Update: Tirilazad

Tirilazad

U74006F (U-74006F) is a member of steroid drugs called 21 aminosteroids, which are potent inhibitors of lipid peroxidation with little or no glucocorticoid or mineralocorticoid activity 1).


Alotaibi et al. performed a post-hoc analysis of 3567 patients who underwent clipping of ruptured intracranial aneurysms in the randomized trials of tirilazad mesylate from 1990 to 1997. These trials included 162 centers and 156 surgeons from 21 countries. Primary and secondary outcomes were: Glasgow outcome scale score and mortality, respectively. Total publications, H-index, and graduate degrees were used as academic indicators for each surgeon. The association between outcomes and academic factors were assessed using a hierarchical logistic regression analysis, adjusting for patient covariates.

Academic profiles were available for 147 surgeons, treating a total of 3307 patients. Most surgeons were from the USA (62, 42%), Canada (18, 12%), and Germany (15, 10%). On univariate analysis, the H-index correlated with better functional outcomes and lower mortality rates. In the multivariate model, patients under the care of surgeons with higher H-indices demonstrated improved neurological outcomes (p = 0.01) compared to surgeons with lower H-indices, without any significant difference in mortality. None of the other academic indicators were significantly associated with outcomes.

Although prognostication following surgery for ruptured intracranial aneurysms primarily depends on clinical and radiological factors, the academic impact of the operating neurosurgeon may explain some heterogeneity in surgical outcomes 2).


The multicenter Tirilazad database (3551 patients) was used to create this clinical outcome prediction model in order to elucidate significant brain-body associations. Traditional binary logistic regression models were used.

Binary logistic regression main effects model included four statistically significant single prognostic variables, namely, neurological grade, age, stroke, and time to surgery. Logistic regression models demonstrated the significance of hypertension and liver disease in development of brain swelling, as well as the negative consequences of seizures in patients with a history of myocardial infarction and post-admission fever worsening neurological outcome.

Using the aforementioned results generated from binary logistic regression models, we can identify potential patients who are in the high risk group of neurological deterioration. Specific therapies can be tailored to prevent these detriments, including treatment of hypertension, seizures, early detection and treatment of myocardial infarction, and prevention of hepatic encephalopathy 3).


Data were extracted from two concurrently conducted randomized clinical trials of the drug tirilazad; the designs of these studies were similar. The studies included 1701 patients with severe and 476 patients with moderate TBI. Differences were primarily investigated between studies performed in Europe and North America, but also among European regions and between Canada and the United States. Associations among regions and outcomes (6-month mortality rate and Glasgow Outcome Scale scores) were studied using multivariable logistic regression analysis. Comparisons between continents and among regions within Europe showed differences in the distribution of patient ages, causes of injury, and several clinical characteristics (motor score, pupillary reactivity, hypoxia, hypotension, intracranial pressure [ICP]). and findings on computerized tomography scans. Secondary referrals occurred 2.5 times more frequently in Europe. Within Europe secondary referral was mainly associated with an increased proportion of patients with mass lesions (46% in the European Study compared with 40% in the North American Study). Therapy for lowering ICP was more frequently applied in North America. After adjustments for case mix and management, mortality and unfavorable outcomes were significantly higher in Europe (odds ratios = 1.58 and 1.46, respectively). Significant differences in outcome between regions within Europe or within North America were not observed.

Despite the use of a strict study protocol, considerable differences in patient characteristics and case management exist between continents and among countries, reflecting variations in social, cultural, and organizational aspects. Outcomes of TBI may be worse in Europe compared with North America, but this finding requires further study 4).


Striking problems with imbalance concerning basic prognostic variables were observed in spite of the large population studied. These imbalances concerned pretreatment hypotension, pretreatment hypoxia, and the incidence of epidural hematomas. In future trials of pharmacological therapy for severe head injury, serious consideration must be given to alternative randomization strategies. Given the heterogeneous nature of head injury and the identification of populations that do relatively well with standard therapy, target populations with a higher risk for mortality and morbidity may be more suitable for clinical trials of such agents 5).


