Tirilazad

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Edward D Hall - One of the best experts on this subject based on the ideXlab platform.

  • Tirilazad widens the therapeutic window for riluzole induced attenuation of progressive cortical degeneration in an infant rat model of the shaken baby syndrome
    Journal of Neurotrauma, 1998
    Co-Authors: Sarah L Smith, Edward D Hall
    Abstract:

    ABSTRACT Our infant rat model of traumatic subarchnoid hemorrhage combines violent shaking and hypoxia to produce subdural hemorrhaging and progressive cortical degeneration similar to that seen in victims of the shaken baby syndrome. Anesthetized, 6-day-old male rats were subjected to one episode of shaking under hypoxic conditions. Brain histologies revealed moderate-to-severe cortical hemorrhaging at 48 h postinjury and progressive cortical degeneration, as indicated by a 15.3% and 20.2% reduction in cortical wet weight, at 7 and 14 days postinjury, respectively. The purpose of the present study was to assess the effects of two antioxidant lipid peroxidation inhibitors (Tirilazad mesylate and PNU-101033E), and the glutamate release inhibitor (riluzole), upon the brain pathology seen in this model. A significant, 54.3–75.3%, reduction in cortical hemorrhaging was observed in rats that were treated with a total of three doses of Tirilazad (10 mg/kg, i.p.): 10 min before or 5–30 min after injury, and agai...

  • attenuation of motor nerve terminal repetitive discharge by the 21 aminosteroid Tirilazad evidence of a neural calcium antagonist action
    Brain Research, 1998
    Co-Authors: Edward D Hall, Patricia A Yonkers
    Abstract:

    Abstract Pretreatment with the 21-aminosteroid antioxidant compound Tirilazad mesylate has been previously shown to retard the axotomy-induced anterograde degeneration of soleus motor nerve terminals in the cat. In the present study, we examined Tirilazad's effects (7.7, 13.0 or 30.0 mg/kg twice daily P.O. for 6 days) on the excitability of normal cat soleus motor nerve terminals. Low frequency (0.4 Hz) neuromuscular transmission was measured as well as the occurrence of muscle contractile potentiation in response to either a 400 Hz/10 s episode of tetanic conditioning stimulation of the soleus nerve or the administration of a 200 μg/kg i.v. dose of the neuromuscular facilitatory drug edrophonium. The mechanism of the post-tetanic potentiation (PTP) or edrophonium-induced facilitatory response involves the occurrence of a stimulus-dependent repetitive discharge of the soleus motor nerve terminals due to an exaggeration of the nerve terminal Ca2+-mediated after-depolarization. Tirilazad pretreatment caused a dose-related suppression of PTP and the edrophonium response indicative of a suppression of motor nerve terminal repetitive discharge. These effects were not shared by 6 days of oral pretreatment of cats with a high dose combination of the antioxidants vitamin E (200 I.U./day) and selenium (50 μg/day). Thus, it is unlikely that the antioxidant properties of Tirilazad are involved in the suppression of motor nerve terminal excitability. Rather, it is proposed that Tirilazad suppresses delayed motor nerve terminal Ca2+ conductances secondary to its ability to decrease membrane phospholipid fluidity, and that this action might in some circumstances contribute to its neuroprotective activity.

  • a comparison of the effects of Tirilazad on subarachnoid hemorrhage induced blood brain barrier permeability in male and female rats
    Journal of Stroke & Cerebrovascular Diseases, 1997
    Co-Authors: Sarah L Smith, Philip G Larson, Edward D Hall
    Abstract:

    Phase III subarachnoid hemorrhage clinical trials have shown a beneficial effect of Tirilazad only in men. One explanation for the decreased efficacy in women is that women metabolize the drug up to 60% faster than men. However, it is also possible that other more subtle differences between the sexes alter the pharmacodynamic response of women to Tirilazad. The purpose of the present study was to compare the efficacy of Tirilazad in attenuating early post-subarachnoid hemorrhage-induced blood-brain barrier damage in the rat, a species in which single-dose metabolism of the drug is comparable between males and females. Male and female rats were treated with 0.1, 0.3, 1.0, or 3.0 mg/kg Tirilazad (intravenous) 10 minutes before and 2 hours after subarachnoid hemorrhage. At 3 hours posthemorrhage, the extent of blood-brain barrier damage, as measured by Evan's blue extravasation, did not differ between male and female vehicle-treated rats. In addition, treatment with Tirilazad produced a similar effect in both males and females at all doses tested. At 0.3 mg/kg, blood-brain barrier damage was reduced 43.4% in males and 48.0% in females ( P ≤.01 vs vehicle), at 1.0 mg/kg, 33.1% in males and 29.1% in females ( P ≤.05), and at 3.0 mg/kg, 28.0% in males and 23.8% in females ( P =NS). The lowest dose, 0.1 mg/kg, failed to protect the blood-brain barrier in both genders. These results suggest that gender differences do not significantly effect the blood-brain barrier protective efficacy of Tirilazad following subarachnoid hemorrhage in the rat.

