Administration Of U-74389G Research Articles

Lazaroid U-74389G in liver ischemia-reperfusion injury: A swine model.

Reactive oxygen species have a key role in liver ischemia-reperfusion (I/R) injury. In the present study, the effect of the anti-oxidant compound lazaroid U-74389G in preventing liver I/R injury was investigated in a swine model. Ischemia was produced by portal vein occlusion. Two sets of experiments were performed, each with two groups (n=7 per group). In the first group, the potential protective effect of an intracaval injection of U-74389G after a 30-min ischemia, followed by a 60-min reperfusion period was assessed (biopsies at 0, 15, 30 and 90 min experimental time). In the second set, the effect of intracaval U-74389G injection after 30 min of ischemia, followed by a longer reperfusion period of 120 min was determined (biopsies at 0, 15, 30 and 150 min experimental time). Liver malondialdehyde, hepatocyte vacuolation-degeneration, venous congestion, inflammatory cell infiltration, sinus congestion-dilation and Chiu score of intestinal damage were determined at up to 150 min of reperfusion. In the second set of experiments, the Chiu score of intestinal damage was improved by the administration of U-74389G (3.17±0.40 vs. 4.33±0.21; P=0.030). However, in the two sets of experiments, the liver inflammatory reaction was more pronounced in the U-74389G groups (P=0.017 for the first set, P=0.021 for the second set). No significant effect of U-74389G on any other parameters was detected. In conclusion, intestinal damage due to portal venous congestion and reflow appears to be mitigated by the lazaroid U-74389G; however, intracaval administration of U-74389G does not appear to exert any protective effects against liver I/R-induced inflammation.

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.

Experimental Hemorrhagic Shock Protocol in Swine Models: The Effects of 21-Aminosteroid on the Small Intestine

BackgroundThe protective potential of lazaroids has been reported in previous studies on ischemia/reperfusion and induced hemorrhagic shock protocols. ObjectivesThe present study is the first experimental protocol on the effects of the antioxidant factor U-74389G on the small intestine of swine models in a hemorrhagic shock protocol and resuscitation with 3 different types of fluids. MethodsThe study included 49 Landrace breed swine that were divided into groups of 7 each. Hemorrhage was provoked 45 minutes after starting the surgical protocol (0 minutes), followed by resuscitation starting 30 minutes after haemorrhage ceased by using 3 different fluids. Three groups (Group A, resuscitation using blood; Group B, resuscitation with Ringer’s lactate solution; and Group C, resuscitation with hypertonic saline solution) underwent resuscitation with fluid alone, and another 3 groups (named A', B,' and C') were administered lazaroid U-74389G in addition to fluid. Control Group S underwent all the surgical procedures without hemorrhagic shock. Vital signs, complete blood count, and biochemical markers were analyzed, and tissue samples of the small intestine were collected from all animals. Further, malondialdehyde, tumor necrosis factor-α, and levels of inflammation in the tissue sample were measured. ResultsIn Group S-A-A' and Group S-C-C', the analysis did not show statistically significant differences in the percentage changes of histopathology, malondialdehyde, and tumor necrosis factor-α through time. In Group S-B-B', the malondialdehyde levels in the small intestine were reduced in both the B and B' groups, without lazaroid (Group B) (P = 0.038) and lazaroid (Group B') (P = 0.011), compared with Group S (control), but the group without lazaroid (Group B) had greater reduction in malondialdehyde levels than the group treated with lazaroid (Group B'). With regard to the biochemistry results, 24% reduction was observed for alkaline phosphatase (P = 0.022) in Group A' treated with lazaroid compared with that in the untreated group. Lastly, for the complete blood count parameters, a 14% reduction in white blood cells was observed in Group B', which was treated with lazaroid in all phases (P = 0.015) (absolute value = 6.23) compared with Group B (absolute value = 13.74). ConclusionsDespite few initial findings of this study suggesting that administration of lazaroid U-74389G may have some potential in attenuation of the effects of hemorrhagic shock in the small intestine of swine models, no differences remained after correction for multiple comparisons was made. Therefore, further research is required to investigate this result thoroughly.

