Longitudinal Impact of Acute Spinal Cord Injury on Clinical Pharmacokinetics of Riluzole, a Potential Neuroprotective Agent.
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SUBMITTER: Nguyen A
PROVIDER: S-EPMC8457124 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Spinal cord injury (SCI) is a devastating event resulting in permanent loss of neurological function. To date, effective therapies for SCI have not been established. With recent progress in neurobiology, however, there is hope that drug administration could improve outcomes after SCI. Riluzole is a benzothiazole anticonvulsant with neuroprotective effects. It has been approved by the U.S. Food and Drug Administration as a safe and well-tolerated treatment for patients with amyotrophic lateral sclerosis. The mechanism of action of riluzole involves the inhibition of pathologic glutamatergic transmission in synapses of neurons via sodium channel blockade. There is convincing evidence that riluzole diminishes neurological tissue destruction and promotes functional recovery in animal SCI models. Based on these results, a phase I/IIa clinical trial with riluzole was conducted for patients with SCI between 2010 and 2011. This trial demonstrated significant improvement in neurological outcomes and showed it to be a safe drug with no serious adverse effects. Currently, an international, multi-center clinical trial (Riluzole in Acute Spinal Cord Injury Study: RISCIS) in phase II/III is in progress with riluzole for patients with SCI (clinicaltrials.gov, registration number NCT01597518). This article reviews the pharmacology and neuroprotective mechanisms of riluzole, and focuses on existing preclinical evidence, and emerging clinical data in the treatment of SCI.
| S-EPMC6272473 | biostudies-literature
Project description:BackgroundGlyburide (also known as glibenclamide) is effective in reducing the severity of tissue destruction and improving functional outcome after experimental spinal cord injury in rodents and so has promise as a therapy in humans. There are many important differences between spinal cord injury in experimental animals and in human clinical cases, making it difficult to introduce new therapies into clinical practice. Spinal cord injury is also common in pet dogs and requires new effective therapies, meaning that they can act as a translational model for the human condition while also deriving direct benefits from such research. In this study we investigated the pharmacokinetics and safety of glyburide in dogs with clinical spinal cord injury.MethodsWe recruited dogs that had incurred an acute thoracolumbar spinal cord injury within the previous 72 h. These had become acutely non-ambulatory on the pelvic limbs and were admitted to our veterinary hospitals to undergo anesthesia, cross sectional diagnostic imaging, and surgical decompression. Oral glyburide was given to each dog at a dose of 75 mcg/kg. In five dogs, we measured blood glucose concentrations for 10 h after a single oral dose. In six dogs, we measured serum glyburide and glucose concentrations for 24 h and estimated pharmacokinetic parameters to estimate a suitable dose for use in a subsequent clinical trial in similarly affected dogs.ResultsNo detrimental effects of glyburide administration were detected in any participating dog. Peak serum concentrations of glyburide were attained at a mean of 13 h after dosing, and mean apparent elimination half-life was approximately 7 h. Observed mean maximum plasma concentration was 31 ng/mL. At the glyburide dose administered there was no observable association between glyburide and glucose concentrations in blood.DiscussionOur data suggest that glyburide can be safely administered to dogs that are undergoing anesthesia, imaging and surgery for treatment of their acute spinal cord injury and can attain clinically-relevant serum concentrations without developing hazardous hypoglycemia. Serum glyburide concentrations achieved in this study suggest that a loading dose of 150 mcg/kg followed by repeat doses of 75 mcg/kg at 8-hourly intervals would lead to serum glyburide concentrations of 25-50 ng/mL within an acceptably short enough period after oral administration to be appropriate for a clinical trial in canine spinal cord injury.
