1Department of Anaesthesia and Pain Management, University of Sydney, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia*Corresponding author
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Abstract |
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Keywords: pharmacology; complications, trauma; brain, cortex, cerebral; spinal cord, subarachnoid
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Introduction |
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Lipid peroxidation and cerebral injury |
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During ischaemia, superoxide anions (O2) are produced by enzymesubstrate reactions in the mitochondria, especially during reperfusion. Other sources of free radicals include the oxidation of monoamine neurotransmitters by monoamine oxidase and activated neutrophils that invade the CNS after trauma and hypoxaemia. Superoxide dismutase breaks the superoxide anion down to hydrogen peroxide (H2O2), which is reduced to a highly reactive hydroxyl free radical (OH). This reduction reaction is catalysed by ferrous ions. These free radicals (OH, O2) are scavenged normally by membrane-bound endogenous antioxidants, especially vitamin E. In primary cerebral injury, the increased formation of these free radicals overwhelms the endogenous defence mechanisms.
Lipid peroxidation, initiated by a chain reaction involving oxygen free radicals, produces lipid peroxyl radical that attacks unsaturated fatty acids of membrane phospholipids, forming unstable, highly reactive lipid hydroperoxide radicals. Alpha-tocopherol, an important endogenous inhibitor, limits lipid peroxidation by scavenging lipid peroxyl radicals, thus preventing the lipid radical chain reaction from occurring.
The CNS is particularly susceptible to lipid peroxidation because its membrane lipids are rich in polyunsaturated fatty acids that possess reactive hydrogen. The brain has a relatively weak antioxidant capacity relative to other organs. In addition it is rich in intracellular iron which is released during injury, and the cerebrospinal fluid (CSF) has less transferrin than plasma to bind the iron.
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History of lazaroids |
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Mechanism of action |
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The lazaroids also have potent cell membrane-stabilizing effects. They have a high affinity for the lipid bilayer and are incorporated into the lipid bilayer.38 The positively charged piperazine nitrogen in tirilazad interacts with the negatively charged phosphate-containing head groups of the membrane lipids29 (Fig. 2). The localization of the bulky 21-amino moiety towards the surface compresses the membrane phospholipid head groups. This membrane-stabilizing action restricts the movement of lipid peroxyl radicals within the membrane so that their interaction with neighbouring fatty acids is reduced, thus inhibiting lipid peroxidation.
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Pharmacodynamics |
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Pharmacokinetics |
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Side effects |
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Central nervous system trauma |
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Preventing and reducing secondary brain injury have been the main areas of CNS trauma research. In head injury, the therapeutic efficacy of the lazaroids has been focussed on their role on membrane damage resulting from free radical reactions and the disruption in cellular ionic homeostasis, with less attention to other pathophysiological mechanisms such as release of excitotoxic amino acids.
Experimental data
Head injury
Studies on functional outcome in animal models of head injury demonstrated beneficial effects of tirilazad. Mice receiving doses of tirilazad ranging from 0.003 to 30 mg kg1 at 5 min after a standard head injury were significantly better neurologically after 1 h compared with controls. Mice treated with tirilazad 1 mg kg1 at 5 min and 1 h post-injury had a survival of 78.6% at 1 week compared with 27.3% in the control group.36 Male SpragueDawley rats subjected to brain injury produced by fluid percussion over the left parietal cortex had no mortality at 48 h post-injury when tirilazad 3 mg kg1 was administered at 15 min and 3 h post-injury, compared with a mortality of 28% in control groups.57 However, in another study, rats that were hypoxic for 45 min after a standard head injury received doses of tirilazad varying from 1 to 30 mg kg1 at 3 min and 3 h after injury. Only the group receiving tirilazad at 10 mg kg1 showed significantly improved motor scores measured at 24 h after injury.69
Further studies demonstrated the beneficial effects of tirilazad on cerebral metabolic function, bloodbrain barrier permeability and cerebral oedema in animals. Tirilazad 1 mg kg1 administered to female mongrel cats 30 min after a severe unilateral cerebral contusion, with a further dose of 0.5 mg kg1 2.5 h after injury, improved the metabolic state in the neighbouring non-oedematous white matter (indicated by the glucose, lactate and glycogen concentrations).16 Oedema and the amount of metabolites in contused tissue were similar in vehicle-treated and drug-treated groups.