The trends of the antioxidant drug “U-74389G” on potassium levels during hypoxia reoxygenation injury in rats

Background: This experimental study examined the effect of the antioxidant drug “U-74389G”, on a rat model and particularly in an hypoxia – reoxygenation (HR) protocol. The beneficial effect or non-effectiveness of that molecule were studied biochemically using blood mean potassium levels.Methods: 40 rats of mean weight 231.875 g were used in the study. Potassium levels were measured at 60 min of reperfusion (groups A and C) and at 120 min of reperfusion (groups B and D) with administration of the drug U-74389G in groups C and D.Results were that U-74389G administration non significantly decreased the K+ levels by 2.14%+5.06% (p= 0.6730). Reoxygenation time non-significantly increased the K+ levels by 8.66%+4.85% (p= 0.0934). However, U-74389G administration and reoxygenation time together non-significantly increased the K+ levels by 2.07%+3.03% (P= 0.4853).Conclusions are that U-74389G administration, reoxygenation time and their interaction have miscellaneous non significant short – term effects on potassium levels. Perhaps, a longer study time may reveal clearer and significant effects.

The effect of the antioxidant drug “U-74389G” on acid phosphatase levels during ischemia reperfusion injury in rats

Introduction: This experimental study examined the effect of the antioxidant drug “U-74389G”, on a rat model and particularly in an ischemia - reperfusion protocol. The effects of that molecule were studied biochemically using blood mean acid phosphatase (ACP) levels. Methods: 40 rats of mean weight 231.875 g were used in the study. ACP levels were measured at 60 min of reperfusion (groups A and C) and at 120 min of reperfusion (groups B and D). Administration of the drug U-74389G was predicted only for groups C and D. Results: U-74389G administration significantly decreased the ACP levels by 128.45% ±14.84% (p= 0.0000). Reperfusion time non-significantly decreased the ACP levels by 22.44% ± 25.86% (p= 0.2000). However, U-74389G administration and reperfusion time together significantly decreased the ACP levels by 74.45% ± 9.63% (p= 0.0000). Conclusions: U-74389G administration whether it interacted or not with reperfusion time, offers spectacular significant decreasing short – term effects on ACP levels.

The trends of the antioxidant drug “U-74389G” on potassium levels during hypoxia reoxygenation injury in rats

Background: This experimental study examined the effect of the antioxidant drug “U-74389G”, on a rat model and particularly in an hypoxia – reoxygenation (HR) protocol. The beneficial effect or non-effectiveness of that molecule were studied biochemically using blood mean potassium levels. Methods: 40 rats of mean weight 231.875 g were used in the study. Potassium levels were measured at 60 min of reperfusion (groups A and C) and at 120 min of reperfusion (groups B and D) with administration of the drug U-74389G in groups C and D. Results were that U-74389G administration non significantly decreased the K + levels by 2.14% + 5.06% (p= 0.6730). Reoxygenation time non-significantly increased the K + levels by 8.66% + 4.85% (p= 0.0934). However, U-74389G administration and reoxygenation time together non-significantly increased the K + levels by 2.07% + 3.03% (P= 0.4853). Conclusions are that U-74389G administration, reoxygenation time and their interaction have miscellaneous non significant short – term effects on potassium levels. Perhaps, a longer study time may reveal clearer and significant effects.

The effect of the antioxidant drug "U-74389G" on amylase during ischemia reperfusion injury in rats

Background: This experimental study examined the effect of the antioxidant drug U-74389G on a rat model and particularly in an ischemia-reperfusion protocol. Settings and Design: The beneficial effect or noneffectiveness of that molecule was studied biochemically using blood mean amylase (A) levels. Materials and Methods: Forty rats of mean weight 231.875 g were used in the study. The levels were measured at 60 min of reperfusion (Groups A and C) and at 120 min of reperfusion (Groups B and D) with the administration of the drug U-74389G in Groups C and D. Results: U-74389G administration significantly decreased the predicted A levels by 8.40 ± 2.02% ( P = 0.0001). Reperfusion time kept nonsignificantly increased the predicted A levels by 1.68 ± 2.44% ( P = 0.4103). However, U-74389G administration and reperfusion time together produced a significant combined effect in keeping decreased the predicted A levels by 4.67 ± 1.26% ( P = 0.0005). Conclusions: U-74389G administration whether it interacted or not with reperfusion time has a significant decreasing beneficial restoring short-term effect on amylase levels.

