The role of pharmacotherapy in modifying the neurological status of patients with spinal and spinal cord injuries (original) (raw)
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Pathophysiology and pharmacologic treatment of acute spinal cord injury
Spine Journal, 2004
The past three decades have witnessed increasing interest in strategies to improve neurologic function after spinal cord injury. As progress is made in our understanding of the pathophysiologic events that occur after acute spinal cord injury, neuroprotective agents are being developed.Clinicians who treat acute spinal cord injuries should have a basic understanding of the pathophysiologic processes that are initiated after the spinal cord has been injured. A familiarity with the literature on which the current use of methylprednisolone is based is also essential.Literature review.Literature review of animal data on pathophysiologic mechanisms, and of both animal and human trials of neuroprotective agents.The mechanical forces imparted to the spinal cord cause primary damage to the neural tissue, but a complex cascade of pathophysiologic processes that imperil adjacent, initially spared tissue to secondary damage rapidly follows this. Attenuating this secondary damage with neuroprotective strategies requires an understanding of these pathophysiologic processes. Many researchers are investigating the role of such processes as ischemia, inflammation, ionic homeostasis and apoptotic cell death in the secondary injury cascade, with hopes of developing specific therapies to diminish their injurious effects. Beyond methylprednisolone, a number of other pharmacologic treatments have been investigated for the acute treatment of spinal cord injury, and even more are on the horizon as potential therapies.This review summarizes some of the important pathophysiologic processes involved in secondary damage after spinal cord injury and discusses a number of pharmacologic therapies that have either been studied or have future potential for this devastating injury.
Methylprednisolone therapy in acute spinal cord injuries
Srpski medicinski casopis Lekarske komore, 2021
Spinal cord injuries represent a major challenge in terms of current concepts of treatment. This condition is frequently associated with long term therapy in addition to a greater incidence of early and late complications. The goal of treatment is to alleviate pressure on the spinal cord caused by hematomas or bone fragments, in the shortest time possible. Hence, surgical decompression of the spinal cord is the first line of treatment, in cases where this approach is indicated. Apart from invasive methods, treatment also consists of the use of various pharmacological agents, whose therapeutic goal is to decrease edema and inflammation, especially in the first several days following injury. One of the most commonly administered drugs in such cases is methylprednisolone, however, controversy with regards to the timing of its administration and proper dosing, still exists. This drug has been in use for decades in the treatment of spinal cord injuries with various protocols having been ...
New pharmacologic approaches to acute spinal cord injury
… : The Journal of Human …, 1996
The incidence of spinal cord injury (SCI) in the United States is approximately 10,000 new cases per year. Strategies to prevent injury or salvage a few dermatomal levels may have significant effects on outcome. Several pharmacologic agents have been evaluated for their efficacy in patients with acute SCI. Methylprednisolone, when administered early, was the first drug to show significant improvement in outcome and is a standard of comparison for future agents. Several new drugs show promising results in animal models of SCI, with more extensive human trials currently under way. Results of more well-controlled clinical trials are necessary ts determine which agents have significant neurologic benefits.
Methylprednisolone and neurological function 1 year after spinal cord injury
Journal of Neurosurgery, 1985
✓ A multi-center double-blind randomized clinical trial was conducted by the National Acute Spinal Cord Injury Study Group to examine the efficacy of high-dose methylprednisolone (1000-mg bolus and 1000 mg daily thereafter for 10 days) compared with that of a standard dose (100-mg bolus and 100 mg daily for 10 days). No significant difference was observed in neurological recovery of motor function, pinprick response, or touch sensation 1 year after injury between the two treatment groups, after adjustment for other potentially confounding factors. Analyses that specifically took into account the patients' total steroid dose and relative weight confirmed the lack of a steroid treatment effect. The case fatality rate was 10.7% during the 1st year after injury, and this was not associated with the steroid treatment protocol or the patient's gender. Deaths did occur significantly more frequently among patients who were completely (15.3%) and partially (8.6%) plegic than among th...
