Evaluation of the Pharmacokinetics and Tolerability of Tirilazad Mesylate, a 21‐Aminosteroid Free Radical Scavenger: I. Single‐Dose Administration

Fleishaker, Joseph C.; Peters, Gary; Cathcart, K. S.

doi:10.1002/j.1552-4604.1993.tb03940.x

Cited by 48 publications

(8 citation statements)

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“…Clinical trials studying the tolerability and pharmacokinetics of lazaroids have been reported [29][30][31]. In one such study, using U-74600F (tirilazad mesylate, a lazaroid compound), Fleishaker et al found that doses of up to 10 mg/kg/day given every 6 h for 5-10 days are tolerable in healthy volunteers.…”

Section: Discussionmentioning

confidence: 99%

Lazaroids inhibit proliferation of cultured human astrocytoma cells

et al. 1996

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Lazaroids (or 21-aminosteroids) are potent lipid peroxidation inhibitors and are more potent antioxidants than steroids which have been shown to suppress tumor proliferation. The effects of two lazaroid compounds (U-75389G and U-83836E) were tested on the proliferation of a human brain astrocytoma cell line U-373MG. Both lazaroids had dose-dependent growth-inhibitory effects on the proliferation of U-373MG. For purposes of comparison, two steroids (methylprednisolone and dexamethasone) and a highly potent antioxidant (alpha-tocopherol) were tested under similar experimental conditions and were found to have antiproliferative effects as well, although at higher dose ranges. As cell growth-inhibitors, lazaroids are more effective than alpha-tocopherol while they are advantageous over glucocorticoids for their actions are devoid of the usual glucocorticoid side-effects.

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Section: Discussionmentioning

confidence: 99%

Lazaroids inhibit proliferation of cultured human astrocytoma cells

et al. 1996

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“…Because the mean half-life of tirilazad mesylate is relatively long (3.7 h for healthy male volunteers [32]), lazaroid reduced reperfusion injury after 3-h warm ischemia when administered as a bolus infusion of 10 mg/kg before ischemia.…”

Section: Original Researchmentioning

confidence: 99%

Effect of Lazaroid U-74389G on Pulmonary Ischemia - Reperfusion Injury in Dogs

Takeyoshi

Iwanami

Kamoshita

et al. 2001

Journal of Investigative Surgery

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Lipid peroxidation induced by oxygen free radicals is a contributing factor in ischemia-reperfusion injury. Lazaroid U-74389G (LAZ-G) is a group of new synthetic 21-aminosteroids and inhibits irondependent lipid peroxidation. We investigated the effects of LAZ-G on pulmonary ischemia-reperfusion injury in dogs. Twenty dogs were divided into three groups. In the LAZ-G group (n = 6), LAZ-G was administered 15 min before ischemia. In the St group (n = 5), methylprednisolone was injected 15 min before ischemia and 15 min before reperfusion. In the control group (n = 9), the vehicle of Lazaroid was injected 15 min before ischemia. Warm ischemia was induced for 3 h by clamping the pulmonary artery and veins. Arterial oxygen saturation (SaO2), cardiac output (CO), left pulmonary vascular resistance (L-PVR), and blood levels of interleukin-1beta mRNA were measured. The lung specimen was harvested for histologic study and polymorphonuclear neutrophils (PMNs) counting. SaO2 levels at 30 min and 2 h after reperfusion were significantly higher in the LAZ-G group than in the control group. After 30 min of reperfusion, CO was significantly better in the LAZ-G group than in the St and control groups, and the L-PVR level was significantly lower in the LAZ-G group than in the control group. Survival rates were significantly better in the LAZ-G group than in the control group. Histological damages and PMNs infiltration were more severe in the control group than in the LAZ-G group. Interleukin-1beta mRNA levels were lower in the LAZ-G group than in the control group. Lazaroid U-74389G appears to generate a protective effect against ischemia-reperfusion injury of the lung.

