model. MATERIALS AND METHODS: Hematocrit levels were evaluated at the 60th reoxygenation min (for groups A, C and E) and at the 120th reoxygenation min (for groups B, D and F) in 60 rats. Groups A and B received no drugs, rats from groups C and D were administered with Epo; whereas rats from groups E and F were administered with U-74389G. RESULTS: The first preliminary study of Epo non-significantly increased the hematocrit levels by 0.24%+1.38% (p-value=0.8586). The second preliminary study of U-74389G significantly raised the hematocrit levels by 3.16%+1.33% (p-value=0.0196). These 2 studies were co-evaluated since they came from the same experimental setting. The outcome of the co-evaluation was that U-74389G has approximately 12.66-fold higher hematopoietic potency than Epo (p-value=0.0000). CONCLUSION: The anti-oxidant capacities of U-74389G provide satisfactory acute hematopoietic properties; presenting approximately 12.66-fold hematocrit level rise than epo (p-value=0.0000).

Lazaroid U-74389G for cardioplegia-related ischemia-reperfusion injury: an experimental study.

BACKGROUND: The adverse effects of myocardial ischemia and reperfusion during cardiopulmonary bypass (CPB) have been thoroughly described. Lazaroid U-74389G, a 21 aminosteroid, has been shown to attenuate ischemia and reperfusion injury and improve recovery in a variety of experimental models. METHODS: Sixteen male swine were randomly divided in two groups. All animals underwent 45 min of ischemic cardioplegic arrest, with U-74389G addition to the standard cardioplegic solution, whereas controls underwent the same procedure without U-74389G. Creatine kinase-MB isoenzyme (CK-MB) and cardiac troponin T levels were measured immediately before CPB (time point 0), during the ischemic period (time point 1) and 30 (time point 2), 60 (time point 3), and 120 (time point 4) min after reperfusion. Myocardial biopsies were obtained at time points 0 and 4. RESULTS: CK-MB levels (in U/L) at time points 0-4 were 205 (186-235) versus 219 (196-269; P = 0.72), 215 (167-248) versus 253 (193-339; P = 0.23), 234 (198-255) versus 338 (249-441; P = 0.02), 244 (217-272) versus 354 (269-496; P = 0.01), and 285 (230-321) versus 439 (432-530; P < 0.01) in lazaroid-treated animals versus controls, respectively. Cardiac troponin T levels (in ng/L) at time points 0-4 were 58 (26-287) versus 237 (26-395; P = 0.72), 129 (61-405) versus 265 (145-525; P = 0.23), 261 (123-467) versus 474 (427-1604; P = 0.04), 417 (204-750) versus 841 (584-1818; P = 0.11), and 643 (353-1259) versus 1600 (1378-2313; P < 0.01), respectively. Necrosis grades at time point 4 were 0.0 (0.0-1.0) versus 1.5 (1.0-2.0; P < 0.01) in lazaroid-treated animals versus controls, respectively. CONCLUSIONS: The present study, in addition to reconfirming the well-described adverse effects of CPB, demonstrates the efficacy of the newer generation lazaroid U-74389G in alleviating these effects.

Effectiveness of sildenafil and U-74389G in a rat model of colitis.

BACKGROUND: Crohn disease is still incurable. Compounds with anti-inflammatory and/or antioxidative effects are tested in various preclinical models of the disease. Our aim was to investigate the effects of sildenafil and lazaroid U-74389G in an experimental rat model of trinitrobenzenesulfonic acid-induced colitis. MATERIALS AND METHODS: Trinitrobenzenesulfonic acid was instilled into the colon of all male Wistar rats except for the rats belonging to the first group. For 6 days, the animals in group 3 were administered daily sildenafil orally, the rats in group 4 were administered daily U-74389G intravenously, and the rats in group 5 were coadministered daily sildenafil orally and intravenous U-74389G. The rats in groups 1 and 2 were not administered any treatment. During the study, the weights were recorded as a marker of clinical condition. The colon damage was evaluated using macroscopic colon mucosal damage index (CMDI), microscopic (Geboes score), and biochemical methods (tissue tumor necrosis factor [TNF]-α and malondialdehyde [MDA]). RESULTS: Sildenafil reduced TNF-α tissue levels and increased body weight. U-74389G reduced TNF-α, the macroscopic index of mucosal damage score (CMDI) and increased body weight. The combined treatment with sildenafil and U-74389G reduced tissue levels of both TNF-α and MDA, lowered CMDI and microscopic Geboes score, and increased body weight. CONCLUSIONS: U-74389G demonstrated a significant anti-inflammatory activity related to its ability to reduce colonic TNF-α, CMDI score, and improve weight change. We confirmed that sildenafil has anti-inflammatory capacity by reducing colonic TNF-α and by improving body weight. Finally, the combined treatment showed superior effects by reducing colonic TNF-α, colonic MDA, CMDI score, Geboes score, and by improving weight.