In a head injury model in rats, tirilazad diminished the post-traumatic increase in bloodbrain barrier permeability. Tirilazad 10 mg kg1 administered 5 min post-injury reduced parenchymal extravasation of protein-bound Evans blue at 30 min by 52%.32 Using autoradiographic techniques, tirilazad 10 mg kg1 has been shown to reduce microvascular changes in permeability when administered 5 min after head injury in rats.56 Another 21-aminosteroid, U-74389F, administered over a range of doses pre- and post-injury, reduced brain swelling in SpragueDawley rats exposed to a cryogenic brain injury.72
Spinal cord injury
Animal studies17 40 41 demonstrated that tirilazad improved functional recovery and blood flow in the white matter of the spinal cord during injury. Female mongrel cats receiving tirilazad 0.16160 mg kg1 48 h1 followed by an infusion for 42 h after a spinal cord injury had improved functional recovery 3 weeks post-injury compared with the control group.2 Tirilazad (single dose of 10 mg kg1) prevented the fall in blood flow in spinal cord white matter after a spinal cord injury in cats. Normal blood flow in the white matter of the spinal cord was reported 4 h post-injury, compared with a 63% decreased flow in the control groups.26 However, tirilazad 3 mg kg1 administered 30 min before spinal cord injury in rats, and 1.5 mg kg1 every hour after injury failed to attenuate the rise in plasma lactate and glutamate concentrations (markers of ischaemia). Most significantly, the lowering of lactate and arginine concentrations early after trauma observed with methylprednisolone pre-treatment was absent after pre-treatment with tirilazad.17
Clinical data
In a multi-centre trial evaluating tirilazad in patients with head injury,54 1120 patients received at least one dose of either tirilazad or placebo. Eighty-five percent of the patients had severe and 15% moderate head injury (Glasgow Coma Score 48). After 6 months, there was no difference in functional recovery or mortality. Subgroup analysis suggested an improvement in mortality in males with severe head injury and accompanying traumatic subarachnoid haemorrhage who received tirilazad. However, there were differences between the two groups with respect to prognostic variables such as pre-treatment hypotension, pre-treatment hypoxaemia and epidural haematoma.54
In a randomized, double-blind multi-centre trial11 investigating the efficacy of tirilazad in spinal cord injury, 499 patients with spinal cord injury diagnosed within 8 h of injury were randomized into three groups. All patients received an initial bolus of methylprednisolone 30 mg kg1. The first group received standard therapy of a methylprednisolone infusion of 5.4 mg kg1 h1 for 24 h. The second group received a similar infusion for 48 h. The tirilazad group received tirilazad (2.5 mg kg1 boluses) every 6 h for 48 h. Patients who received tirilazad had equivalent recovery rates to those patients receiving methylprednisolone for 24 h with respect to motor function changes and functional independence at 6 weeks and 6 months. However, those patients who received therapy within 38 h after injury had a significantly better outcome at 6 months (P=0.01) with a regimen of methylprednisolone for 48 h, compared with a regimen of methylprednisolone for 24 h or tirilazad for 48 h. Although the group receiving tirilazad for 48 h had fewer complications, this was not clinically or statistically significant. It was postulated that the reduced efficacy of tirilazad compared with methylprednisolone might be due to a suboptimal dosage. Further analysis showed that the patients randomized to receive tirilazad had significantly worse motor scores prior to treatment compared with the other groups.11 In conclusion, the study did not justify the use of tirilazad clinically in spinal injuries, and further studies with higher doses and longer regimes are required.