The effect of the antioxidant drug &amp;#147;U-74389G&amp;#148; on acid phosphatase levels during ischemia reperfusion injury in rats

Introduction: This experimental study examined the effect of the antioxidant drug “U-74389G”, on a rat model and particularly in an ischemia - reperfusion protocol. The effects of that molecule were studied biochemically using blood mean acid phosphatase (ACP) levels. Methods: 40 rats of mean weight 231.875 g were used in the study. ACP levels were measured at 60 min of reperfusion (groups A and C) and at 120 min of reperfusion (groups B and D). Administration of the drug U-74389G was predicted only for groups C and D. Results: U-74389G administration significantly decreased the ACP levels by 128.45%+14.84% (p= 0.0000). Reperfusion time non-significantly decreased the ACP levels by 22.44%+25.86% (p= 0.2000). However, U-74389G administration and reperfusion time together significantly decreased the ACP levels by 74.45%+9.63% (p= 0.0000). Conclusions: U-74389G administration whether it interacted or not with reperfusion time, offers spectacular significant decreasing short – term effects on ACP levels.

The Acute Effect Of The Antioxidant Drug “U-74389g” On Platelet Distribution Width During Hypoxia Reoxygenation Injury In Rats

Background: Platelet activation causes morphologic changes of platelets, including both the spherical shape and pseudopodia formation increasing platelet distribution width (PDW), ascribed to platelet anisocytosis. Furthermore, coagulation is activated in vaso-occlusive situations, increasing PDW. Early diagnosis of progressive activation of coagulation or any factor declining PDW levels, can prevent these thromboembolic diseases successfully. The probable beneficial effect of the molecule “U-74389” was studied hematologically using blood mean platelet distribution width PDW) levels. Methods: 40 rats of mean weight 231.875g were used in the study. PDW levels were measured at 60 min of reoxygenation (groups A and C) and at 120 min of reoxygenation (groups B and D) with administration of the drug U-74389G in groups C and D. Results: U-74389G administration kept significantly increased the PDW levels by 1.79%±0.76% (p=0.0314). Reoxygenation time non significantly declined the PDW levels by 0.745%±0.81% (p=0.3280). However, U-74389G administration and reoxygenation time together kept significantly increased the PDW levels by 0.96%±0.46% (p=0.0396). Conclusion:U-74389G administration whether it interacted or not with reoxygenation time borderline declines from significant to non significant the PDW levels, within short-time study period of 2 hours. This finding has huge clinical interest in coagulopathy prevention or reversion.

Neuronal tumour necrosis factor-α and interleukin-1β expression in a porcine model of intracerebral haemorrhage: Modulation by U-74389G