Effects of lazaroid U-74389G on intestinal ischemia and reperfusion injury in porcine experimental model.

BACKGROUND: The readmission of molecular oxygen into an ischemic tissue promotes the oxidation of resuscitated tissue with certain pathophysiologic mechanisms. MATERIALS AND METHODS: Twenty four pigs (male or female) were randomized in this study. The animals were allocated to four groups with an equal number (n = 6) in each group: (1) control group-ischemia for 30 min and reperfusion for 60 min. (2) control group-ischemia for 30 min and reperfusion for 120 min. (3) ischemia for 30 min and immediate iv injection of lazaroid U-74389G and reperfusion for 60 min. (4) ischemia for 30 min and immediate iv injection of lazaroid U-74389G and reperfusion for 120 min. RESULTS: We investigated further the role of an antioxidant molecule such as U-74389G and we concluded that there is statistically significant relation in MDA (malondialdeyde), TNF -α (tumor necrosis factor-α) measurement in tissue, while the histological score in the groups that the lazaroid was administered was improved. CONCLUSIONS: In many emergency clinical situations, such as reperfusion of the intestine, the role of U-74389G can be protective.

National socioeconomic indicators are associated with outcomes after aneurysmal subarachnoid hemorrhage: a hierarchical mixed-effects analysis.

OBJECT: Although heterogeneity exists in patient outcomes following subarachnoid hemorrhage (SAH) across different centers and countries, it is unclear which factors contribute to such disparities. In this study, the authors performed a post hoc analysis of a large international database to evaluate the association between a country's socioeconomic indicators and patient outcome following aneurysmal SAH. METHODS: An analysis was performed on a database of 3552 patients enrolled in studies of tirilazad mesylate for aneurysmal SAH from 1991 to 1997, which included 162 neurosurgical centers in North and Central America, Australia, Europe, and Africa. Two primary outcomes were assessed at 3 months after SAH: mortality and Glasgow Outcome Scale (GOS) score. The association between these outcomes, nation-level socioeconomic indicators (percapita gross domestic product [GDP], population-to-neurosurgeon ratio, and health care funding model), and patientlevel covariates were assessed using a hierarchical mixed-effects logistic regression analysis. RESULTS: Multiple previously identified patient-level covariates were significantly associated with increased mortality and worse neurological outcome, including age, intraventricular hemorrhage, and initial neurological grade. Among national-level covariates, higher per-capita GDP (p < 0.05) was associated with both reduced mortality and improved neurological outcome. A higher population-to-neurosurgeon ratio (p < 0.01), as well as fewer neurosurgical centers per population (p < 0.001), was also associated with better neurological outcome (p < 0.01). Health care funding model was not a significant predictor of either primary outcome. CONCLUSIONS: Higher per-capita gross GDP and population-to-neurosurgeon ratio were associated with improved outcome after aneurysmal SAH. The former result may speak to the availability of resources, while the latter may be a reflection of better outcomes with centralized care. Although patient clinical and radiographic phenotypes remain the primary predictors of outcome, this study shows that national socioeconomic disparities also explain heterogeneity in outcomes following SAH.

SAHIT Investigators--on the outcome of some subarachnoid hemorrhage clinical trials.