  • protective effects of Tirilazad mesylate and metabolite u 89678 against blood brain barrier damage after subarachnoid hemorrhage and lipid peroxidative neuronal injury
    Journal of Neurosurgery, 1996
    Co-Authors: Sarah L Smith, H M Scherch, Edward D Hall
    Abstract:

    ✓ The 21-aminosteroid lipid-peroxidation inhibitor, Tirilazad mesylate (U-74006F), recently was shown in a large multinational Phase III clinical trial to decrease mortality and improve neurological recovery in patients 3 months after onset of aneurysmal subarachnoid hemorrhage (SAH). A major Tirilazad metabolite in animals and man, U-89678 is formed when the 4–5 double bond in the A-ring is reduced and has been postulated to contribute significantly to Tirilazad's neuroprotective effects. In the first experiment of the present study, the authors compared the effects of Tirilazad and U-89678 on acute blood-brain barrier (BBB) damage in rats subjected to SAH via injection of 300 µl of autologous nonheparinized blood under the dura of the left cortex. The rats were treated by intravenous administration of either 0.3 or 1.0 mg/kg of Tirilazad or U-89678 10 minutes before and 2 hours after SAH, and BBB damage was quantified according to the extravasation of the protein-bound Evans' blue dye into the injured c...

  • cyclophosphamide is neuroprotective in a gerbil model of transient severe focal cerebral ischemia correlation with effects of Tirilazad mesylate u 74006f
    Journal of Neurotrauma, 1996
    Co-Authors: Lawrence R Williams, Edward D Hall, Jo A Oostveen, Robert A Jolly, Paul S Satoh, Thomas W Petry
    Abstract:

    Using a gerbil model of severe, temporary focal ischemia (3 h unilateral carotid occlusion), preliminary experiments identified an involvement of neutrophils in the reperfusion injury to the ischemic hemisphere. The present experiments were designed to (1) quantitate the temporal accumulation of neutrophils in the gerbil model, (2) determine if cyclophosphamide-induced neutropenia provided cytoprotection to the ischemic hemisphere, and (3) attempt to correlate the cytoprotective efficacy of Tirilazad mesylate with possible effects on postischemic neutrophil accumulation. Following 3 h of unilateral carotid occlusion, animals were collected at increasing times of reperfusion and the CA1 region of the hippocampus and the lateral cortex were assessed for postischemic neuronal damage using a semiquantitative index (N.D.I.) of 0 (no damage) to 4 (>75% neuronal loss). The extent of neutrophil accumulation was determined by counting intensely cytochrome oxidase-positive cells. Minimal neuronal death was evident after 2 h of reperfusion, mean N.D.I. = 0.36. However, between 2 and 4 h of reperfusion, neuronal death did not increase. By 6 h of reperfusion, the neuronal death began to proceed at an accelerated rate, N.D.I. = 0.78. By 12 h, the N.D.I. reached 3.20. The accelerated neuronal death coincided with parenchymal invasion of neutrophils. Cyclophosphamide administration delayed neuronal death in the hippocampus, but exhibited a more sustained protective effect in the lateral cortex. Administration of Tirilazad mesylate also resulted in a significant reduction in neutrophil accumulation and significant neuronal protection in both brain areas. Thus, in this gerbil model of transient, but prolonged focal cerebral ischemia, neutrophils appear to play an active role in the reperfusion injury to brain tissue. Our experiments confirm the previously demonstrated neuroprotective efficacy of Tirilazad mesylate in this model and provide evidence for a similar protective effect of cyclophosphamide. Although other effects of this antioxidant are also thought to contribute to the overall efficacy, the data are consistent with the hypothesis that one mechanism by which Tirilazad acts involves limiting the ability of neutrophils to participate in the reperfusion phase of ischemic cerebral injury.

Joseph C Fleishaker - One of the best experts on this subject based on the ideXlab platform.