| S-EPMC5831157 | biostudies-literature
Project description:Objective: In spinal cord injury (SCI), heterotopic ossification is a frequent secondary complication, commonly associated with limited range of motion of affected joints, which could lead to secondary disability in activities of daily living. Additionally, heterotopic ossifications might challenge the effect of regeneration-promoting therapies on neurological and functional recovery. This study evaluated the impact of heterotopic ossification on clinical recovery within the first year after SCI. Methods: The study was conducted as a monocentric longitudinal paired cohort study. Recruitment was based on consecutive sampling in the framework of the European Multicenter about Spinal Cord Injury (EMSCI). Recovery profiles were determined using standardized neurological and functional clinical assessments within the 1st year following SCI. All study participants underwent at least two comprehensive standardized neurological and functional clinical examinations according to the International Standards for Neurological Classification of SCI and the Spinal Cord Independence Measure, respectively. Data regarding the diagnosis and treatment of heterotopic ossification were obtained by reviewing the patient medical records. The most similar "digital twin" from the entire EMSCI database were matched in terms of age, acute neurological and functional status to each individual with SCI, and heterotopic ossification. Results: Out of 25 participants diagnosed with heterotopic ossification, 13 individuals were enrolled and matched to control individuals. Most individuals presented with motor complete injury (75%). Ossifications were most frequently located at the hip joints (92%) and mainly occurred within the first 3 months after SCI. Individuals with heterotopic ossification achieved around 40% less functional improvement over time compared to their matched counterparts, whereas neurological recovery was not altered in individuals with SCI and heterotopic ossification. Conclusion: Heterotopic ossification-a common complication of SCI-unfavorably affects functional recovery, which in the end is most relevant for the best possible degree of independence in activities of daily living. Upon presentation with heterotopic ossification, neurological improvement achieved through potential restorative therapies might not translate into clinically meaningful functional improvement. Diagnostic algorithms and effective early prevention/treatment options for heterotopic ossification need to be established to ensure the best possible functional outcome. Clinical Trial Registration: NCT01571531 (https://clinicaltrials.gov).
| S-EPMC8864137 | biostudies-literature
Project description:Spinal cord injury (SCI) is a devastating condition that affects approximately 11,000 patients each year in the United States. Although a significant amount of research has been conducted to clarify the pathophysiology of SCI, there are limited therapeutic interventions that are currently available in the clinic. Moderate hypothermia has been used in a variety of experimental and clinical situations to target several neurological disorders, including traumatic brain and SCI. Recent studies using clinically relevant animal models of SCI have reported the efficacy of therapeutic hypothermia (TH) in terms of promoting long-term behavioral improvement and reducing histopathological damage. In addition, several clinical studies have demonstrated encouraging evidence for the use of TH in patients with a severe cervical spinal cord injury. Moderate hypothermia (33°C) introduced systemically by intravascular cooling strategies appears to be safe and provides some improvement of long-term recovery of function. TH remains an experimental clinical approach and randomized multicenter trials are needed to critically evaluate this potentially exciting therapeutic intervention targeting this patient population.
| S-EPMC3101829 | biostudies-other
Project description:One of the most investigated molecular mechanisms involved in the secondary pathophysiology of acute spinal cord injury (SCI) is free radical-induced, iron-catalyzed lipid peroxidation (LP) and protein oxidative/nitrative damage to spinal neurons, glia, and microvascular cells. The reactive nitrogen species peroxynitrite and its highly reactive free radicals are key initiators of LP and protein nitration in the injured spinal cord, the biochemistry, and pathophysiology of which are first of all reviewed in this article. This is followed by a presentation of the antioxidant mechanistic approaches and pharmacological compounds that have been shown to have neuroprotective properties in preclinical SCI models. Two of these, which act by inhibition of LP, are high-dose treatment with the glucocorticoid steroid methylprednisolone (MP) and the nonglucocorticoid 21-aminosteroid tirilazad, have been demonstrated in the multicenter NASCIS clinical trials to produce at least a modest improvement in neurological recovery when administered within the first 8 hours after SCI. Although these results have provided considerable validation of oxidative damage as a clinically practical neuroprotective target, there is a need for the discovery of safer and more effective antioxidant compounds for acute SCI.