Outcome of patients with aneurysmal subarachnoid hemorrhage (SAH) has improved over the last decades. Yet, case fatality remains nearly 40% and survivors often have permanent neurological, cognitive and/or behavioural sequelae. Other than nimodipine drug or clinical trials have not consistently improved outcome. We formed a collaboration of SAH investigators to create a resource for prognostic analysis and for studies aimed at optimizing the design and analysis of phase 3 trials in aneurysmal SAH. We identified investigators with data from randomized, clinical trials of patients with aneurysmal SAH or prospectively collected single- or multicentre databases of aneurysmal SAH patients. Data are being collected and proposals to use the data and to design future phase 3 clinical trials are being discussed. This paper reviews some issues discussed at the first meeting of the SAH international trialists (SAHIT) repository meeting. Investigators contributed or have agreed to contribute data from several phase 3 trials including the tirilazad trials, intraoperative hypothermia for aneurysmal SAH trial, nicardipine clinical trials, international subarachnoid aneurysm trial, intravenous magnesium sulphate for aneurysmal SAH, magnesium for aneurysmal SAH and from prospectively-collected data from four institutions. The number of patients should reach 15,000. Some industry investigators refused to provide data and others reported that their institutional research ethics boards would not permit even deidentified or anonymized data to be included. Others reported conflict of interest that prevented them from submitting data. The problems with merging data were related to lack of common definitions and coding of variables, differences in outcome scales used, and times of assessment. Some questions for investigation that arose are discussed. SAHIT demonstrates the possibility of SAH investigators to contribute data for collaborative research. The problems are similar to those already documented in other similar collaborative efforts such as in head injury research. We encourage clinical trial and registry investigators to contact us and participate in SAHIT. Key issues moving forward will be to use common definitions (common data elements), outcomes analysis, and to prioritize research questions, among others.

Clinical outcome prediction in aneurysmal subarachnoid hemorrhage using Bayesian neural networks with fuzzy logic inferences.

OBJECTIVE: The novel clinical prediction approach of Bayesian neural networks with fuzzy logic inferences is created and applied to derive prognostic decision rules in cerebral aneurysmal subarachnoid hemorrhage (aSAH). METHODS: The approach of Bayesian neural networks with fuzzy logic inferences was applied to data from five trials of Tirilazad for aneurysmal subarachnoid hemorrhage (3551 patients). RESULTS: Bayesian meta-analyses of observational studies on aSAH prognostic factors gave generalizable posterior distributions of population mean log odd ratios (ORs). Similar trends were noted in Bayesian and linear regression ORs. Significant outcome predictors include normal motor response, cerebral infarction, history of myocardial infarction, cerebral edema, history of diabetes mellitus, fever on day 8, prior subarachnoid hemorrhage, admission angiographic vasospasm, neurological grade, intraventricular hemorrhage, ruptured aneurysm size, history of hypertension, vasospasm day, age and mean arterial pressure. Heteroscedasticity was present in the nontransformed dataset. Artificial neural networks found nonlinear relationships with 11 hidden variables in 1 layer, using the multilayer perceptron model. Fuzzy logic decision rules (centroid defuzzification technique) denoted cut-off points for poor prognosis at greater than 2.5 clusters. DISCUSSION: This aSAH prognostic system makes use of existing knowledge, recognizes unknown areas, incorporates one's clinical reasoning, and compensates for uncertainty in prognostication.

Blood alcohol concentration as a determinant of outcomes after traumatic spinal cord injury.