The efficacy of U74006F in reducing cerebral infarct size was investigated in a rabbit model of thromboembolic stroke. Each animal received either U74006F (3.0 mg/kg immediately before and 2 hr after embolization, n = 8) or vehicle control (n = 10). Hematocrit, mean arterial pressure, PCO2, PO2, and pH were measured and controlled both before and after the administration of an autologous clot into one internal carotid artery. Regional cerebral blood flow (in ml/100 g/min, mean +/- SEM) measured by hydrogen clearance was similar in both groups, being reduced from 68.2 +/- 9.6 to 5.2 +/- 1.9 in the control group immediately after clot embolization and from 73.3 +/- 14.9 to 7.0 +/- 1.7 in the U74006F group. Four hours after embolization the brain was harvested and cerebral infarct size was determined using the triphenyl-tetrazolium chloride technique (% hemisphere, mean +/- SEM). In the U74006F-treated group, the infarct size was significantly reduced (P < 0.05) to 14.8 +/- 6.4 from a control value of 36.0 +/- 6.4. Additionally, cerebral blood flow values after embolization were consistently higher in the U74006F group, although the differences were not statistically significant. This data suggests that the 21-aminosteroid U74006F may have a protective effect in cerebral ischemia 6).


The ability of a non-glucocorticoid 21 aminosteroid U74006F to inhibit lipid peroxidation of central nervous system tissue in vitro and to enhance the early neurological recovery and survival of mice after a severe concussive head injury is described. In the in vitro studies, U74006F was found to be an extremely potent inhibitor of lipid peroxidation in an assay system where the glucocorticoid steroid methylprednisolone and the non-glucocortoid steroids U72099E and U75718A were almost completely ineffective. In the head-injury studies, unanesthetized male CF-1 mice were subjected to a 900 gm-cm closed head injury produced by a 50-gm weight being dropped 18 cm. This concussive injury resulted in immediate unconsciousness (loss of righting reflex) in all animals and death in approximately 30%. Survivors received a tail vein injection of either vehicle or U74006F (0.001 to 30 mg/kg) within 5 minutes postinjury. Their neurological status was evaluated 1 hour later using a grip test. The grip-test score indicated that intravenous administration of a single dose of U74006F resulted in a significant improvement by as much as 168.6% in the neurological status 1 hour postinjury over a broad dose range (0.003 to 30 mg/kg). A 1-mg/kg dose given intravenously within 5 minutes and again at 1 1/2 hours after a severe injury, in addition to improving early recovery, also increased the 1-week survival rate to 78.6% compared to 27.3% in vehicle-treated mice (p less than 0.02). The compound was also effective in enhancing early recovery after a more moderate injury. This study demonstrates that early treatment after severe concussive head injury with a potent inhibitor of iron-dependent lipid peroxidation can significantly benefit the injured brain in mice and promote both early neurological recovery and long-term survival 7).


In a study it was tested for effects on brain edema and metabolites after impact injury to the closed skull. Anesthetized cats were blindly treated with U-74006F or vehicle at 30 min (1 mg/kg) and 2.5 hr (0.5 mg/kg) after head or sham injury. They were sacrificed 4 hr after injury by in situ fixation of the brain. Head-injured cats were selected for unilateral (left) cerebral contusion. Metabolites (enzyme fluorometry) and edema (specific gravity) were measured in the cerebral cortex and white matter bilaterally. Cerebral hemisphere, contusion, and vasogenic edema volumes were morphometrically measured. Magnitude of edema and metabolites in tissue with vasogenic edema was similar in vehicle- and drug-treated cats. By contrast, the cortex and nonedematous white matter neighboring contusion in drug-treated cats had lactate, glucose, and glycogen levels that suggested an improved metabolic state over vehicle treatment. Most metabolites were not affected by trauma or treatment in the uncontused hemisphere. These results suggest that postinjury treatment with the nonglucocorticoid steroid U-74006F may benefit the metabolism of nonedematous tissue adjacent to contusion 8).


The present study evaluated the effect on the development of regional cerebral edema after lateral fluid-percussion (FP) brain injury. Male Sprague-Dawley rats (n = 40) were anesthetized and subjected to FP brain injury of moderate severity centered over the left parietal cortex (2.5-2.6 atms). Fifteen minutes after brain injury, animals randomly received an i.v. bolus of either U74006F (3 mg/kg, n = 21) followed by a second bolus (3 mg/kg) at 3 hr or buffered sodium citrate vehicle (equal volume, n = 15). An additional group of 12 surgically prepared but uninjured animals served as preinjury controls. At 48 hr after injury, animals were sacrificed and brain tissue assayed for water content and regional cation concentrations. With the use of specific gravimetric techniques, no significant differences were observed in posttraumatic cerebral edema between drug- and control-treated animals. However, using wet weight/dry weight methodology, we found that administration of U74006F significantly reduced water content in the right hippocampus (contralateral to the site of injury) compared to saline-treated animals (p less than 0.05). U74006F also significantly prevented the postinjury increase in sodium concentrations in the ipsilateral hippocampus (p less than 0.05) and thalamus (p less than 0.03). Regional concentrations of potassium were unaltered after drug treatment. Administration of U74006F significantly reduced postinjury mortality, from 28% in control animals to zero in treated animals (p = 0.01). These results suggest that lipid peroxidation may be involved in the pathophysiological sequelae of brain injury and that 21-aminosteroids may be beneficial in the treatment of brain injury 9).


