Disease relevance of U 74006

• Our laboratories have developed a novel series of potent lipid peroxidation inhibitors known as the 21-aminosteroids or "lazaroids." One of these compounds, U-74006F or tirilazad mesylate, has shown efficacy in animal models of brain injury and focal cerebral ischemia [1].
• Amelioration of impaired cerebral metabolism after severe acidotic ischemia by tirilazad posttreatment in dogs [2].
• Effects of tirilazad mesylate on vasospasm and phospholipid hydroperoxides in a primate model of subarachnoid hemorrhage [3].
• BACKGROUND AND PURPOSE: We tested the hypothesis that administration of the antioxidant tirilazad mesylate improves electrophysiological recovery and decreases infarct volume after transient focal cerebral ischemia in cats [4].
• High-dose tirilazad for acute stroke (RANTTAS II). RANTTAS II Investigators [5].

High impact information on U 74006

• The involvement of ROS was assessed by either combined superfusion of the antioxidants: superoxide dismutase and catalase over the blister base in acute-injury, or intramuscular injection of tirilazad in chronically injured rats [6].
• Levels of LPO in the injured sciatic nerves were significantly reduced using either early or late treatment, however tirilazad had opposing effects on recovery, prolonging or alleviating thermal hyperalgesia, respectively [7].
• METHODS: Included in the study were 256 eligible patients from the Randomized Trial of Tirilazad Mesylate in Acute Stroke (RANTTAS) [8].
• After the induction of experimental SAH around the right middle cerebral artery on day 0, tirilazad or vehicle was administered intravenously every 8 hours for 6 days [3].
• The present study was designed to determine whether the efficacy of mild hypothermia (33 degrees C) can be increased by combination pharmacotherapy with tirilazad and magnesium (MgCl(2)) [9].

Chemical compound and disease context of U 74006

• 21-Aminosteroid (U-74006 F) at 3 mg/kg or alpha-tocopherol succinate at 10 mg/kg was administered intravenously once before bilateral renal ischemia and again before reperfusion [10].
• We tested the hypothesis that administration of the antioxidant tirilazad at the start of reperfusion improves early metabolic recovery after severe acidotic ischemia and ameliorates depletion of the endogenous antioxidant glutathione [2].
• The pharmacokinetics of the following drugs in patients with severe head injury have been studied: phenytoin, pentobarbital (pentobarbitone), thiopental (thiopentone), tirilazad, and the agents used as marker substrates, antipyrine, lorazepam and indocynanine green (ICG) [11].
• RESULTS: Tirilazad mesylate enhanced relative ganglion cell survival after plating, with detectable effects at 200 nM and a maximal increase above diluent control of 148% +/- 2% at 20 microM [12].
• Effects of nalmefene, CG3703, tirilazad, or dopamine on cerebral blood flow, oxygen delivery, and electroencephalographic activity after traumatic brain injury and hemorrhage [13].

Biological context of U 74006

• Effect of age and gender on tirilazad pharmacokinetics in humans [14].
• Recovery of somatosensory evoked potential amplitude was greater with tirilazad (49 +/- 3%) than vehicle (33 +/- 6%) [15].
• Pretreatment of rats intraperitoneally with the lazaroid U74389F (16-desmethyl tirilazad) (10 mg/kg in two doses) attenuated the biochemical consequences of endrin-induced oxidative stress [16].
• By 45 min, the tirilazad group had a higher intracellular pH (6.5 +/- 0.5 vs. 5.9 +/- 0.6) and a lower intracranial pressure (18 +/- 6 vs. 52 +/- 24 mm Hg) [17].
• Protective effects of lazaroid U74389F (16-desmethyl tirilazad) on endrin-induced lipid peroxidation and DNA damage in brain and liver and regional distribution of catalase activity in rat brain [16].

Anatomical context of U 74006

• Forebrain blood flow fell below baseline levels at 180 minutes of reperfusion in the tirilazad-treated animals but not in the vehicle-treated dogs (vehicle, 28 +/- 4 ml/min/100 g; tirilazad, 18 +/- 5 ml/min/100 g) [18].
• The degree of vasospasm in the cerebral arteries was significantly attenuated in the tirilazad group (P<0.005) [3].
• We describe the effects of the 21-aminosteroid tirilazad mesylate (U-74006F) on postischemic lipid peroxidation (depletion of brain vitamin E) and cortical extracellular calcium recovery in gerbils subjected to 3 hours of unilateral carotid artery occlusion [19].
• Spinal cord injury studies utilising tirilazad are currently underway to determine the optimal combination of medications [20].
• CONCLUSIONS: The lipid peroxidation blocker tirilazad mesylate inhibits retinal ganglion cell death in vitro [12].

Associations of U 74006 with other chemical compounds

• The effect of phenytoin on the pharmacokinetics of tirilazad mesylate in healthy male volunteers [21].
• Experimental results suggest that different mechanisms of cytoprotective action may exist for tirilazad and the antioxidant gossypol [22].
• Lack of effect of postinjury treatment with methylprednisolone or tirilazad mesylate on the increase in eicosanoid levels in the acutely injured cat spinal cord [23].
• In addition, we found that treatment of the graft tissue with tirilazad mesylate (a lazaroid allowed for clinical use) almost doubled the survival of grafted dopamine neurons [24].
• Ketoconazole increased tirilazad mesylate bioavailability by decreasing the first-pass liver and gut wall metabolism of tirilazad mesylate to similar degrees [25].

Gene context of U 74006

• Collectively, these data suggest that formation of U-89678, a circulating pharmacologically active metabolite, contributes to the total metabolic elimination of tirilazad in humans and that clearance of U-89678 is mediated primarily via CYP3A4 metabolism [26].
• Hormonal effects on tirilazad clearance in women: assessment of the role of CYP3A [27].
• Fibroblasts pre-incubated with tirilazad at a concentration of 30 muM show significantly less IL-6 in the extracellular medium after UVA exposure [28].
• Treatment with antioxidants, superoxide dismutase (SOD) or tirilazad significantly improved the neurogenic vascular response while tirilazad treatment significantly alleviated thermal hyperalgesia [29].
• METHODS: Tirilazad (a lipid peroxidase inhibitor) or FK and acYVAD-cmk (a caspase inhibitor), were added to embryonic porcine ventral mesencephalic tissue and viability was assessed in vitro [30].

Analytical, diagnostic and therapeutic context of U 74006

• Improvement in high-energy phosphate recovery 17 minutes after starting tirilazad infusion during reperfusion is consistent with an early onset of a functionally significant oxygen radical injury [2].
• Plasma tirilazad mesylate concentrations were determined by HPLC [14].
• In both periods, 1.5 mg/kg tirilazad mesylate was administered (as 10-minute intravenous infusions) every 6 hours for 21 doses (5 days) [21].
• The objective of the present study was to explore the effects of tirilazad mesylate on DA neuron survival in cultures of rat ventral mesencephalon and its capacity to promote the in vitro cell viability of embryonic rat and human mesencephalic tissue, treated and dissociated in the same way as in clinical trials [31].
• METHODS: Using a double-blind study design, eight volunteers received tirilazad mesylate, and eight others received only vehicle [32].

References