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Central nervous system ischaemia |
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Experimental data
Focal transient ischaemia
In a model of temporary hemispheric cerebral ischaemia in Mongolian gerbils, tirilazad 10 mg kg1, when administered before and after a 3-h unilateral carotid artery occlusion, significantly improved the 24 and 48 h survival, and preserved neurones in the hippocampus and lateral cortex.30 The neuroprotective mechanisms of tirilazad attenuated post-ischaemic depletion of vitamin E,70 improved post-ischaemic recovery in extracellular calcium levels,31 preserved levels of the antioxidant ascorbic acid,68 and diminished hydroxyl radical production during reperfusion.5 Tirilazad also decreased the infiltration of neutrophils into the reperfused hemisphere61 associated with reduced brain concentrations of the leukotrienes C4 and B4 post-ischaemia.6 In cats, tirilazad, administered as a series of boluses after middle cerebral artery occlusion for 1 h, reduced infarct size71 73 but had no effect when the arterial occlusion was prolonged to 90 min.22 77
In focal ischaemia, tirilazad 10 mg kg1 administered to Wistar rats 2 h before middle cerebral artery occlusion (for a 2-h period) reduced post-ischaemia infarct volume at 24 h by 67% compared with controls.83 In a similar study with male SpragueDawley rats, tirilazad administered before and after a 90-min occlusion of the middle cerebral artery reduced infarct size at 24 h by 48%, compared with controls.71 In Cynomolgous monkeys subjected to 3 h middle cerebral artery occlusion, the administration of tirilazad 3 mg kg1 10 min before reperfusion attenuated post-ischaemia brain oedema.9
Permanent focal ischaemia
As lazaroids act primarily by preventing damage caused by free radicals generated during cerebral reperfusion after a period of ischaemia, it is suggested that lazaroids are most effective in transient ischaemia and less effective in permanent ischaemia. However, there are good experimental data to support their role in therapy for permanent focal ischaemia.62
A number of studies investigating the effects of single or multiple doses of tirilazad 13 mg kg1 administered after permanent unilateral middle cerebral artery occlusion in SpragueDawley rats have reported a reduction in infarct size and oedema formation.8 53 85 A reduction in cerebral oedema, Na+ accumulation and K+ loss mainly limited to areas of the cortex adjacent to the infarct site has been demonstrated.85 In a similar rat model of permanent focal ischaemia, tirilazad significantly reduced the amount of lipid peroxidation products and free arachidonic acid in the infarcted hemisphere. The extent of ischaemic damage is significantly correlated with the concentration of these products.78 However, two studies investigating tirilazad 10 mg kg1 failed to show a protective effect in models of permanent focal ischaemia in the spontaneously hypertensive rats84 and hyperglycaemic cats.59
Tirilazad has been shown to be efficacious in two rabbit models of thromboembolic stroke. Pre- and post-treatment with tirilazad of rabbits subjected to an internal carotid arterial injection of a 3.5-cm embolus significantly reduced infarct size in the affected hemisphere.82 In the second study, microspheres were injected into the internal carotid artery until a functional deficit was produced. In this study, pre-treatment but not post-treatment with tirilazad 3 mg kg1 doubled the number of microspheres needed to produce a 50% functional deficit.15
Global cerebral ischaemia
The efficacy of tirilazad in cardiac arrest and resuscitation has been examined in animal models of global cerebral ischaemia and reperfusion. In a rat model (employing transient bilateral carotid occlusion with hypotension for 10 min), tirilazad, in doses ranging from 0.3 to 10 mg kg1 given before and after the ischaemic injury, abolished post-ischaemic increases in nitric oxide synthase and cyclic guanosine monophosphate concentrations in brain homogenates18 and reduced cortical neuronal loss.51 Another study showed that when tirilazad was given before or after ischaemia, there was a faster recovery of high-energy phosphates during early reperfusion.37 In this model, however, selectively vulnerable neurones in the hippocampus and striatum were not protected by tirilazad.8 39 51 However, the production of toxic hydroxyl radicals in the rat hippocampus during ischaemia and reperfusion is attenuated by lazaroids.86 When the duration of global ischaemia was increased to 30 min, the protective effect of tirilazad was lost.45 64
Other animal models of global ischaemia have also shown a generally positive outcome with tirilazad. In a model of incomplete cerebral ischaemia in anaesthetized dogs,55 cerebral perfusion pressure was reduced to 12 mm Hg for 30 min with an intraventricular fluid infusion. Tirilazad 1 mg kg1, administered pre- and post-ischaemia, augmented recovery of inorganic phosphate and somatosensory-evoked potentials with resolution of intracellular acidosis during reperfusion and decreased cerebral oedema.55 Tirilazad 0.252.5 mg kg1 administered only in the reperfusion stage significantly improved recovery in cerebral oxygenconsumption, cerebral blood flow, ATP and the resolution of intracellular acidosis in this dog model.47
When complete cerebral ischaemia was produced for 12 min in anaesthetized dogs by raising ICP above systemic arterial pressure with ventricular fluid infusion, functional recovery at 48 h markedly improved with tirilazad 1.5 mg kg1 given before and after ischaemia.63 However, tirilazad had no effect on the recovery of intracellular pH, oxygen consumption, somatosensory-evoked potentials and cerebral blood flow during a 3-h reperfusion phase.23
Clinical data
Clinical studies looking at the cerebroprotective efficacy of tirilazad in cerebral ischaemia have been disappointing. A large prospective double-blind, randomized trial in which 660 patients received either vehicle (control) or tirilazad 6 mg kg1 day1 for 3 days (with the first dose given within 6 h of onset of acute stroke) evaluated the outcome at 3 months after stroke.65 Tirilazad had no positive effect on the Glasgow Outcome Scale and the Barthel index of activities of daily living. The odds ratio of a favourable outcome in favour of tirilazad was 0.87 (95% confidence interval, 0.61.25) for both the Glasgow Outcome Scale and the Barthel Index. This lack of benefit might be due to inadequate dosage. A second clinical study66 using higher doses in both men (12.5 mg kg1 on day 1 and then 10 mg kg1 day1 for 2 days) and women (15 mg kg1 on day 1 then 12.5 mg kg1 day1 for 2 days) was conducted. One hundred and twenty-six patients were enrolled and matched for baseline characteristics in each treatment group. Tirilazad was associated with an absolute reduction in mortality of 14% in both sexes. However, the numbers in this study were small and the differences were not statistically significant.66 No clinical studies evaluating the role of tirilazad in cerebroprotection during cardiopulmonary resuscitation have been conducted as yet.