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“…No satisfactory biochemical explanation for toxicity exists. In particular, although tirilazad is a steroid, it has not been found to exhibit glucocorticoid activity in humans 15,16 or to affect the pituitary adrenocortical axis in rats. 41 Hence, it is unlikely that tirilazad worsened outcome through glucocorticoid effects, although it remains unclear what effects corticosteroids have in acute ischemic stroke.…”

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confidence: 97%

“…However, tirilazad had variable effects on neurological outcome in transient forebrain ischemia in the rat. 13,14 Phase I results in normal, healthy, human volunteers found that single and multiple intravenous doses of up 12 mg/kg tirilazad were well tolerated [15][16][17] ; local infusion-related irritation and thrombophlebitis were the main adverse events, partially explained by the presence of citrate in the vehicle solution. 16 Tirilazad did not alter cerebral blood flow or its reactivity to carbon dioxide or cerebral oxygen metabolism in normal subjects.…”

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Tirilazad Mesylate in Acute Ischemic Stroke

2000

Stroke

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Background and Purpose-Tirilazad is a nonglucocorticoid, 21-aminosteroid that inhibits lipid peroxidation. Studies in experimental models of ischemic stroke had suggested that tirilazad had neuroprotective properties. As a result, clinical studies were undertaken to assess the safety and efficacy of tirilazad in the treatment of acute ischemic stroke. We performed a systematic review of randomized, controlled trials that assessed the safety and efficacy of tirilazad in patients with acute ischemic stroke. Methods-Trials of tirilazad were identified from searches of the Cochrane Library and communication with the Pharmacia & Upjohn company, the manufacturer of tirilazad. Data relating to early and end-of-trial case fatality, disability (Barthel Index and Glasgow Outcome Scale), phlebitis, and corrected QT interval were extracted by treatment group from published data and company reports and analyzed by using the Cochrane Collaboration meta-analysis software REVMAN. Results-Six trials (4 published, 2 unpublished) assessing tirilazad in 1757 patients with presumed acute ischemic stroke were identified; all were double-blind and placebo controlled in design. Tirilazad did not alter early case fatality (odds ratio [OR] 1.11, 95% confidence interval [CI] 0.79 to 1.56) or end-of-trial case fatality (OR 1.12, 95% CI 0.88 to 1.44).A just-significant increase in death and disability, assessed as either the expanded Barthel Index (OR 1.23, 95% CI 1.01 to 1.51) or Glasgow Outcome Scale (OR 1.23, 95% CI 1.01 to 1.50) was observed. Tirilazad significantly increased the rate of infusion site phlebitis (OR 2.81, 95% CI 2.14 to 3.69). Functional outcome (expanded Barthel Index) was significantly worse in prespecified subgroups of patients: females (OR 1.46, 95% CI 1.08 to 1.98) and subjects receiving low-dose tirilazad (OR 1.31, 95% CI 1.03 to 1.67); a nonsignificant worse outcome was also seen in patients with mild to moderate stroke (OR 1.40, 95% CI 0.99 to 1.98). Conclusions-Tirilazad mesylate increases death and disability by about one fifth when given to patients with acute ischemic stroke. Although further trials of tirilazad are now unwarranted, analysis of individual patient data from the trials may help elucidate why tirilazad appears to worsen outcome in acute ischemic stroke. (Stroke. 2000;32:2257-2265.)Key Words: cerebral infarction Ⅲ meta-analysis Ⅲ neuroprotective agents Ⅲ treatment outcome T irilazad mesylate (U-74006F, Freedox; Pharmacia & Upjohn, Kalamazoo, Mich) is a synthetic, lipid-soluble, nonglucocorticoid, 21-aminosteroid (or lazaroid) that has been developed for the acute treatment of subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), spinal cord injury, and ischemic stroke. Its proposed mechanism of action is to inhibit iron-dependent lipid peroxidation within membranes, effects that are mediated through (1) free-radical scavenging of lipid peroxyl and hydroxyl groups, (2) reducing the formation of hydroxyl radicals, (3) decreasing membrane phospholipid fluidity, and (4) maintaining endogenous...

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Evaluation of the Pharmacokinetics and Tolerability of Tirilazad Mesylate, a 21‐Aminosteroid Free Radical Scavenger: I. Single‐Dose Administration

Cited by 48 publications

References 12 publications

Lazaroids inhibit proliferation of cultured human astrocytoma cells

Lazaroids inhibit proliferation of cultured human astrocytoma cells

Effect of Lazaroid U-74389G on Pulmonary Ischemia - Reperfusion Injury in Dogs

Tirilazad Mesylate in Acute Ischemic Stroke

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