Tumour necrosis factor α (TNF-α) and interleukin 1β (IL-1β) are important mediators of intracerebral haemorrhage (ICH) inflammatory response. Lazaroids, established antioxidants and neuroprotectants, have been studied in several brain pathologies. The present study was designed to investigate: a) TNF-α and IL-1β changes, in neurons and b) U-74389G effects, 4 and 24h after haematoma induction in a porcine model of intracerebral haemorrhage.In twenty male landrace pigs (swines) aged 135–150 days old, autologous whole blood was injected around the right basal ganglia territory; in ten of the pigs the lazaroid compound U-74389G was administered. Brain TNF-α and IL-1β immunopositive neurons were determined by immunoarray techniques at 4 and 24h timepoints.After the haematoma induction the number of TNF-α immunopositive neurons ipsilateral to the haematoma was significantly higher compared to the contralateral site at 4h (p<0.0005), while U-74389G significantly reduced the number of TNF-α immunopositive neurons, ipsilateral to the haematoma, at 4h (p=0.002); at 24h, TNF-α immunopositive neurons were found significantly lower in the control group ipsilateral to the haematoma in comparison to 4h timepoint(p<0.0005).The number of IL-1β immunopositive neurons at 4h after the hematoma induction was significantly higher ipsilateral to the haematoma site (p<0.0005). U-74389G had no statistical significant effect.TNF-α and IL-1β, increase in neurons, 4h after the haematoma induction, ipsilateral to the haematoma site. The administration of the antioxidant compound U-74389G, results in early (at 4h) decrease of TNF-α immunopositive neurons but shows no statistical significant effect to IL-1β immunopossitive neurons.

The Effect of the Antioxidant Drug 'U-74389G' on Uterus Inflammation during Ischemia Reperfusion Injury in Rats

This experimental study was to examine the effect of the antioxidant drug “U-74389G”, on rat model and particularly in a uterus ischemia reperfusion (IR) protocol. The beneficial effect or non-effectiveness of that molecule were studied pathologically using uterus inflammation (UI) lesions.40 rats of mean weight 231.875 gr were used in the study. UI lesions were evaluated 60 min after reperfusion (groups A and C) and 120 min after reperfusion with administration of the drug U-74389G in groups C and D.

The effect of the antioxidant drug “U-74389G” on alkaline phosphatase levels during ischemia reperfusion injury in rats

The aim of this experimental study was to examine the effect of the antioxidant drug “U-74389G”, on rat model and particularly in a liver ischemia reperfusion (IR) protocol. The beneficial effect or non effectiveness of that molecule were studied biochemically using mean blood alkaline phosphatase levels (ALP). Forty rats of mean weight 231.875 gr were used in the study. ALP levels were measured 60 min after reperfusion (groups A and C) and 120 min after reperfusion (groups B and D) with administration of the drug U-74389G in groups C and D. U-74389G administration non significantly increased the ALP levels by 19.76%±15.06% (p=0.1784), but by 31.91%±7.69% (p=0.0001) for predicted values. Reperfusion time non-significantly decreased the ALP levels by 25.21%±14.83% (p=0.0675), also by 6.38%±9.30% (p=0.3650) for predicted values. However, U-74389G administration and reperfusion time together non-significantly increased the ALP levels by 8.08%±9.19% (p=0.3696), but also by 17.75%±4.79% (p=0.0005) for predicted values. This study indicates that U-74389G administration and its interaction with reperfusion time non significantly increased short-term effects on ALP levels. However, the predicted ALP values adjusted for rats weight, kept significantly increased ones, which stand for the restorating effects of U-74389G, that are slower than it seems.

The acute effect of the antioxidant drug “U-74389G” on red blood cells levels during hypoxia reoxygenation injury in rats

ObjectiveTo examine the effect of the antioxidant drug “U-74389G”, on rat model and particularly in a hypoxia reoxygenation (HR) protocol. The beneficial effect or non-effectiveness of that molecule was studied hematologically using mean red blood cells levels. Methods40 rats of mean weight 231.875 g were used in the study. Red blood cells levels were measured 60 min after reoxygenation (groups A and C) and 120 min after reoxygenation (groups B and D) with administration of the drug U-74389G only in groups C and D. ResultsU-74389G administration non-significantly increased the red blood cells level by (0.64±0.32)% (P=0.810 6). Reoxygenation time also non-significantly increased the red blood cells level by (4.63±2.36)% (P=0.068 0). However, U-74389G administration and reoxygenation time together non-significantly increased the red blood cells level by (1.05±0.53)% (P=0.491 1). ConclusionsResults of this study show that U-74389G administration, reoxygenation time and their interaction non significantly increased the red blood cells levels within 2 hours' time interval.