BACKGROUND: Pre-clinical studies indicate a potential detrimental effect of ethanol on tissue sparing and locomotor recovery in animal models of spinal cord injury (SCI). Given this, an examination of whether blood alcohol concentration (BAC) is a potential determinant of survival and neurological and functional recovery after acute traumatic SCI was carried out. METHODS: All patients who were enrolled in the Third National Spinal Cord Injury Study (NASCIS-3) were included. The study population was divided into 'non-alcohol' (BAC equal to 0‰), 'legal' (BAC greater than 0 up to 0.8‰) and 'illegal' (BAC greater than 0.8‰) subgroups. Outcome measures included survival, NASCIS motor and sensory scores, NASCIS pain scores and Functional Independence Measure (FIM) determinants at baseline and at 6 weeks, 6 months and 1 year post-SCI. Analyses were adjusted for major potential confounders: age, sex, ethnicity, trial protocol, Glasgow coma score, and cause, level and severity of SCI. RESULTS: Among 499 patients (423 males and 76 females; ages from 14 to 92 years), the mean BAC was 0.054 ± 0.006‰ (range 0-1). The survival at 1 year (94.4%) was not associated with the BAC (P = 0.374). Moreover, BAC was not significantly correlated with motor recovery (P > 0.166), sensory recovery (P > 0.323), change in pain score (P > 0.312) or functional recovery (P > 0.133) at 6 weeks, 6 months and 1 year post-SCI. CONCLUSIONS: Our results, for the first time, show that the BAC at emergency admission does not adversely affect the patients' mortality, neurological impairment or functional disability over the course of the first year after SCI.

Sliding dichotomy compared with fixed dichotomization of ordinal outcome scales in subarachnoid hemorrhage trials.

OBJECT: In randomized clinical trials of subarachnoid hemorrhage (SAH) in which the primary clinical outcomes are ordinal, it has been common practice to dichotomize the ordinal outcome scale into favorable versus unfavorable outcome. Using this strategy may increase sample sizes by reducing statistical power. Authors of the present study used SAH clinical trial data to determine if a sliding dichotomy would improve statistical power. METHODS: Available individual patient data from tirilazad (3552 patients), clazosentan (the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage trial [CONSCIOUS-1], 413 patients), and subarachnoid aneurysm trials (the International Subarachnoid Aneurysm Trial [ISAT], 2089 patients) were analyzed. Treatment effect sizes were examined using conventional fixed dichotomy, sliding dichotomy (logical or median split methods), or proportional odds modeling. Whether sliding dichotomy affected the difference in outcomes between the several age and neurological grade groups was also evaluated. RESULTS: In the tirilazad data, there was no significant effect of treatment on outcome (fixed dichotomy: OR = 0.92, 95% CI 0.80-1.07; and sliding dichotomy: OR = 1.02, 95% CI 0.87-1.19). Sliding dichotomy reversed and increased the difference in outcome in favor of the placebo over clazosentan (fixed dichotomy: OR = 1.06, 95% CI 0.65-1.74; and sliding dichotomy: OR = 0.85, 95% CI 0.52-1.39). In the ISAT data, sliding dichotomy produced identical odds ratios compared with fixed dichotomy (fixed dichotomy vs sliding dichotomy, respectively: OR = 0.67, 95% CI 0.55-0.82 vs OR = 0.67, 95% CI 0.53-0.85). When considering the tirilazad and CONSCIOUS-1 groups based on age or World Federation of Neurosurgical Societies grade, no consistent effects of sliding dichotomy compared with fixed dichotomy were observed. CONCLUSIONS: There were differences among fixed dichotomy, sliding dichotomy, and proportional odds models in the magnitude and precision of odds ratios, but these differences were not as substantial as those seen when these methods were used in other conditions such as head injury. This finding suggests the need for different outcome scales for SAH.

Neuroprotection for ischaemic stroke: translation from the bench to the bedside.

Neuroprotection seeks to restrict injury to the brain parenchyma following an ischaemic insult by preventing salvageable neurons from dying. The concept of neuroprotection has shown promise in experimental studies, but has failed to translate into clinical success. Many reasons exist for this including the heterogeneity of human stroke and the lack of methodological agreement between preclinical and clinical studies. Even with the proposed Stroke Therapy Academic Industry Roundtable criteria for preclinical development of neuroprotective agents for stroke, we have still seen limited success in the clinic, an example being NXY-059, which fulfilled nearly all the Stroke Therapy Academic Industry Roundtable criteria. There are currently a number of ongoing trials for neuroprotective strategies including hypothermia and albumin, but the outcome of these approaches remains to be seen. Combination therapies with thrombolysis also need to be fully investigated, as restoration of oxygen and glucose will always be the best therapy to protect against cell death from stroke. There are also a number of promising neuroprotectants in preclinical development including haematopoietic growth factors, and inhibitors of the nicotinamide adenine dinucleotide phosphate oxidases, a source of free radical production which is a key step in the pathophysiology of acute ischaemic stroke. For these neuroprotectants to succeed, essential quality standards need to be adhered to; however, these must remain realistic as the evidence that standardization of procedures improves translational success remains absent for stroke.