  • population pharmacokinetics of Tirilazad effects of weight gender concomitant phenytoin and subarachnoid hemorrhage
    Pharmaceutical Research, 1999
    Co-Authors: Joseph C Fleishaker, Jill Fiedlerkelly, Thaddeus H Grasela
    Abstract:

    Purpose. Data collected during Phase I and II in the development of Tirilazad were pooled and analyzed using nonlinear mixed effects models to assess covariates which might affect Tirilazad pharmacokinetics.

  • hormonal effects on Tirilazad clearance in women assessment of the role of cyp3a
    The Journal of Clinical Pharmacology, 1999
    Co-Authors: Joseph C Fleishaker, Paul G Pearson, Larry C Wienkers, Laura K Pearson, Nancy K Hopkins, Gary Peters
    Abstract:

    This study assessed whether the previously reported difference in Tirilazad clearance between pre- and postmenopausal women is reversed by hormone replacement and whether this observation can be explained by differences in CYP3A4 activity. Ten healthy women from each group were enrolled: premenopausal (ages 18-35), postmenopausal (ages 50-70), postmenopausal receiving estrogen, and postmenopausal women receiving estrogen and progestin. Volunteers received 0.0145 mg/kg midazolam and 3.0 mg/kg Tirilazad mesylate intravenously on separate days. Plasma Tirilazad and midazolam were measured by HPLC/dual mass spectrophotometry (MS/MS) assays. Tirilazad clearance was significantly higher in premenopausal women (0.51 ± 0.09 L/hr/kg) than in postmenopausal groups (0.34 ± 0.07, 0.32 ± 0.06, and 0.36 ± 0.08 L/hr/kg, respectively) (p = 0.0001). Midazolam clearance (0.64 ± 0.12 L/hr/kg) was significantly higher in premenopausal women compared to postmenopausal groups (0.47 ± 0.11, 0.49 ± 0.11, and 0.53 ± 0.19 L/hr/kg, respectively) (p = 0.037). Tirilazad clearance was weakly correlated with midazolam clearance (r 2 = 0.129, p = 0.02). Tirilazad clearance is faster in premenopausal women than in postmenopausal women, but the effect of menopause on clearance is not reversed by hormone replacement. Tirilazad clearance in these women is weakly related to midazolam clearance, a marker of CYP3A activity.

  • biotransformation of Tirilazad in human 4 effect of finasteride on Tirilazad clearance and reduced metabolite formation
    Journal of Pharmacology and Experimental Therapeutics, 1998
    Co-Authors: Joseph C Fleishaker, Paul G Pearson, Larry C Wienkers, Laura K Pearson, Theresa A Moore, Gary Peters
    Abstract:

    The effect of oral finasteride, an inhibitor of 5α-reductase, on the clearance of Tirilazad, a membrane lipid peroxidation inhibitor, was assessed in eight healthy men who received: 1) 10 mg/kg Tirilazad mesylate solution orally on the 7th day of a 10-day regimen of 5 mg finasteride once daily, 2) 10 mg/kg Tirilazad mesylate orally, 3) 2 mg/kg Tirilazad mesylate i.v. on the 7th day of a 10-day regimen of 5 mg finasteride once daily and 4) 2 mg/kg Tirilazad mesylate i.v., in a four-way cross-over design. Plasma concentrations of Tirilazad and its active reduced metabolites (U-89678 and U-87999) were measured by liquid chromatography with tandem mass spectrometry (LC-MS-MS). Finasteride increased mean Tirilazad areas under the curve by 21 and 29% for i.v. and p.o. Tirilazad, respectively. Mean U-89678 areas under the curve were decreased 92 and 75% by finasteride administration with i.v. and p.o. Tirilazad, respectively, and decreases of 94 and 85% in mean U-87999 area under the curve values were observed. These differences were statistically significant. These results indicate that finasteride inhibits the metabolism of Tirilazad to U-89678. However, this inhibition has only a moderate effect on the overall clearance of Tirilazad. These results thus confirm earlier in vitro work that showed that Tirilazad is predominantly metabolized by CYP3A4. Although the major circulating metabolites of Tirilazad are formed via reduction, this represents a minor route of Tirilazad elimination in man.