It is important to emphasize that the mediators of secondary damage during ischaemia and reperfusion include release of excitotoxic amino acids, free radicals and microcirculatory disturbances. Free radical damage of cell membranes is only one pathophysiological mechanism of many during reperfusion. A combination of several therapeutic modalities such as arterial pressure stabilization, glutamate antagonists and correction of tissue acidosis may significantly improve outcome.
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Subarachnoid haemorrhage |
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Experimental data
Effect on cerebral microvascular hypoperfusion
In a model of subarachnoid haemorrhage produced by injecting autologous blood into the cisternae magna of anaesthetized cats, tirilazad 0.1 mg kg1 and 1 mg kg1 administered 30 min after the insult attenuated significantly the fall in blood flow in the caudate nucleus and diminished the increase in intracranial pressure. It also attenuated the concomitant fall in mean arterial pressure and cerebral perfusion pressure.33
Effect on bloodbrain barrier permeability
Endothelial cell cultures undergo marked increase in permeability when exposed to haemolysed red cells. This was significantly attenuated by pre-treatment with tirilazad,48 indicating that free radical generation causing lipid peroxidation was a critical mechanism responsible for the increased permeability. Two studies72 87 investigating the effect of pre- and post-treatment with tirilazad on bloodbrain barrier permeability after the injection of autologous blood into the subarachnoid spaces of rats showed that tirilazad significantly attenuated the increase in permeability to albumin compared with control. Tirilazad has been shown to attenuate increased bloodbrain barrier permeability associated with subarachnoid injection of arachidonic acid and FeCl2.87
Effects on delayed cerebral vasospasm
Tirilazad is potentially beneficial in the management of delayed onset vasospasm as its action is primarily at the vascular endothelium. Lipid peroxidation plays a substantial role in cerebral vasospasm,7 which normally occurs several days after the initial subarachnoid bleed. Consequently, therapy can be started before its onset.
In a canine model of subarachnoid haemorrhage, tirilazad 0.5 mg kg1 administered every 8 h for 6 days, either as an infusion or as boluses significantly attenuated intraluminal narrowing of the basilar artery compared with control.57 Three studies43 44 75 using the Cynomolgous monkey model of subarachnoid haemorrhage have shown that tirilazad 0.33 mg kg1 administered every 8 h for 6 days post-haemorrhage, significantly reduced middle cerebral artery vasospasm. However, tirilazad did not significantly attenuate internal carotid artery and the anterior cerebral artery vasospasm. In a rabbit model, tirilazad 1 mg kg1, given 12 h before the onset of experimental subarachnoid haemorrhage completely eliminated basilar artery vasospasm (seen in the placebo group), as assessed by morphometric analysis at 48 h post-injury.79 In the same model, tirilazad administered 30 min after the onset of subarachnoid haemorrhage abolished basilar artery vasospasm as assessed by digital subtraction angiogram at 72 h.88
Vasospasm is the main treatable cause of death and disability following subarachnoid haemorrhage. Tirilazad is a potent scavenger of oxygen free radicals and an inhibitor of lipid peroxidation, which may play a central role in the development of vasospasm. However, more research is required before free radicals and reactions induced by them can be said to be the main cause of vasospasm.