Suboccipital steroid injections for transitional treatment of patients with more than two cluster headache attacks per day: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Suboccipital steroid injections can be used for preventive treatment of cluster headache but few data are available for the efficacy of this approach in clinical trials. We aimed to assess efficacy and safety of repeated suboccipital injections with cortivazol compared with placebo as add-on therapy in patients having frequent daily attacks. METHODS: In our randomised, double-blind, placebo-controlled trial at the Emergency Headache Centre in Paris, France, we enrolled adults aged 18-65 years with more than two cluster headache attacks per day. We randomly allocated patients to receive three suboccipital injections (48-72 h apart) of cortivazol 3·75 mg or placebo, as add-on treatment to oral verapamil in patients with episodic cluster headache and as add-on prophylaxis for those with chronic cluster headache, on the basis of a computer-generated list (blocks of four for each stratum). Injections were done by physicians who were aware of treatment allocation, but patients and the evaluating physician were masked to allocation. The primary outcome was reduction of the number of daily attacks to a mean of two or fewer in the 72 h period 2-4 days after the third injection. We assessed all patients who received at least one dose of study drug in the intention-to-treat analysis. This study is registered with ClinicalTrials.gov, number NCT00804895. FINDINGS: Between November, 2008, and July, 2009, we randomly allocated 43 patients (15 with chronic and 28 with episodic cluster headache) to receive cortivazol or placebo. 20 of 21 patients who received cortivazol had a mean of two or fewer daily attacks after injections compared with 12 of 22 controls (odds ratio 14·5, 95% CI 1·8-116·9; p=0·012). Patients who received cortivazol also had fewer attacks (mean 10·6, 95% CI 1·4-19·9) in the first 15 days of study than did controls (30·3, 21·4-39·3; mean difference 19·7, 6·8-32·6; p=0·004). We noted no serious adverse events, and 32 (74%) of 43 patients had other adverse events (18 of 21 patients who received cortivazol and 14 of 22 controls; p=0·162); the most common adverse events were injection-site neck pain and non-cluster headache. INTERPRETATION: Suboccipital cortivazol injections can relieve cluster headaches rapidly in patients having frequent daily attacks, irrespective of type (chronic or episodic). Safety and tolerability need to be confirmed in larger studies. FUNDING: None.

The effects of lazaroid U-74389G in a rat sepsis model.

OBJECTIVE AND DESIGN: To examine the protective effects of a lazaroid, 21-aminosteroid U-74389G, in a rat septic shock model. MATERIALS OR SUBJECTS: Male Sprague-Dawley rats (n = 60) aged 6-8 months. TREATMENT: Groups were exposed to 500 cGy radiation followed by E. coli inoculation, and either placebo or lazaroid injection (10 mg/kg intraperitoneal) 5 days after irradiation. METHODS: Hemodynamic measurements, arterial blood gases, serum lactate, total antioxidative capacity, and cytokine levels were measured at specific time intervals. RESULTS: Treatment with the lazaroid U-74389G maintained cardiac output and mean aortic pressure. Lazaroid treatment also prevented the increase in serum lactate seen in placebo-treated rats. Cytokine serum levels in lazaroid-treated rats were not significantly different from those in placebo-treated rats at any time point. CONCLUSIONS: Lazaroid treatment of E. coli-inoculated septic animals lessens the hemodynamic deterioration seen in sepsis.

Tirilazad for aneurysmal subarachnoid haemorrhage.