  • biotransformation of Tirilazad in human 3 Tirilazad a ring reduction by human liver microsomal 5α reductase type 1 and type 2
    Journal of Pharmacology and Experimental Therapeutics, 1998
    Co-Authors: Larry C Wienkers, Joseph C Fleishaker, Rick C Steenwyk, Michael J Hauer, Paul G Pearson
    Abstract:

    Tirilazad mesylate (FREEDOX), a potent inhibitor of membrane lipid peroxidation in vitro , is under clinical development for the treatment of subarachnoid hemorrhage. In humans, Tirilazad is cleared almost exclusively via hepatic elimination with a medium-to-high extraction ratio. In human liver microsomal preparations, Tirilazad is biotransformed to multiple oxidative products and one reduced, pharmacologically active metabolite, U-89678. Characterization of the reduced metabolite by mass spectrometry and cochromatography with an authentic standard demonstrated that U-89678 was formed via stereoselective reduction of the Δ 4 bond in the steroid A-ring. Kinetic analysis of Tirilazad reduction in human liver microsomes revealed that kinetically distinct type 1 and type 2 5α-reductase enzymes were responsible for U-89678 formation; the apparent K M values for type 2 and type 1 were ∼15 and ∼0.5 μM, respectively. Based on pH dependence and finasteride inhibition studies, it was inferred that 5α-reductase type 1 was the high affinity/low capacity microsomal reductase that contributed to Tirilazad clearance in vivo . In addition, a role for CYP3A4 in the metabolism of U-89678 was established using cDNA expressed CYP3A4 and correlation studies comparing U-89678 consumption with cytochrome P450 activities across a population of human liver microsomes. 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. Therefore, concurrent administration of therapeutic agents that modulate 5α-reductase type 1 or CYP3A activity are anticipated to affect the pharmacokinetics of PNU-89678.

  • induction of Tirilazad clearance by phenytoin
    Biopharmaceutics & Drug Disposition, 1998
    Co-Authors: Joseph C Fleishaker, Laura K Pearson, Gary Peters
    Abstract:

    Tirilazad is a membrane lipid peroxidation inhibitor being studied for the management of subarachnoid hemorrhage; phenytoin is used for seizure prophylaxis in the same disorder. The induction of Tirilazad clearance by phenytoin was assessed in 12 volunteers (6 male, 6 female). Subjects received phenytoin orally every 8 h for 7 days (200 mg for nine doses and 100 mg for 13 doses) in one phase of a crossover study. In both study phases, 1.5 mg kg−1 Tirilazad mesylate was administered by IV infusion every 6 h for 29 doses. Tirilazad mesylate and U-89678 (an active metabolite) in plasma were quantified by HPLC. After the final dose, Tirilazad clearance was increased by 91.8% in subjects receiving phenytoin+Tirilazad versus Tirilazad alone. AUC0–6 for U-89678 after the last Tirilazad dose was reduced by 93.1% by concomitant phenytoin. These effects were statistically significant. The time course of induction was consistent with that of phenytoin's effect on the ratio of urinary 6β -hydroxycortisol to cortisol, a measure of hepatic CYP3A activity. The results show that phenytoin induces metabolism of Tirilazad and U-89678 in healthy subjects and that, under these conditions, Tirilazad clearance approaches liver blood flow. © 1998 John Wiley & Sons, Ltd.

G R Peters - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetics of Tirilazad in healthy male subjects at doses above 6 mg kg day
    International Journal of Clinical Pharmacology and Therapeutics, 1997
    Co-Authors: J C Fleishaker, G R Peters
    Abstract:

    The dose proportionality of Tirilazad pharmacokinetics at dosages above 6.0 mg/kg/day were assessed in 18 healthy male volunteers between the ages of 19 and 46 years. Subjects were randomized to receive either 1.5 mg/kg, 3.0 mg/kg, or 4.0 mg/kg Tirilazad mesylate every 6 hours for 29 doses (daily doses of 6.0, 12.0, and 16.0 mg/kg/day for 7 days). Each drug dose was administered intravenously over 10 minutes. Plasma Tirilazad, U-89678, and U-87999 (active reduced metabolites) were quantified by HPLC. Two subjects in the high dose group withdrew before the end of the study. Following the first dose of Tirilazad, dose-corrected pharmacokinetic parameters for all 3 compounds did not differ significantly among dose groups. After the final Tirilazad dose the mean half-life of Tirilazad was approximately 80 hours. Mean apparent Tirilazad clearance did not differ significantly among groups. Mean U-89678 AUC 0-6 following the last Tirilazad dose did not differ significantly between the 6.0 and 12.0 mg/kg/day doses, but the value for the 16.0 mg/kg dose was higher than values from both lower doses (p = 0.044 and 0.056, respectively). Similar results were obtained for U-87999. The dose effects observed for the pharmacokinetics of these 2 metabolites may have been a function of intersubject variability. When combined with previous data concerning the dose proportionality of Tirilazad pharmacokinetics at doses less than 6.0 mg/kg/day, the data from the present study suggest that the pharmacokinetics of Tirilazad are approximately linear over a dosage range of 1.0 - 16.0 mg/kg/day. Due to the inability to assess the plasma protein binding of Tirilazad and its reduced metabolites, the clinical significance of the departure from linearity of the pharmacokinetics of U-89678 and U-87999 cannot be directly assessed. Further study at higher doses will be needed to address this issue.

