The discovery that a main neuroprotective function of MP is due to its lipid peroxidase action instead of its glucocorticoid receptor action initiated the development of steroid analogues that were mechanistically similar but did not cause associated side-effects. One such drug, tirilazad mesylate, was especially effective for recovering neural function in spinal cord injured animal models (e.g. Anderson et al. 1988; Hall 1988; Holtz & Gerdin 1991, 1992). Like MP, tirilazad mesylate inhibits lipid peroxidation and stabilizes neuronal membranes by scavenging oxygen free radicals. Tirilazad mesylate incorporates into the membrane lipid bilayer, where it restricts the movement of free oxygen radicals and prevents them from spreading to neighbouring nerves (Kavanagh & Kam 2001). In a large RCT of tirilazad mesylate used in head injured individuals, this pharmaceutical agent was shown to have no effect on recovery after six months compared to placebo (Marshall et al. 1998). Only one clinical trial has examined the effectiveness of tirilazad mesylate in acute SCI (Bracken et al. 1997), where its neuroprotective benefits were compared to those of MP.
|Bracken et al. (1997)
|Population: Mean age: not specified; Gender: male=85%, female=15%; Level of injury: not specified; Severity of injury: complete=50%, incomplete=50%.
Treatment: Patients were randomly assigned to receive either tirilazad mesylate for 48 hr (2.5 mg/kg), methylprednisolone (MP) for 24 hr (5.4 mg/kg), or MP for 48 hr (5.4 mg/kg). All treatment groups initially received a bolus of MP (30 mg/kg). The 24 hr MP group served as the reference; there was no placebo group.
Outcome Measures: The following after 6 weeks and 6 months: motor function, sensory function (pinprick, light touch, deep pain), adverse event outcomes.
The following after 6 months: Functional Independence Measure (FIM).
Chronicity: Individuals received the study treatment within 8 hr of sustaining injury.
- Patients who received tirilazad mesylate recovered motor function at rates similar to or slightly higher than patients who received 24 hr MP (p>0.05).
- Patients who received tirilazad mesylate did not achieve significantly higher FIM scores compared to patients who received 24 hr MP 6 weeks (p=0.27) and 6 months (p=0.15) after injury.
- There were no significant differences in sensory function (pinprick, light touch, deep pain) among patients who received any of the treatments at 6 weeks or 6 months post injury (p>0.05 in all cases).
- Patients who received tirilazad mesylate or 24 hr MP experienced significantly less severe pneumonia after 6 weeks than patients who received 48 hr MP (p=0.02).
|Bracken et al. (1998)
(One year follow up to Bracken et al. 1997)
|Outcome Measures: The following after 1 year: motor function, sensory function (pinprick and light touch), Functional Independence Measure (FIM).
- Patients who received tirilazad mesylate recovered motor function at rates similar to patients who received 24 hr MP (p>0.05).
- There were no significant differences in FIM scores across any of the treatment groups (p>0.05).
- Patients who received tirilazad mesylate and 48 hr MP experienced more deaths from pneumonia, respiratory distress syndrome, and respiratory failure compared to patients who received 24 hr MP, however this difference was not significant (p=0.056).
- Urinary tract infections were significantly more common in patients who received 48 hr tirilazad mesylate compared to patients who received MP (p=0.01).
Analyses of patients treated within 3 hr compared to patients treated between 3-8 hr:
- Patients who received any treatment within 3 hr did not differ significantly in motor function (p>0.05).
Analyses of Severity of the Injury (complete vs. incomplete):
- The authors note that patients with incomplete injuries experienced more motor function recovery than patients with complete injuries (data not shown).
At present, there have been no studies comparing acute SCI individuals who received tirilazad mesylate to those who received a placebo. The only study involving this drug to date was conducted by Bracken et al. (1997) that compared a long-term and short-term dose of MP to a long term dose of tirilazad mesylate. In this study, tirilazad mesylate exhibited the same effectiveness as a short-term dose of MP and was also associated with significantly higher rates of complications (Bracken et al. 1998).
There is level 1b evidence (from one RCT: Bracken et al. 1997) that tirilazad mesylate is no more effective than methylprednisolone in promoting neurological recovery in acute SCI individuals.