The effect of U-74389G on pancreas ischemia–reperfusion injury in a swine model

BackgroundOxidative stress is a crucial factor in the pathophysiology of acute pancreatitis and its systemic complications. Lazaroids are a novel class of antioxidants that potently protect pancreatic acinar cells against oxidant attack. The aim of our study was to evaluate the therapeutic potential of 21-aminosteroid U-74389G in pancreatic injury after ischemia and reperfusion of the organ in a swine model. Materials and methodsTwelve pigs (weighing 28–35 kg) were randomized into the following two experimental groups: group A (control group, n = 6): ischemia of pancreas (30 min) followed by reperfusion for 120 min; and group B (n = 6): ischemia of pancreas (30 min), U-74389G intravenous injection (10 mg/kg) in the inferior vena cava, and reperfusion for 120 min. Tissue and blood sampling was conducted at 0, 30, 60, 90 and 120 min after reperfusion. Repeated measures analysis of variance was performed for the evaluation of differences between the two groups. ResultsHistopathologic evaluation did not reveal a statistically significant difference concerning hemorrhage (P = 0.193), leukocyte infiltration (P = 0.838), acinar necrosis (P = 0.183), and vacuolization (P = 0.185) in the pancreatic tissue between the two groups; nevertheless, edema seemed to be more pronounced in the U-74389G group (P = 0.020). Serum metabolic data in the control and therapy groups were not significantly different; accordingly, tissue malondialdehyde levels (P = 0.705) and tumor necrosis factor α values (P = 0.863) did not differ between the two groups. ConclusionsOn the basis of the histologic data and the absence of reduction in the malondialdehyde and tumor necrosis factor α levels, it is concluded that the administration of U-74389G does not seem to exert a sizable therapeutic effect in attenuating pancreatic damage from ischemia–reperfusion injury.

Modulation of crucial adenosinetriphosphatase activities due to U-74389G administration in a porcine model of intracerebral hemorrhage

Spontaneous intracerebral hemorrhage (ICH) represents a partially-understood cerebrovascular disease of high incidence, morbidity and mortality. We, herein, report the findings of our study concerning the role of two important adenosinetriphosphatases (ATPases) in a porcine model of spontaneous ICH that we have recently developed (by following recent references as well as previously-established models and techniques), with a focus on the first 4 and 24 h following the lesion's induction, in combination with a study of the effectiveness of the lazaroid antioxidant U-74389G administration. Our study demonstrates that the examined ICH model does not cause a decrease in Na(+),K(+)-ATPase activity (the levels of which are responsible for a very large part of neuronal energy expenditure) in the perihematomal basal ganglia territory, nor a change in the activity of Mg(2+)-ATPase. This is the first report focusing on these crucial ATPases in the experimental setting of ICH and differs from the majority of the findings concerning the behavior of these (crucial for central nervous system cell survival) enzymes under stroke-related ischemic conditions. The administration of U-74389G (an established antioxidant) in this ICH model revealed an injury specific type of behavior, that could be considered as neuroprotective provided that one considers that Na(+),K(+)- and Mg(2+)-ATPase inhibition might in this case diminish the local ATP consumption.

The Effect of U-74389G on Liver Recovery After Acute Liver Ischemia-Reperfusion Injury in a Swine Model

The potential of U-74389G in attenuating liver damage after ischemia and reperfusion of the liver was studied in a swine model. Eighteen pigs, weighting 28-35 kg, were used in the study. The animals were divided into the following three experimental groups: Group A (control group): Ischemia time 30 min and reperfusion for 120 min (with tissue and blood sampling at both 60 min (A-60) and 120 min (A-120)); Group B: Ischemia time 30 min, U-74389G intraportal injection, and reperfusion for 60 min; and Group C: Ischemia time 30 min, U-74389G intraportal injection, and reperfusion for 120 min. The dose of U-74389G administered was 10 mg/kg animal body weight. Anesthesia was induced with propofol, pancuronium, and fentanyl. Surgery was performed through a midline laparotomy. The portal vein and the common hepatic artery were isolated and prepared for occlusion. Histopathological evaluation revealed a statistically significant difference in portal infiltration in the liver tissue between control group A-60 and group B (P = 0.01), and between control group A-120 and group C (P = 0.002). Hemodynamic and metabolic data in the control and therapy groups at 0, 30, 60, and 120 min were not statistically significantly different. Tissue malondialdehyde levels were statistically significantly different. Tumor necrosis factor-alpha values were statistically significantly different between groups A-60 and B but not between groups A-120 and C. Based on the histological data and the reduction of the malondialdehyde and tumor necrosis factor-alpha levels, administration of U-74389G in ischemia-reperfusion injury of the liver in a swine model has potential in attenuating liver damage.