Clinical data
Initial phase II trials with tirilazad in patients with subarachnoid haemorrhage were first carried out in 1995. Tirilazad was administered in doses of 0.6, 2 and 6 mg kg1 day1 i.v. for 10 days after SAH, in conjunction with nimodipine. No serious side effects were demonstrated at any of the three doses and there was a trend towards improvement in patient outcome in the 2 mg kg1 day1 group compared with the vehicle-controlled group at 3 months.24
More recently, there have been two large randomized, double-blind, controlled trials of tirilazad in patients with aneurysmal subarachnoid haemorrhage. The first involved neurosurgical centres in Europe, Australia and New Zealand, and enrolled 1023 patients. The patients were assigned randomly to receive either 0.6, 2 or 6 mg kg1 day1 of tirilazad or placebo. The patients also received nimodipine. Patients in the 6 mg kg1 day1 group had a greater frequency of good recovery on the Glasgow Coma Scale at 3 months (P=0.01) and a reduced mortality (P=0.01). There was also a reduction in symptomatic vasospasm in this group, but the difference was not statistically significant. The groups receiving 0.6 and 2 mg kg1 day1 showed no improvement. The benefits were predominantly in men.46
The second trial involved 902 patients enrolled from 54 North American neurosurgical centres. Patients were allocated randomly to three treatment groups, receiving either vehicle (control), 2 or 6 mg kg1 day1 tirilazad beginning within 48 h of a SAH and continued for 10 days. At 3 months, there was no significant difference in Glasgow Coma Score, mortality or employment status between the groups. There was also no significant difference in the incidence of vasospasm between the groups. When the mortality data were stratified according to gender and neurological grade on admission, men with grades IV and V in the 6 mg kg1 day1 group had a mortality of 5% compared with 33% in the control group, but this was not statistically significant (P=0.03).25 The difference between the findings of the trials could be explained by differences in admission characteristics or management protocols, including the use of anticonvulsant medications.
A further study looked at 31 women with SAH allocated randomly to receive either vehicle or 15 mg kg1 day1 tirilazad for 10 days, and looked at more sensitive neuropsychological and psychosocial outcomes.60 There was no difference in 3-month Glasgow Coma Scale or mortality in the two groups, although the tirilazad group showed less impairment of concentration, sustained attention and psychomotor speed (P<0.02), and debilitating fatigue (P<0.01). However, this study group is too small to make any conclusions and the results would have to be confirmed with larger patient groups.
A prospective double-blind, vehicle-controlled study49 of high-dose tirilazad in 819 women with aneurysmal SAH randomized to receive 15 mg kg1 tirilazad or placebo was conducted at 56 neurosurgical centres in Europe, Australia, New Zealand and South Africa, and concluded that high-dose tirilazad significantly reduced the incidence of symptomatic vasospasm from 33.3% in the placebo group to 24.8% in patients treated with tirilazad. However, there was no difference in the 3-month mortality rate. The more frequent use of other potentially effective rescue therapy (hypervolaemia, haemodilution and induced hypertension) in the placebo group (33.3%) compared with the tirilazad-treated patients (24.8%) may have been responsible for these contrasting observations between the two groups. In North America, a double-blind randomized study in women involving 832 patients50 found that high-dose tirilazad 15 mg kg1 day1 significantly reduced the mortality from 43.4% to 24.6% among patients who were neurological grade IV or V on admission, confirming the beneficial effect observed in male patients in previous studies.25 46 These latest findings may influence future management of high-grade cerebral aneurysms.
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Discussion |
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Experimental evidence in animal models of head injury, spinal cord injury, stroke and subarachnoid haemorrhage indicates that tirilazad obtunds secondary injury phenomena, promotes neurological recovery and improves outcome in these conditions. However, the evidence of the efficacy of tirilazad from phase III clinical trials is far from conclusive.
In the management of head trauma only one large clinical trial54 has been carried out and showed no improvement in outcome. In spinal cord injury a 48-h infusion of tirilazad following an initial bolus of methylprednisolone was as effective as the established 24 h therapy with methylprednisolone.11 However, tirilazad did not produce any additional benefit over standard steroid therapy either in terms of improved neurological outcome or in a lower rate of serious long-term complications. In addition, patients treated for 48 h with methylprednisolone or tirilazad commenced 38 h post-injury had a better outcome with methylprednisolone compared with tirilazad. The only large phase III trial in stroke patients showed no improvement in outcome with tirilazad.65 In subarachnoid haemorrhage, a large phase III trial showed an improvement in outcome with 6 mg kg1 day1 tirilazad administered for 10 days.46 The effect was most marked in men in whom mortality was reduced from 20 to 6%. However, a second American study25 failed to show any significant benefit with tirilazad, although there was a trend towards a better outcome in men with grade IVV subarachnoid haemorrhage. However, two recent studies utilizing a high-dose (15 mg kg1 day1) regimen of tirilazad concluded that there was a significant reduction in both the incidence of vasospasm and the mortality rate among women with aneurysmal subarachnoid haemorrhage.