  • comparison of the pharmacokinetics of Tirilazad mesylate in healthy volunteers and stable subjects with mild liver cirrhosis
    European Journal of Clinical Pharmacology, 1996
    Co-Authors: Laura K Pearson, Joseph C Fleishaker, G R Peters
    Abstract:

    Objective: The pharmacokinetics of Tirilazad mesylate and an active reduced metabolite, U89678, were studied in 7 volunteers with mild cirrhosis of the liver and seven age, sex, weight and smoking status matched healthy normal volunteers. Subjects received a single intravenous infusion of 2.0 mg ⋅kg−1 Tirilazad mesylate over 10 min.

  • Gender does not affect the degree of induction of Tirilazad clearance by phenobarbital.
    European journal of clinical pharmacology, 1996
    Co-Authors: J C Fleishaker, L K Pearson, G R Peters
    Abstract:

    Tirilazad mesylate is a membrane lipid peroxidation inhibitor being evaluated for the treatment of patients with subarachnoid haemorrhage (SAH); phenobarbital may be administered to these patients for seizure prophylaxis. Therefore, the effect of phenobarbital on Tirilazad mesylate pharmacokinetics was assessed in 15 healthy volunteers (7M, 8F). Subjects received 100 mg phenobarbital orally daily for 8 days in one phase of a two-way crossover study. In both phases, 1.5 mg.kg-1 tirilazed mesylate was administered (as a 10 minute IV infusion) every 6 hours for 29 doses. Three weeks separated study phases. Tirilazad mesylate and U-89678 (an active metabolite) in plasma were quantified by HPLC. Phenobarbital had no effect on the first dose pharmacokinetics of Tirilazad or U-89678. After the final dose, clearance for Tirilazad was increased 25% in males and 29% in females receiving phenobarbital + Tirilazad versus Tirilazad mesylate alone. These differences were statistically significant, and the degree of induction was not significantly different between genders. AUC(zero)-6 for U-89678 after the last Tirilazad mesylate dose was reduced 51% in males and 69% in females. The decreases were statistically significant, and there was no gender by treatment interaction. The results show that phenobarbital induces metabolism of Tirilazad and U-89678 similarly in both men and women. Lower levels of Tirilazad and U-89678 in SAH patients receiving phenobarbital may adversely impact clinical response.

  • gender does not affect the degree of induction of Tirilazad clearance by phenobarbital
    European Journal of Clinical Pharmacology, 1996
    Co-Authors: Joseph C Fleishaker, Laura K Pearson, G R Peters
    Abstract:

    Objective: Tirilazad mesylate is a membrane lipid peroxidation inhibitor being evaluated for the treatment of patients with subarachnoid haemorrhage (SAH); phenobarbital may be administered to these patients for seizure prophylaxis. Therefore, the effect of phenobarbital on Tirilazad mesylate pharmacokinetics was assessed in 15 healthy volunteers (7M, 8F).

  • Effect of Gender and Menopausal Status on the Pharmacokinetics of Tirilazad Mesylate in Healthy Subjects.
    American Journal of Therapeutics, 1995
    Co-Authors: Joseph C Fleishaker, Laura K. Hulst-pearson, G R Peters
    Abstract:

    The pharmacokinetics of Tirilazad were assessed in men ages 40--60 years, women

Wayne M Alves - One of the best experts on this subject based on the ideXlab platform.