Lazaroid U-74389G attenuates edema in rat brain subjected to post-ischemic reperfusion injury

The aim of the present study was to determine the potential therapeutic value of 21-aminosteroid U-74389G, on blood–brain barrier (BBB) breakdown and edema in association with the changes in synaptosomal Na +/K + and Mg 2+/Ca 2+-ATPase activities in rat brain subjected to post-ischemic reperfusion injury. Brain ischemia was achieved by means of four-vessel occlusion model for 25 min and animals were sacrificed after 12 h reperfusion. An increase of cerebral tissue water content, blood–brain disruption and the changes of synaptosomal Na +/K + and Mg 2+/Ca 2+-ATPases activities were evaluated. U-74389G was given intraperitoneally at two times as 5 mg/kg at 10 min prior to ischemia and at the beginning of reperfusion. Edema was determined by means of wet-dried weight method, and BBB of extravasation of Evan's blue dye. Extravasation of Evan's blue dye into brain following ischemia and reperfusion was 2.4-fold of control value and brought close to control levels by the effect of U-74389G ( p<0.001). Post-ischemic reperfusion injury caused an increase of 3.7% in tissue water content of whole brain and administration of U-74389G lowered the cerebral edema ( p<0.001). The loses in the Na +/K +-ATPase and Mg 2+/Ca 2+-ATPase activities occurred as 42.1% ( p<0.01) and 65.7% ( p<0.001) of control value, respectively. While Mg 2+/Ca 2+-ATPase activity was enhanced compared to vehicle-treated group of animals ( p<0.01), Na +/K +-ATPase activity was fully recovered when compared to control by U-74389G ( p>0.05). U-74389G also significantly attenuated neuronal necrosis ( p<0.001) which was determined in the hippocampal CA1 subfield. Blood–brain barrier protection, attenuation of brain edema and neuronal necrosis concomitant with the stabilizing of membrane-bound enzymes brought about by the effect of U-74389G suggest that 21-aminosteroids are worthy of consideration in the acute treatment of cerebral ischemia.

Reduction in intestinal leukocyte adherence in rat experimental endotoxemia by treatment with the 21-aminosteroid U-74389G.

To investigate leukocyte adherence in intestinal venules in experimental endotoxemia after treatment with the 21-aminosteroid U-74389G. Prospective, randomized, controlled animal study in an experimental laboratory. Twenty-one male Wistar rats weighing 190 +/- 40 g. The rats were divided equally into three groups: (a) control group, (b) endotoxemia (5 mg/kg lipopolysacharide from Escherichia coli O55:B5), and (c) endotoxemia and U-74389G administration 30 min before (3 mg/kg) and 60 min after endotoxin challenge (1.5 mg/ kg). The distal small intestine of the animals was examined using intravital fluorescence videomicroscopy 2 h after endotoxin challenge. Leukocytes were stained in vivo by means of rhodamine 6G. In the endotoxemic animals we observed a fourfold increase in the count of firmly adherent leukocytes in submucosal post-capillary and collecting venules. Treatment with the 21-aminosteroid U-74389G significantly attenuated the count of sticking leukocytes in the collecting venules (control, 61 +/- 10 cells/mm2; lipopolysaccharide, 237 +/- 42 cells/mm2; U-74389G 125 +/- 9 cells/mm2; p < 0.05). In these venules leukocyte rolling behavior was comparable to that in the control group without endotoxin challenge. Administration of U-74389G, which has radical scavenging properties, attenuates leukocyte adherence in selected populations of intestinal venules which is found increased during endotoxemia. Thus, 21-aminosteroids may have an impact in the treatment of endotoxin-induced intestinal injury.