The effects of 5 days of pretreatment with the 21-aminosteroid anti-oxidant U74006F have been examined on the rate of functional degeneration of cat soleus motor nerve terminals after axon section. Female cats were dosed for 5 days with either 7.7, 13.0 or 30.0 mg/kg (average doses) of U74006F p.o. twice daily followed by unilateral sciatic nerve section at the hip level on day 5. On day 7, the bilateral in vivo soleus nerve muscle prep. was set up to assess the neuromuscular functional status of the 48 h degenerating soleus nerve terminals in comparison to the contralateral non-sectioned preparation. In untreated cats, the ratio of the nerve-evoked (0.4 Hz) contractile tension of the 48 h nerve-sectioned to that of the contralateral non-sectioned was only 52 +/- 8%. U74006F pretreatment produced a dose-related improvement with the 13.0 mg/kg dose having the best effect; the ratio was 86 +/- 5% (P less than 0.01 vs untreated). The maintenance of tetanic tension during a 10 s period of 100 Hz nerve stimulation was also improved by the 13.0 mg/kg dose from only 54.0 +/- 5.2% in untreated animals to 72.2 +/- 5.7 (P less than 0.02). These results show a preservation of motor nerve function during early degeneration by the anti-oxidant U74006F thus providing further evidence for a free radical-mediated process in anterograde degeneration 10).


Vollmer et al. performed a work to establish whether the nonglucocorticoid, 21-aminosteroid, U74006F, could prevent the development of delayed cerebral vasospasm after experimental subarachnoid hemorrhage. The subarachnoid hemorrhage was produced by percutaneous injection of 4.5 mL of nonheparinized autologous blood into the cisterna magna of rabbits. U74006F (1 mg/kg) or placebo was injected intraperitoneally every 12 hours starting 12 hours prior to induction of hemorrhage for a total of six doses. The animals were sacrificed by perfusion fixation. The basilar artery was removed on day 2 and processed for morphometric analysis. Control/placebo and subarachnoid hemorrhage/placebo basilar artery diameters were 651.2 +/- 25.4 and 366.3 +/- 34.2 mu, respectively. Control/U74006F basilar artery diameters (669.8 +/- 21.8 mu) were not significantly different from that of the control/placebo group. U74006F treatment greatly minimized subarachnoid hemorrhage-induced reduction in mean luminal diameter (563.7 +/- 48.2 mu) (p less than 0.001). These results demonstrate considerable therapeutic promise for U74006F in the prevention of cerebral vasospasm 11).


Young et al. investigated the effects of U74006F on the early ionic edema produced by middle cerebral artery occlusion in rats. Intravenous doses of 3 mg/kg U74006F were given 10 minutes and 3 hours after occlusion. Tissue concentrations of Na+, K+, and water at and around the infarct site were measured by atomic absorption spectroscopy and by wet-dry weight measurements 24 hours after occlusion. Compared with vehicle treatment, U74006F treatment reduced brain water entry, Na+ accumulation, K+ loss, and net ion shift by 25-50% in most brain areas sampled in the frontal and parietal cortex. However, reductions of ionic edema were most prominent and reached significance (p less than 0.005, unpaired two-tailed t test) mostly in the frontoparietal and parietal cortex areas adjacent to the infarct site. Our findings suggest that a steroid drug without glucocorticoid or mineralocorticoid activity can reduce edema in cerebral ischemia but that the effects are largely limited to tissues in which collateral blood flow may be present 12).

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.


Marshall et al., prospectively studied the efficacy of tirilazad mesylate, a novel aminosteroid, in humans with head injuries.

A cohort of 1120 head-injured patients received at least one dose of study medication (tirilazad or placebo). Eighty-five percent (957) of the patients had suffered a severe head injury (Glasgow Coma Scale [GCS] score 4-8) and 15% (163) had sustained a moderate head injury (GCS score 9-12). Six-month outcomes for the tirilazad- and placebo-treated groups for the Glasgow Outcome Scale categories of both good recovery and death showed no significant difference (good recovery in the tirilazad-treated group was 39% compared with the placebo group in which it was 42% [p=0.461]; death in the tirilazad-treated group occurred in 26% of patients compared with the placebo group, in which it occurred in 25% [p=0.750]). Subgroup analysis suggested that tirilazad mesylate may be effective in reducing mortality rates in males suffering from severe head injury with accompanying traumatic subarachnoid hemorrhage (death in the tirilazad-treated group occurred in 34% of patients; in the placebo group it occurred in 43% [p=0.026]). No significant differences in frequency or types of serious adverse events were shown between the treatment and placebo groups.