  • double blind randomized vehicle controlled study of high dose Tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage part i a cooperative study in europe australia new zealand and south africa
    Journal of Neurosurgery, 1999
    Co-Authors: Giuseppe Lanzino, Neal F Kassell, Nicholas W C Dorsch, A Pasqualin, Lennart Brandt, P Schmiedek, Laura L Truskowski, Wayne M Alves
    Abstract:

    Object. Findings from previous multicenter clinical trials have suggested that Tirilazad mesylate, a synthetic nonhormonal 21-aminosteroid, might be effective in preventing delayed cerebral ischemia following subarachnoid hemorrhage (SAH). This beneficial effect, however, was greater in males than females, possibly because of gender-related pharmacokinetic differences. The authors sought to assess the effects of administering a larger dose of Tirilazad in women with SAH. Methods. To test the efficacy of a higher Tirilazad mesylate dose in female patients, a prospective randomized, doubleblind, vehicle-controlled trial was conducted at 56 neurosurgical centers in Europe, Australia, New Zealand, and South Africa. Eight hundred nineteen patients were randomly assigned to receive either 15 mg/kg/day of Tirilazad mesylate or a placebo containing the citrate vehicle. The two groups were similar in prognostic factors for delayed cerebral ischemia and overall outcome. High-dose Tirilazad appeared to be well toler...

  • economic analysis of Tirilazad mesylate for aneurysmal subarachnoid hemorrhage economic evaluation of a phase iii clinical trial in europe and australia
    International Journal of Technology Assessment in Health Care, 1998
    Co-Authors: Henry A Glick, Neal F Kassell, Wayne M Alves, Richard J Willke, Daniel Polsky, Ted Llana, Kevin A Schulman
    Abstract:

    This study used data from a multinational phase III randomized, double-blind, vehicle-controlled trial to evaluate the cost-effectiveness of Tirilazad mesylate (Freedox®) in the treatment of aneurysmal subarachnoid hemorrhage. In men, therapy with 6 mg/kg per day of Tirilazad mesylate was associated with significantly increased survival, increased cost of care, and ratios of cost per death averted that compare favorably with the ratios of other life and death interventions. In women, it appeared to have no effects on costs or survival. Further clinical studies may provide additional information about the cost-effectiveness of this intervention.

  • a randomized double blind vehicle controlled trial of Tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage a cooperative study in north america
    Journal of Neurosurgery, 1997
    Co-Authors: E C Haley, Neal F Kassell, C Appersonhansen, M H Maile, Wayne M Alves
    Abstract:

    ✓ To test the safety and efficacy of Tirilazad mesylate, a nonglucocorticoid 21-aminosteroid, in improving the outcome of patients with aneurysmal subarachnoid hemorrhage (SAH), 902 patients were enrolled in a prospective randomized, double-blind, vehicle-controlled trial at 54 North American neurosurgical centers. Five patients were excluded prior to receiving any study drug. Of 897 patients who received at least one dose of study medication, 300 received a placebo containing a citrate vehicle, 298 received 2 mg/kg per day Tirilazad, and 299 received 6 mg/kg per day Tirilazad, all administered intravenously beginning within 48 hours of the SAH and continuing through 10 days posthemorrhage. All patients were also treated with orally administered nimodipine. At 3 months post-SAH, there were no significant differences (p < 0.025) among the groups with regard to mortality rate, favorable outcome on the Glasgow Outcome Scale, or employment status. During the first 14 days after the SAH, there were no signific...

  • randomized double blind vehicle controlled trial of Tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage a cooperative study in europe australia and new zealand
    Journal of Neurosurgery, 1996
    Co-Authors: Neal F Kassell, E C Haley, C Appersonhansen, Wayne M Alves
    Abstract:

    ✓ Tirilazad mesylate, a nonglucocorticoid 21-aminosteroid, has been shown in experimental models to reduce vasospasm following subarachnoid hemorrhage (SAH) and to reduce infarct size from focal cerebral ischemia. To test whether treatment with Tirilazad would reduce ischemic symptoms from vasospasm and improve overall outcome in patients with ruptured aneurysms, a prospective randomized, double-blind, vehicle-controlled trial was conducted at 41 neurosurgical centers in Europe, Australia, and New Zealand. One thousand twenty-three patients were randomly assigned to receive 0.6, 2, or 6 mg/kg per day of intravenously administered Tirilazad or a placebo containing the citrate vehicle. All patients were also treated with intravenously administered nimodipine. Patients receiving 6 mg/kg per day of Tirilazad had reduced mortality (p = 0.01) and a greater frequency of good recovery on the Glasgow Outcome Scale 3 months after SAH (p = 0.01) than similar patients treated with vehicle. There was a reduction in sy...