Effects of the 21-aminosteroid U74389G in a model of chronic myocardial infarction in the rat.

21-Aminosteroids are a group of new synthetic compounds developed as antiperoxidants. Although several studies have demonstrated their cardioprotective properties in acute ischemic models, none has assessed their long-term benefits after chronic myocardial infarction. In this investigation, we examined the cardioprotective effects of U74389G, a novel 21-aminosteroid, in a model of chronic myocardial infarction in the rat. After permanent ligation of the proximal branch of the left coronary artery, the experimental animals were treated daily by gavage with U74389G (10 mg/kg) for 21 days. After the study period, harvested hearts were perfused ex vivo and submitted to cold cardioplegia with 90-min global ischemia and 30-min reperfusion (surgical stress). Myocardial function and coronary endothelial (bradykinin, 1 microM) and smooth muscle (sodium nitroprusside, 1 microM) reactivity were assessed before and after exposure to the surgical stress. Percentage infarct size of the left ventricle was computed as the ratio of infarct area (mg)/total left ventricle (mg) x 100. During or immediately after surgery, there were eight deaths, which were considered technical failures. No further deaths occurred during the follow-up period (21 days). Compared with vehicle-treated rats, long-term administration of U74389G elicited a significant reduction of infarct size (percentage of left ventricle, 9 +/- 5% in the U74389G-treated group vs. 32 +/- 5% in the vehicle-treated group; p < 0.01). Ex vivo heart-perfusion studies showed no significant difference in baseline coronary flow, left ventricular developed pressure, and heart rate between normal and chronic infarcted hearts treated with the vehicle or with U74389G. However, a reduced endothelium-dependent coronary dilator response was observed in infarcted hearts from vehicle-treated controls but not in those from U74389G-treated rats. When cardioplegia and global myocardial ischemia/reperfusion were added, most of the benefits from U74389G were lost. These results indicate that 21-aminosteroids can reverse oxygen-derived free radicals and lipid peroxidation-induced myocardial and coronary dysfunction associated with chronic myocardial infarction. However, additive protective measures are required when an acute ischemic stress is superimposed.

Inhibition of tumor necrosis factor-alpha release in rat experimental endotoxemia by treatment with the 21-aminosteroid U-74389G.

To determine the effect of the 21-aminosteroid U-74389G on tumor necrosis factor (TNF)-alpha release in experimental endotoxemia. Prospective, randomized, controlled animal study. Experimental laboratory. Twenty-one male Wistar rats weighing 190+/-40 g. The rats were divided equally into 3 groups: a) control; b) endotoxemia (5 mg/kg lipopolysaccharide [LPS] from Escherichia coli 055:B5); and c) endotoxemia and U-74389G administration 30 mins before (3 mg/kg) and 60 mins after (1.5 mg/kg) endotoxin challenge. At 0, 120, and 240 mins, serum levels of TNF-alpha were measured using a specific rat TNF-alpha ELISA kit. U-74389G-treated endotoxemic animals showed significantly reduced TNF-alpha release 120 mins after endotoxin challenge (control, 2.5+/-2.1 pg/mL; LPS, 4041+/-871 pg/mL; U-74389G, 1627+/-474 pg/mL [p < .05]). Two hundred forty minutes after LPS administration, TNF-alpha levels decreased, whereas values in the untreated LPS group remained twice as high as those in the U-74389G group (LPS, 863+/-182 pg/mL; U-74389G, 369+/-54 pg/mL [p < .05]). The study demonstrated that administration of U-74389G, which has radical-scavenging and membrane-stabilizing properties, decreased TNF-alpha release during endotoxemia. Thus, 21-aminosteroids may lend themselves to evaluation in the treatment of septic states.