Striking problems with imbalance concerning basic prognostic variables were observed in spite of the large population studied. These imbalances concerned pretreatment hypotension, pretreatment hypoxia, and the incidence of epidural hematomas. In future trials of pharmacological therapy for severe head injury, serious consideration must be given to alternative randomization strategies. Given the heterogeneous nature of head injury and the identification of populations that do relatively well with standard therapy, target populations with a higher risk for mortality and morbidity may be more suitable for clinical trials of such agents 13).

Trials

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.

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).

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 14).

1) , 6)

Wilson JT, Bednar MM, McAuliffe TL, Raymond S, Gross CE. The effect of the 21-aminosteroid U74006F in a rabbit model of thromboembolic stroke. Neurosurgery. 1992 Nov;31(5):929-33; discussion 933-4. PubMed PMID: 1436419.
2)

Alotaibi NM, Ibrahim GM, Wang J, Guha D, Mamdani M, Schweizer TA, Macdonald RL. Neurosurgeon academic impact is associated with clinical outcomes after clipping of ruptured intracranial aneurysms. PLoS One. 2017 Jul 20;12(7):e0181521. doi: 10.1371/journal.pone.0181521. eCollection 2017. PubMed PMID: 28727832; PubMed Central PMCID: PMC5519166.
3)

Lo BW, Fukuda H, Angle M, Teitelbaum J, Macdonald RL, Farrokhyar F, Thabane L, Levine MA. Clinical outcome prediction in aneurysmal subarachnoid hemorrhage – Alterations in brain-body interface. Surg Neurol Int. 2016 Aug 1;7(Suppl 18):S527-37. doi: 10.4103/2152-7806.187496. eCollection 2016. PubMed PMID: 27583179; PubMed Central PMCID: PMC4982352.
4)

Hukkelhoven CW, Steyerberg EW, Farace E, Habbema JD, Marshall LF, Maas AI. Regional differences in patient characteristics, case management, and outcomes in traumatic brain injury: experience from the tirilazad trials. J Neurosurg. 2002 Sep;97(3):549-57. PubMed PMID: 12296638.
5) , 13)

Marshall LF, Maas AI, Marshall SB, Bricolo A, Fearnside M, Iannotti F, Klauber MR, Lagarrigue J, Lobato R, Persson L, Pickard JD, Piek J, Servadei F, Wellis GN, Morris GF, Means ED, Musch B. A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury. J Neurosurg. 1998 Oct;89(4):519-25. PubMed PMID: 9761043.
7)

Hall ED, Yonkers PA, McCall JM, Braughler JM. Effects of the 21-aminosteroid U74006F on experimental head injury in mice. J Neurosurg. 1988 Mar;68(3):456-61. PubMed PMID: 3343616.
8)

Dimlich RV, Tornheim PA, Kindel RM, Hall ED, Braughler JM, McCall JM. Effects of a 21-aminosteroid (U-74006F) on cerebral metabolites and edema after severe experimental head trauma. Adv Neurol. 1990;52:365-75. PubMed PMID: 2396533.
9)

McIntosh TK, Thomas M, Smith D, Banbury M. The novel 21-aminosteroid U74006F attenuates cerebral edema and improves survival after brain injury in the rat. J Neurotrauma. 1992 Spring;9(1):33-46. PubMed PMID: 1619674.
10)

Hall ED, Yonkers PA. Preservation of motor nerve function during early degeneration by the 21-aminosteroid anti-oxidant U74006F. Brain Res. 1990 Apr 16;513(2):244-7. PubMed PMID: 2350694.
11)

Vollmer DG, Kassell NF, Hongo K, Ogawa H, Tsukahara T. Effect of the nonglucocorticoid 21-aminosteroid U74006F experimental cerebral vasospasm. Surg Neurol. 1989 Mar;31(3):190-4. PubMed PMID: 2922661.
12)

Young W, Wojak JC, DeCrescito V. 21-Aminosteroid reduces ion shifts and edema in the rat middle cerebral artery occlusion model of regional ischemia. Stroke. 1988 Aug;19(8):1013-9. PubMed PMID: 3400099.
14)

Tirilazad mesylate in acute ischemic stroke: A systematic review. Tirilazad International Steering Committee. Stroke. 2000 Sep;31(9):2257-65. Erratum in: Stroke 2001 Jan;32(1):279. PubMed PMID: 10978061.

Leave a Reply