Two possible conclusions can be drawn from the disparity between the beneficial effects of tirilazad in pre-clinical animal studies compared with clinical trials. Firstly it may well be that tirilazad is ineffective as a cerebroprotectant after CNS injury in humans. It may be wrong to extrapolate the results of pre-clinical trials to humans because of controversy regarding the applicability of the animal model to human injury, the reproducibility of the model, and different responses of animals and humans to different drugs. The lazaroids do have limitations. Lipid peroxidation is only one of a number of biological mechanisms involved in the secondary injury, and other destructive secondary processes initiated by the primary insult such as the release of excitatory amino acid neurotransmitters and the loss of intracellular calcium homeostasis occur. The prevention of lipid peroxidation alone therefore may be ineffective in reducing the secondary injury. The poor penetration of the bloodbrain barrier of the lazaroids and its localization in the vascular membrane may significantly limit their efficacy. Their ability to prevent lipid peroxidation may be dependent upon administration within minutes of the primary insult, something rarely possible in the clinical situation. It is notable that in the experimental studies the first dose of tirilazad was often administered within minutes of the primary insult, and in some studies the first dose was given pre-injury. However, in the clinical studies looking at spinal cord injury11 and stroke,65 approximately half the patients received their first dose of tirilazad more than 3 h post-injury, and this could contribute to the apparent lack of clinical efficacy.
However, the lack of efficacy of tirilazad in a number of clinical studies may have resulted from weaknesses within those studies. In the phase III study54 looking at the effect of tirilazad compared with placebo in 1120 patients with head injuries, it was noted that there was a marked imbalance between the groups concerning the basic prognostic variables such as hypoxaemia and hypotension. It was also noted that there was a trend towards improved outcome in the small subgroup of patients with severe head injury associated with traumatic subarachnoid haemorrhage. It may be that a further study, using an alternate method of randomization and targeting populations with a higher risk of morbidity and mortality, would show an improved outcome with tirilazad.
It has also been suggested that the range of doses of tirilazad used in all these clinical studies (210 mg kg1 day1) may be suboptimal, and the findings of the two important studies49 50 of high-dose tirilazad in women with aneurysmal subarachnoid haemorrhage support this hypothesis. It may also explain the frequent finding that the beneficial effects of tirilazad are limited to men, in whom metabolism of the steroid moiety of tirilazad is less efficient compared with women. In the large phase III clinical study looking at tirilazad (6 mg kg1 day1 for 3 days) in stroke patients there was no improvement in outcome. However, a second smaller study looking at larger doses (1015 mg kg1 day1 for 3 days) did show a reduction in mortality of 14%, although the study group was too small to make the difference significant. In the two large studies looking at the efficacy of tirilazad in the treatment of subarachnoid haemorrhage, one European, Australian and New Zealand study46 has shown a marked improvement in outcome for men, whereas a second North American study25 showed no difference in outcome. In the North American trial more than 80% of patients were on anticonvulsants, compared with 50% of patients in the first trial. The increased elimination of tirilazad caused by enzyme-inducing anti-convulsants could have resulted in lower blood concentrations of the study drug in North American patients. Higher doses of the drug might have obviated the gender difference in the European study and improved the results in the North American study. Recent multicentre studies of high-dose (15 mg kg1 day1) tirilazad in women have indeed shown a significant reduction in the incidence of vasospasm associated with aneurysmal subarachnoid haemorrhage and the mortality in patients who were neurological grade IV or V on admission. These findings may well influence future treatment of high-grade cerebral aneurysms.
At the present time, the clinical evidence available is not strong enough to justify the routine use of tirilazad in the management of CNS trauma, ischaemia or subarachnoid haemorrhage. However, further studies using larger doses of tirilazad may show significant efficacy.49 50 There is also increasing interest in using tirilazad in combination with thrombolytic agents in the management of ischaemic strokes.74 Finally, there are now early animal studies investigating the pyrrolopyrimidines,28 a group of antioxidants that have improved penetration of the bloodbrain barrier and gain direct access to neural tissue.
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