JAMA: The Journal of the American Medical Association, 1997
; for the National Acute Spinal Cord Injury Study Objective.\p=m-\Tocompare the efficacy of methylprednisolone administered for 24 hours with methyprednisolone administered for 48 hours or tirilazad mesylate administered for 48 hours in patients with acute spinal cord injury. Design.\p=m-\Double-blind, randomized clinical trial. Setting.\p=m-\Sixteen acute spinal cord injury centers in North America. Patients.\p=m-\Atotal of 499 patients with acute spinal cord injury diagnosed in National Acute Spinal Cord Injury Study (NASCIS) centers within 8 hours of injury. Intervention.\p=m-\All patients received an intravenous bolus of methylprednisolone (30 mg/kg) before randomization. Patients in the 24-hour regimen group (n=166) received a methylprednisolone infusion of 5.4 mg/kg per hour for 24 hours, those in the 48-hour regimen group (n=167) received a methylprednisolone infusion of 5.4 mg/kg per hour for 48 hours, and those in the tirilazad group (n=166) received a 2.5 mg/kg bolus infusion of tirilazad mesylate every 6 hours for 48 hours. Main Outcome Measures.\p=m-\Motorfunction change between initial presentation and at 6 weeks and 6 months after injury, and change in Functional Independence Measure (FIM) assessed at 6 weeks and 6 months. Results.\p=m-\Compared with patients treated with methylprednisolone for 24 hours, those treated with methylprednisolone for 48 hours showed improved motor recovery at 6 weeks (P=.09) and 6 months (P=.07) after injury. The effect of the 48-hour methylprednisolone regimen was significant at 6 weeks (P=.04) and 6 months (P=.01) among patients whose therapy was initiated 3 to 8 hours after injury. Patients who received the 48-hour regimen and who started treatment at 3 to 8 hours were more likely to improve 1 full neurologic grade (P=.03) at 6 months, to show more improvement in 6-month FIM (P=.08), and to have more severe sepsis and severe pneumonia than patients in the 24-hour methylprednisolone group and the tirilazad group, but other complications and mortality (P=.97) were similar. Patients treated with tirilazad for 48 hours showed motor recovery rates equivalent to patients who received methylprednisolone for 24 hours. Conclusions.\p=m-\Patientswith acute spinal cord injury who receive methylprednisolone within 3 hours of injury should be maintained on the treatment regimen for 24 hours. When methylprednisolone is initiated 3 to 8 hours after injury, patients should be maintained on steroid therapy for 48 hours.
Neuroprotection and acute spinal cord injury: A reappraisal
NeuroRX, 2004
It has long been recognized that much of the posttraumatic degeneration of the spinal cord following injury is caused by a multi-factorial secondary injury process that occurs during the first minutes, hours, and days after spinal cord injury (SCI). A key biochemical event in that process is reactive oxygeninduced lipid peroxidation (LP). In 1990 the results of the Second National Acute Spinal Cord Injury Study (NASCIS II) were published, which showed that the administration of a high-dose regimen of the glucocorticoid steroid methylprednisolone (MP), which had been previously shown to inhibit post-traumatic LP in animal models of SCI, could improve neurological recovery in spinal-cord-injured humans. This resulted in the registration of high-dose MP for acute SCI in several countries, although not in the U.S. Nevertheless, this treatment quickly became the standard of care for acute SCI since the drug was already on the U.S. market for many other indications. Subsequently, it was demonstrated that the non-glucocorticoid 21-aminosteroid tirilazad could duplicate the antioxidant neuroprotective efficacy of MP in SCI models, and evidence of human efficacy was obtained in a third NASCIS trial (NASCIS III). In recent years, the use of high-dose MP in acute SCI has become controversial largely on the basis of the risk of serious adverse effects versus what is perceived to be on average a modest neurological benefit. The opiate receptor antagonist naloxone was also tested in NASCIS II based upon the demonstration of its beneficial effects in SCI models. Although it did not a significant overall effect, some evidence of efficacy was seen in incomplete (i.e., paretic) patients. The monosialoganglioside GM1 has also been examined in a recently completed clinical trial in which the patients first received high-dose MP treatment. However, GM1 failed to show any evidence of a significant enhancement in the extent of neurological recovery over the level afforded by MP therapy alone. The present paper reviews the past development of MP, naloxone, tirilazad, and GM1 for acute SCI, the ongoing MP-SCI controversy, identifies the regulatory complications involved in future SCI drug development, and suggests some promising neuroprotective approaches that could either replace or be used in combination with high-dose MP.
