Disease relevance of (8S,10S,13R,14S,17S)-17-[2-[4-(2,6-dipyrrolidin-1-ylpyrimidin-4-yl)piperazin-1-yl]acetyl]-10,13-dimethyl-6,7,8,12,14,15,16,17-octahydrocyclopenta[a]phenanthren-3-one

• U-101033E improved neurological function immediately after ischemia, whereas U-74389G led to improvement only at the end of the observation period [1].
• We examined the ability of U74389F, a lipid peroxidation inhibitor, to ameliorate the toxicity of high-dose SOD in the isolated perfused rabbit heart preparation [2].
• BACKGROUND: In a prior study the 21-aminosteroid (lazaroid) U74389F provided in vivo protection from oxidative stress when used as a preventive therapy in ischemia-reperfusion injury in the kidney [3].
• These data suggest that U74389F modulates early pathophysiologic alterations in experimental pneumococcal meningitis [4].
• Inhibition of tumor necrosis factor-alpha release in rat experimental endotoxemia by treatment with the 21-aminosteroid U-74389G [5].

High impact information on (8S,10S,13R,14S,17S)-17-[2-[4-(2,6-dipyrrolidin-1-ylpyrimidin-4-yl)piperazin-1-yl]acetyl]-10,13-dimethyl-6,7,8,12,14,15,16,17-octahydrocyclopenta[a]phenanthren-3-one

• The authors evaluated the role of oxidative stress in ischemic cerebral infarction after photothrombosis and the relation between oxidative stress and caspase-related cell death 6 and 24 hours after ischemia with and without U-74389G, a potent free radical scavenger (10 mg/kg, 30 minutes before and after ischemia induction) [6].
• The data suggest an involvement of an oxidative stress in the neurotoxicity and hepatotoxicity induced by endrin, which can be attenuated by the lazaroid U74389F [7].
• Infected rats injected intravenously with vehicle of [corrected] U74389F developed increases in regional cerebral blood flow (rCBF), intracranial pressure (ICP), brain water content, and white blood cells (WBC) in cerebrospinal fluid (CSF) within 8 h after intracisternal challenge [4].
• In vitro, U74389F inhibited iron-dependent lipid peroxidation of astrocyte cultures and the production of tumor necrosis factor-alpha, interleukin-6, and nitric oxide by stimulated macrophages [4].
• One of three groups of uninephrectomized rats received vehicles, another CsA 25 mg/kg/day and the third, CsA plus antioxidant lazaroid (U-74389 G) 20 mg/kg/day, for 8 weeks [8].

Chemical compound and disease context of (8S,10S,13R,14S,17S)-17-[2-[4-(2,6-dipyrrolidin-1-ylpyrimidin-4-yl)piperazin-1-yl]acetyl]-10,13-dimethyl-6,7,8,12,14,15,16,17-octahydrocyclopenta[a]phenanthren-3-one

• Effects of the 21-aminosteroid, U74389F, on bleomycin-induced pulmonary fibrosis in rats [9].
• As expected, iron delocalization occurred during ischemia and persisted on reperfusion, with U-74500A effectively binding iron, whereas U-74389 did not [10].
• Pretreatment with nimodipine or U-74389F offered no protection (mean area of infarction 77.5% +/- 4% and 59% +/- 10%, respectively) [11].
• Hyperoxia caused lung injury evidenced by pleural effusions, increases in BAL protein concentrations, and pulmonary edema; U-74389G attenuated the first two indices of lung injury, but did not alter edema [12].
• Edema formation and leukocyte infiltration in jejunal segments of horses treated with lactated Ringer's solution or U-74389G were increased, compared with Carolina rinse solution or DMSO treatments [13].

Biological context of (8S,10S,13R,14S,17S)-17-[2-[4-(2,6-dipyrrolidin-1-ylpyrimidin-4-yl)piperazin-1-yl]acetyl]-10,13-dimethyl-6,7,8,12,14,15,16,17-octahydrocyclopenta[a]phenanthren-3-one

• Inhibition of peroxidation with the free radical scavenger 21-aminosteroid U74389F (2.5 mg/kg) widened the range of RBF and ChBF autoregulation (ocular perfusion pressure from 30 to 131 mm Hg) [14].
• Effect of treatment with 21-aminosteroid U-74389G and glucocorticoid steroid methylprednisolone on somatosensory evoked potentials in rat spinal cord during mild compression [15].
• INTERVENTIONS: U74389F (10 mg/kg) in CS4 vehicle or CS4 vehicle alone, was administered intravenously to bronchoalveolar lavage B/c mice 15 mins before 30% blood volume hemorrhage, with resuscitation 60 mins later [16].
• Apoptosis induced by gp120 in the neocortex of rat involves enhanced expression of cyclooxygenase type 2 and is prevented by NMDA receptor antagonists and by the 21-aminosteroid U-74389G [17].
• We hypothesized that U-74389G treatment may protect against hepatic injury by suppressing proinflammatory gene up-regulation through inhibition of activation of nuclear factor kappa B (NF-kappa B) [18].

