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

Abstract

The multiple dose tolerability and pharmacokinetics of tirilazad mesylate, a 21-aminosteroid free radical scavenger, were assessed in 50 healthy male volunteers. Volunteers were randomized to receive intravenous normal saline placebo (n = 10), citrate vehicle placebo (n = 10), or 0.5 mg/kg/day (n = 6), 1.0 mg/kg/day (n = 6), 2.0 mg/kg/day (n = 6), 4.0 mg/kg/day (n = 6), or 6.0 mg/kg/day (n = 6) tirilazad mesylate in divided doses every 6 hours for 5 days, for a total of 21 doses. Drug was infused over 10 or 30 minutes. All tirilazad mesylate treatment groups and the citrate vehicle group had significantly more frequent and more intense pain at the injection site than did the saline group, but the pain intensity did not require interruption of dosing. Three episodes of clinical thrombophlebitis were observed. No statistically significant effects of tirilazad mesylate on blood pressure, heart rate, electrocardiograms, or renal function were apparent. Moderate and transient increases in serum alanine transaminase were observed in several subjects. In the 6.0 mg/kg/day group, 50% of the subjects exhibited increased alanine transaminase. Tirilazad mesylate did not significantly affect measures of glucocorticoid activity (blood glucose, adrenocorticotropic hormone, cortisol, eosinophil, or lymphocyte levels). Tirilazad mesylate pharmacokinetics were linear over the dosage range studied. Steady state appeared to be achieved by the fifth day of dosing. After the last dose, a mean terminal half-life of 35 hours was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of methylprednisolone, tirilazad mesylate and vitamin E on lipid peroxidation after experimental spinal cord injury

“…8 In vitro studies suggest that tirilazad exerts its antioxidant activity by multiple mechanisms including; increasing membrane stability, scavenging of lipid peroxyl radicals, reducing LP, induced arachidonic acid release, decreased formation or scavenging of hydroxyl radicals, and maintenance of the level of endogenous vitamin E. 11,21,22 In contrast to MP, it has no steroidal side e ects or peripheral vasodilator activity and is far more potent. 3,29,30 These characteristics make TM an interesting compound for possible treatment of CNS injury. In this study, even short-term therapy with TM at a dose of 10 mg/kg signi®cantly improved the LP after experimental SCI in the rats.…”

“…23,28,29 TM is a free radical scavenger, antioxidant, and LP inhibitor, and had a lack of side e ects in volunteers. 30 Vitamin E (alpha-tocopherol) also known as an antioxidant has protective e ects on central nervous system (CNS) trauma. 24,25 Based upon those results, the purpose of the present study was to compare the antioxidant neuroprotective e ects of MP, TM and vitamin E after compression injury of the spinal cord in rats.…”

Tirilazad Mesylate in Acute Ischemic Stroke

“…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.…”

“…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.…”

“…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. 18 A number of phase II and III trials have been undertaken, of which 2 are so-far unpublished, with tirilazad in patients with ischemic stroke, and this systematic review assesses these trials in the context of safety and efficacy.…”