  • phase ii trial of Tirilazad in aneurysmal subarachnoid hemorrhage a report of the cooperative aneurysm study
    Journal of Neurosurgery, 1995
    Co-Authors: E C Haley, Neal F Kassell, Wayne M Alves, Bryce Weir, C A Hansen
    Abstract:

    ✓ Tirilazad mesylate, a 21-aminosteroid free-radical scavenger, has been shown to ameliorate cerebral vasospasm and reduce infarct size in animal models of subarachnoid hemorrhage (SAH) and focal cerebral ischemia. In preparation for performing large-scale clinical trials in humans with aneurysmal SAH, the safety of varying doses of Tirilazad was tested in a randomized, double-blind, vehicle-controlled, sequential dose-escalation study at 12 Canadian neurosurgical centers. Two hundred forty-five patients with an aneurysmal SAH documented by angiography were enrolled in the study sequentially within 72 hours of hemorrhage. The patients were assigned to one of three dosage tiers: receiving 0.6 mg/kg, 2 mg/kg, or 6 mg/kg Tirilazad or vehicle per day intravenously in divided doses through Day 10 following the SAH. All patients also received oral nimodipine. No serious side effects of Tirilazad treatment were identified at any of the three doses, despite close monitoring of hepatic and cardiac toxicity. A tren...

Richard J Traystman - One of the best experts on this subject based on the ideXlab platform.

  • amelioration of impaired cerebral metabolism after severe acidotic ischemia by Tirilazad posttreatment in dogs
    Stroke, 1996
    Co-Authors: Raymond C Koehler, Edward D Hall, Patricia D Hurn, Richard J Traystman
    Abstract:

    Background and Purpose Acidosis may contribute to ischemic injury by mobilizing iron because the iron chelator deferoxamine improves early metabolic recovery from hyperglycemic ischemia. Mobilized iron may then promote oxygen radical-induced lipid peroxidative injury during reperfusion. 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. Methods In anesthetized dogs, arterial glucose concentration was increased to 500 to 600 mg/dL and global incomplete cerebral ischemia was produced for 30 minutes by ventricular fluid infusion to reduce perfusion pressure to 10 to 12 mm Hg. Metabolic recovery and intracellular pH were measured by phosphorus MR spectroscopy. In the first experiment, four groups of eight dogs each received either vehicle or 0.25, 1, or 2.5 mg/kg of Tirilazad mesylate at reperfusion. Cerebral blood flow was mea...

  • Tirilazad pretreatment improves early cerebral metabolic and blood flow recovery from hyperglycemic ischemia
    Journal of Cerebral Blood Flow and Metabolism, 1995
    Co-Authors: Yuichi Maruki, Raymond C Koehler, Jeffrey R Kirsch, Kathleen K Blizzard, Richard J Traystman
    Abstract:

    Summary: Acidosis may augment cerebral ischemic injury by promoting lipid peroxidation. We tested the hypothesis that when acidosis is augmented by hyperglyce-mia, pretreatment with the 21-aminosteroid Tirilazad mes-ylate (U74006F), a potent inhibitor of lipid peroxidation in vitro, improves early cerebral metabolic recovery. In a randomized, blinded study, anesthetized dogs received either Tirilazad mesylate (1 mg/kg plus 0.2 mg/kg/h; n = 8) or vehicle (n = 8). Hyperglycemia (400-500 mg/dl) was produced prior to 30 min of global incomplete cerebral ischemia. Intracellular pH and high energy phosphates were measured by phosphorus magnetic resonance spec-troscopy. During ischemia, microsphere-determined CBF decreased to 8 ± 4 ml min"' 100 g"' and intracellular pH decreased to 5.6 ± 0.2 in both groups. During the first 20 min of reperfusion, ATP partially recovered in the vehicle group to 57 ± 21% of baseline, but then declined progres-sively in association with elevated intracranial pressure. By 30 min, ATP recovery was greater in the Tirilazad group (77 ± 35 vs. 36 ± 19%), although postischemic hyperemia was similar. 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). By 180 min, blood flow and ATP were undetectable in seven of eight vehicle-treated dogs, whereas ATP was >67% and pH was >6.7 in six of eight Tirilazad-treated dogs. Thus, Tirilazad acts during early reperfusion to prevent secondary metabolic decay associated with severe acidotic ischemia. If Tirilazad acts by inhibiting lipid peroxidation, then these data are consistent with extreme acidosis limiting recovery by a mechanism involving lipid peroxidation.