Anatomical context of (8S,10S,13R,14S,17S)-17-[2-[4-(2,6-dipyrrolidin-1-ylpyrimidin-4-yl)piperazin-1-yl]acetyl]-10,13-dimethyl-6,7,8,12,14,15,16,17-octahydrocyclopenta[a]phenanthren-3-one

• The present data indicate that both the glucocorticoid steroid MP and the 21-aminosteroid U-74389G protect spinal cord function to a similar extent during mild compression [15].
• Protection of ischemic and reperfused rat myocardium by the nonglucocorticoid 21-aminosteroid U-74389G, a new inhibitor of lipid peroxidation [19].
• OBJECTIVE: To investigate the role of eicosanoid generation and neutrophilic infiltration in the protective effects of U74389F against ischemia/reperfusion injury in the small intestines of rats [20].
• No effects of therapy with U74389F were found in modulating posthemorrhage cytokine expression among alveolar macrophages or peripheral blood mononuclear cells [16].
• INTERVENTIONS: Groups (5-8) of rats treated with U74389F or vehicle were subjected to a sham operation and 30 mins of ischemia by occlusion of the superior mesenteric artery or 30 mins of ischemia followed by 60 or 120 mins of reperfusion [20].

Associations of (8S,10S,13R,14S,17S)-17-[2-[4-(2,6-dipyrrolidin-1-ylpyrimidin-4-yl)piperazin-1-yl]acetyl]-10,13-dimethyl-6,7,8,12,14,15,16,17-octahydrocyclopenta[a]phenanthren-3-one with other chemical compounds

• Further, glial swelling from AA or linoleic acid was completely inhibited by the aminosteroid U-74389F, an antagonist of lipid peroxidation [21].
• Treatment with U-74389 did not significantly (p > 0.05) inhibit the BAL neutrophilia and did not significantly (p > 0.05) reduce hyperoxia-induced increases in mRNA expression for P-selectin and E-selectin [22].
• MAIN RESULTS: Desmethyl tirilazad (20 mg/kg) and 100 mg/kg deferoxamine inhibit lipid peroxidation [23].
• An additional group of animals received U-74389F (2 mg/kg, n = 7), U-74500A (2 mg/kg, n = 7), or vehicle (n = 11) intraarterially before infrarenal aortic clamping was performed for 120 minutes, followed by reperfusion for 30 minutes [10].
• Finally, U-74389G in vitro (12.5, 25 and 50 microM) significantly inhibited nitrite production in endotoxin stimulated peritoneal macrophages [24].

Gene context of (8S,10S,13R,14S,17S)-17-[2-[4-(2,6-dipyrrolidin-1-ylpyrimidin-4-yl)piperazin-1-yl]acetyl]-10,13-dimethyl-6,7,8,12,14,15,16,17-octahydrocyclopenta[a]phenanthren-3-one

• Treatment with the antioxidant U-74389G abrogated p53 activation. p53 activation was followed by expression and mitochondrial translocation of the proapoptotic protein Bax [25].
• The protective effect of U-74389G was dose dependent, but SOD (6,000 U/kg) or catalase (50,000 U/kg) exhibited no protective effect [26].
• Perfusion of isolated lungs with superoxide dismutase (100 U/ml) completely inhibited the chemiluminescence response to PMN activation, whereas treatment with 100 microM U-74389F, a lipid-soluble antioxidant, also significantly decreased PMN-dependent chemiluminescence [27].
• CONCLUSIONS: These findings suggest that U-74389G can suppress proinflammatory gene up-regulation through inhibition of NF-kappa B activation and that it is a promising new antioxidant drug for the treatment of endotoxin shock [18].
• OBJECTIVE: To determine the effects of therapy with the antioxidant 21-aminosteroid, U74389F, on cytokine mRNA levels following hemorrhage and resuscitation [16].

Analytical, diagnostic and therapeutic context of (8S,10S,13R,14S,17S)-17-[2-[4-(2,6-dipyrrolidin-1-ylpyrimidin-4-yl)piperazin-1-yl]acetyl]-10,13-dimethyl-6,7,8,12,14,15,16,17-octahydrocyclopenta[a]phenanthren-3-one

• In contrast, U74389F significantly (p < .05) attenuated the severity of injury after reperfusion [20].
• The time taken to complete the SEPs suppression was significantly shorter in the control group (p < 0.001, Wilcoxon) than in the groups with either MP or U-74389G [15].
• CONCLUSIONS: The 21-aminosteroid U-74389G exhibits a radioprotectant effect on normal brain tissue, but does not appear to protect the tumor in an in vivo rat radiosurgery model [28].
• We hypothesized that the lazaroid U-74389G would minimize postresuscitation myocardial dysfunction and thereby improve neurologically meaningful survival in a rodent model after resuscitation from 8 mins of ventricular fibrillation [29].
• MEASUREMENTS AND MAIN RESULTS: Semiquantitative polymerase chain reactions were used to determine the effects of therapy with U74389F on cytokine mRNA levels among intraparenchymal pulmonary mononuclear cells, alveolar macrophages, and peripheral blood mononuclear cells obtained 2 hrs and 3 days after hemorrhage [16].

References