Turkish Neurosurgery, 2015
AIm: To evaluate the neuroprotective effects of adalimumab in an experimental spinal cord injury model and compare them with those of the widely-used methylprednisolone. mATERIAl and mEThODS: Forty male Wistar rats were divided into 5 as the sham, trauma, adalimumab, methylprednisolone, and adalimumab+methylprednisolone groups. Only laminectomy was performed in the sham group. Laminectomy and trauma was performed to the trauma group but no treatment was given. A single dose of 40 mg/kg subcutaneous adalimumab was administered after the laminectomy and trauma to group 3. A single dose of intravenous 30 mg/kg methylprednisolone was administered right after laminectomy and trauma to group 4. Single doses of 40 mg/kg adalimumab and 30 mg/kg methylprednisolone were administered together after laminectomy and trauma to group 5. Serum malondialdehyde (MDA), TNF-α, IL-1β and IL-6 levels were measured and sections were obtained for histopathological study at the end of the 7 th day. RESulTS: MDA, TNF-α, IL-1β and IL-6 levels in serum were significantly decreased in the adalimumab group with clinical and histopathological improvement not less than the methylprednisolone group. The serum MDA levels were similar when the two drugs were given together or separately but there was a statistically quite significant decrease in TNF-α, IL-1β and IL-6 levels with concurrent use. Statistically significantly better results were obtained on histopathological evaluation with the use of both drugs together. COnCluSIOn: This study revealed that adalimumab is as effective as methylprednisolone in compressive spinal cord injury in rats.
Animal Studies in Spinal Cord Injury: A Systematic Review of Methylprednisolone
Alternatives to Laboratory Animals, 2009
The objective of this study was to examine whether animal studies can reliably be used to determine the usefulness of methylprednisolone (MP) and other treatments for acute spinal cord injury (SCI) in humans. This was achieved by performing a systematic review of animal studies on the effects of MP administration on the functional outcome of acute SCI. Data were extracted from the published articles relating to: outcome; MP dosing regimen; species/strain; number of animals; methodological quality; type of injury induction; use of anaesthesia; functional scale used; and duration of follow-up. Subgroup analyses were performed, based on species or strain, injury method, MP dosing regimen, functional outcome measured, and methodological quality. Sixty-two studies were included, which involved a wide variety of animal species and strains. Overall, beneficial effects of MP administration were obtained in 34% of the studies, no effects in 58%, and mixed results in 8%. The results were inco...
Medical treatments of acute spinal cord injury
Journal of Neurology, Neurosurgery & Psychiatry, 1992
Medical treatments of acute spinal cord injury In the past three decades, advances in medical care have greatly increased survival and longevity of spinal-injured patients without improving neurological recovery. The second National Acute Spinal Cord Injury Study (NASCIS 2) changed this trend in 1990 by showing that methylprednisolone (MP) significantly improved motor and sensory recovery of spinal-injured patients compared with placebo-treatment.' I shall summarise some lessons from the first trial (NASCIS 1) preceding NASCIS 2, describe the findings, discuss some controversial aspects of NASCIS 2, assess the impact of NASCIS 2 on spinal cord injury (SCI) research and care, and describe some promising new treatments. NASCIS 1 MP is a synthetic glucocorticoid drug that has long been used by neurosurgeons to treat brain oedema. The doses used (100-1000 mg/day) greatly exceeded those necessary for the drug to act as a glucocorticoid. At doses of 1000 mg/day, MP may be working as antioxidant or free radical scavenger at high doses23 NASCIS 1 began in 1979 to compare neurological recovery patterns of spinal-injured patients treated with "high dose" MP (1000 mg bolus followed by 1000 mg/day for 10 days) or "low dose" MP (100 mg bolus followed by 100 mg/day for 10 days). Between 1980-84, NASCIS 1 randomised 330 spinal-injured patients to the "high" and "low" dose MP treatments within 48 hours of injury. At 6 months4 and one year' after injury, the two treatment groups did not differ significantly from each other in any respect, save a slight trend for increased wound infections in the MP-treated group. By 1985, however, data from several animal