  • Tirilazad treatment does not decrease early brain injury after transient focal ischemia in cats
    Stroke, 1994
    Co-Authors: Reiko Takeshima, Raymond C Koehler, Jeffrey R Kirsch, Richard J Traystman
    Abstract:

    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. Halothane-anesthetized cats underwent 90 minutes of left middle cerebral artery and bilateral common carotid artery occlusion followed by 180 minutes of reperfusion. Cats were assigned to receive Tirilazad (1.5 mg/kg plus 0.2 mg/kg per hour IV infusion) either at the beginning (n = 9) or conclusion (n = 9) of ischemia. Control cats received an equal volume of diluent (citrate buffer, pH 3.0; n = 7) at the beginning and conclusion of ischemia in a blinded fashion. Infarct volume was measured by 2,3,5-triphenyltetrazolium chloride staining. Blood flow to the left temporoparietal cortex decreased to less than 10 mL/min per 100 g with ischemia but was minimally affected on the right side. Blood flow distribution during ischemia or reperfusion was not different in the Tirilazad-treated groups. No group demonstrated postischemic hyperemia or delayed hypoperfusion. Somatosensory evoked potential recorded over the left cortex was ablated during ischemia and recovered to less than 15% of baseline amplitude at 180 minutes of reperfusion in all groups. There were no differences among groups in infarct volume of left hemisphere (pretreatment, 25 +/- 6% [mean +/- SE]; posttreatment, 33 +/- 5%; control, 28 +/- 8% of hemisphere) or caudate nucleus (pretreatment, 46 +/- 7%; posttreatment, 41 +/- 10%; control, 55 +/- 13% of hemisphere). In an experimental model of focal ischemia involving severe reductions of blood flow followed by reperfusion in cats, administration of Tirilazad at the onset of either ischemia or reperfusion does not ameliorate infarct volume assessed during early reperfusion. Our study does not address potential efficacy of Tirilazad in the setting of a different dosing strategy or duration of reperfusion.

  • effect of the 21 aminosteroid Tirilazad on cerebral ph and somatosensory evoked potentials after incomplete ischemia
    Stroke, 1993
    Co-Authors: Yuichi Maruki, Raymond C Koehler, Jeffrey R Kirsch, Kathleen K Blizzard, Richard J Traystman
    Abstract:

    Postischemic evoked potential recovery correlates with acidosis during ischemia and early reperfusion. Acidosis promotes lipid peroxidation in vitro. We tested the hypothesis that the 21-aminosteroid Tirilazad mesylate (U74006F), an inhibitor of lipid peroxidation in vitro, ameliorates somatosensory evoked potential recovery and acidosis during reperfusion after severe incomplete cerebral ischemia.Cerebral perfusion pressure was reduced to 11 +/- 1 mm Hg (+/- SEM) for 30 minutes by cerebral ventricular fluid infusion in anesthetized dogs. Cerebral intracellular pH and high-energy phosphates were measured by magnetic resonance spectroscopy. Dogs were randomized to receive vehicle (citrate buffer; n = 8) or Tirilazad (1 mg/kg; n = 8) before ischemia in a blinded study.Cerebral blood flow was reduced to 6 +/- 1 mL/min per 100 g during ischemia, resulting in nearly complete loss of high-energy phosphates and an intracellular pH of 6.0-6.1 in both groups. Initial postischemic hyperemia was similar between grou...

  • Tirilazad mesylate does not improve early cerebral metabolic recovery following compression ischemia in dogs
    Stroke, 1992
    Co-Authors: Mark A Helfaer, Raymond C Koehler, Jeffrey R Kirsch, Kathleen K Blizzard, Patricia D Hurn, Richard J Traystman
    Abstract:

    Tirilazad mesylate (U74006F) has been reported to improve recovery following cerebral ischemia. We conducted a randomized blinded study to determine if the drug would improve immediate metabolic recovery after complete cerebral compression ischemia.Mongrel dogs were anesthetized with pentobarbital and fentanyl and treated with either vehicle (citrate buffer, n = 8) or Tirilazad (1.5 mg/kg i.v. plus 0.18 mg/kg/hr, n = 8). Normothermic complete cerebral compression ischemia was produced for 12 minutes by lateral ventricular fluid infusion to raise intracranial pressure above systolic arterial pressure. Cerebral high-energy phosphate concentrations and intracellular pH were measured by phosphorus magnetic resonance spectroscopy. Cerebral blood flow was measured with radiolabeled microspheres, and oxygen consumption was calculated from sagittal sinus blood samples. Somatosensory evoked potentials were measured throughout the experiment.During ischemia, both groups demonstrated complete loss of high-energy pho...

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