BACKGROUND: Delayed cerebral ischaemia is a significant contributor to poor outcome (death or disability) in patients with aneurysmal subarachnoid haemorrhage (SAH). Tirilazad is considered to have neuroprotective properties in animal models of acute cerebral ischaemia. OBJECTIVES: To assess the efficacy and safety of tirilazad in patients with aneurysmal SAH. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched October 2009); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2009); MEDLINE (1966 to October 2009); EMBASE (1980 to October 2009); and the Stroke Trials Directory, the National Center for Complementary and Alternative Medicine, and the National Institute of Health Clinical Trials Database (searched October 2009). We handsearched 10 Chinese journals, searched the reference lists of relevant publications, and contacted the manufacturers of tirilazad. SELECTION CRITERIA: Randomised trials of tirilazad started within four days of SAH onset, compared with placebo or open control in patients with aneurysmal SAH documented by angiography and computerised tomography (CT) scan or cerebrospinal fluid examination, or both. DATA COLLECTION AND ANALYSIS: We extracted data relating to case fatality, poor outcome (death, vegetative state, or severe disability), delayed cerebral ischaemia (or symptomatic vasospasm), cerebral infarction and adverse events of treatments. We pooled the data using the Peto fixed-effect method for dichotomous data. MAIN RESULTS: We included five double-blind, placebo-controlled trials involving 3821 patients; there was no significant heterogeneity. Oral or intravenous nimodipine was used routinely as a background treatment in both groups in all trials. There was no significant difference between the two groups at the end of follow up for the primary outcome, death (odds ratio (OR) 0.89, 95% confidence interval (CI) 0.74 to 1.06), or in poor outcome (death, vegetative state or severe disability) (OR 1.04, 95% CI 0.90 to 1.21). During the treatment period, fewer patients developed delayed cerebral ischaemia in the tirilazad group than in the control group (OR 0.80, 95% CI 0.69 to 0.93). Subgroup analyses did not demonstrate any significant difference in effects of tirilazad on clinical outcomes. Leukocytosis and prolongation of Q-T interval occurred significantly more frequently in the treatment group in only one trial evaluating tirilazad at high dose. There was no significant difference in infusion site disorders or other laboratory parameters between the two groups. AUTHORS' CONCLUSIONS: There is no evidence that tirilazad, in addition to nimodipine, reduces mortality or improves poor outcome in patients with aneurysmal SAH.

U74389F, a 21-aminosteroid antioxidant, improves neoendothelial morphology, but not neointimal thickening after balloon catheter injury.

U74389F is a compound in a family of 21-aminosteroids devoid of classical glucocorticoid action that inhibit lipid peroxidation. These compounds improve neurologic function and tissue survival after head or spinal cord injury. Dexamethasone inhibits development of intimal hyperplasia (IH) and improves attenuated nitric oxide (NO) production of the rabbit aorta subsequent to balloon catheter injury. We tested the hypothesis that U74389F is protective in a catheter-induced endothelial-denuded and arterial injury model. A 4-Fr Fogarty balloon (BALL) embolectomy catheter was passed through the thoracic aorta of New Zealand White rabbits treated with 15 mg/kg U74389F (LAZ) 2 days before and 1 week after injury. Animals were killed at 4 weeks after surgical intervention, and formation of IH was determined by calculating the intimal/medial ratio (I/M). The treatment groups of animals were injured untreated (BALL), injured treated (BALL/LAZ), uninjured treated (CONTROL/LAZ), and sham-operated treated (SHAM/LAZ). Scanning electron microscopy revealed that after injury lazaroid treatment produced an improvement of the neoendothelium (alignment in the direction of blood and fewer intercellular gaps) as compared with injured but untreated aortas. Relaxation to acetylcholine (NO formation) was impaired in aortic rings from catheterized animals; lazaroid treatment improved the relaxation to 10-6 mol/L acetylcholine but not to lower concentrations. I/M for SHAM/LAZ, BALL, and BALL/LAZ was 0.02 +/- 0.02, 21.6 +/- 1.6, and 17.2 +/- 2.5, respectively; BALL vs. BALL/LAZ, p < 0.06. An increased contractile response to 120 mmol/L KCl was observed after lazaroid treatment. This is the first report of lazaroid-mediated improvement in the neoendothelial morphology, improved neoendothelial NO generation, and augmented hypopolarizing contractile response, but no attenuation in the development of IH.