| S-EPMC3101837 | biostudies-other
Project description:A prospective, multicenter phase I trial was undertaken by the North American Clinical Trials Network (NACTN) to investigate the pharmacokinetics and safety of, as well as obtain pilot data on, the effects of riluzole on neurological outcome in acute spinal cord injury (SCI). Thirty-six patients, with ASIA impairment grades A-C (28 cervical and 8 thoracic) were enrolled at 6 NACTN sites between April 2010 and June 2011. Patients received 50?mg of riluzole PO/NG twice-daily, within 12?h of SCI, for 14 days. Peak and trough plasma concentrations were quantified on days 3 and 14. Peak plasma concentration (Cmax) and systemic exposure to riluzole varied significantly between patients. On the same dose basis, Cmax did not reach levels comparable to those in patients with amyotrophic lateral sclerosis. Riluzole plasma levels were significantly higher on day 3 than on day 14, resulting from a lower clearance and a smaller volume of distribution on day 3. Rates of medical complications, adverse events, and progression of neurological status were evaluated by comparison with matched patients in the NACTN SCI Registry. Medical complications in riluzole-treated patients occurred with incidences similar to those in patients in the comparison group. Mild-to-moderate increase in liver enzyme and bilirubin levels were found in 14-70% of patients for different enzymes. Three patients had borderline severe elevations of enzymes. No patient had elevated bilirubin on day 14 of administration of riluzole. There were no serious adverse events related to riluzole and no deaths. The mean motor score of 24 cervical injury riluzole-treated patients gained 31.2 points from admission to 90 days, compared to 15.7 points for 26 registry patients, a 15.5-point difference (p=0.021). Patients with cervical injuries treated with riluzole had more-robust conversions of impairment grades to higher grades than the comparison group.
| S-EPMC3904533 | biostudies-literature
Project description:Riluzole is a sodium-glutamate antagonist that attenuates neurodegeneration in amyotrophic lateral sclerosis (ALS). It has shown favorable results in promoting recovery in pre-clinical models of traumatic spinal cord injury (tSCI) and in early phase clinical trials. This study aimed to evaluate the efficacy and safety of riluzole in acute cervical tSCI. An international, multi-center, prospective, randomized, double-blinded, placebo-controlled, adaptive, Phase III trial (NCT01597518) was undertaken. Patients with American Spinal Injury Association Impairment Scale (AIS) A-C, cervical (C4-C8) tSCI, and <12 h from injury were randomized to receive either riluzole, at an oral dose of 100 mg twice per day (BID) for the first 24 h followed by 50 mg BID for the following 13 days, or placebo. The primary efficacy end-point was change in Upper Extremity Motor (UEM) scores at 180 days. The primary efficacy analyses were conducted on an intention to treat (ITT) and completed cases (CC) basis. The study was powered at a planned enrolment of 351 patients. The trial began in October 2013 and was halted by the sponsor on May 2020 (and terminated in April 2021) in the face of the global COVID-19 pandemic. One hundred ninety-three patients (54.9% of the pre-planned enrolment) were randomized with a follow-up rate of 82.7% at 180 days. At 180 days, in the CC population the riluzole-treated patients compared with placebo had a mean gain of 1.76 UEM scores (95% confidence interval: -2.54-6.06) and 2.86 total motor scores (CI: -6.79-12.52). No drug-related serious adverse events were associated with the use of riluzole. Additional pre-planned sensitivity analyses revealed that in the AIS C population, riluzole was associated with significant improvement in total motor scores (estimate: standard error [SE] 8.0; CI 1.5-14.4) and upper extremity motor scores (SE 13.8; CI 3.1-24.5) at 6 months. AIS B patients had higher reported independence, measured by the Spinal Cord Independence Measure score (45.3 vs. 27.3; d: 18.0 CI: -1.7-38.0) and change in mental health scores, measured by the Short Form 36 mental health domain (2.01 vs. -11.58; d: 13.2 CI: 1.2-24.8) at 180 days. AIS A patients who received riluzole had a higher average gain in neurological levels at 6 months compared with placebo (mean 0.50 levels gained vs. 0.12 in placebo; d: 0.38, CI: -0.2-0.9). The primary analysis did not achieve the predetermined end-point of efficacy for riluzole, likely related to insufficient power. However, on pre-planned secondary analyses, all subgroups of cervical SCI subjects (AIS grades A, B and C) treated with riluzole showed significant gains in functional recovery. The results of this trial may warrant further investigation to extend these findings. Moreover, guideline development groups may wish to assess the possible clinical relevance of the secondary outcome analyses, in light of the fact that SCI is an uncommon orphan disorder without an accepted neuroprotective treatment.
| S-EPMC10460693 | biostudies-literature
Project description:We have previously shown that induction of ketosis by ketogenic diet (KD) conveyed neuroprotection following spinal cord injury in rodent models, however, clinical translation may be limited by the slow raise of ketone levels when applying KD in the acute post-injury period. Thus we investigated the use of exogenous ketone supplementation (ketone sodium, KS) combined with ketogenic diet as a means rapidly inducing a metabolic state of ketosis following spinal cord injury in adult rats. In uninjured rats, ketone levels increased more rapidly than those in rats with KD alone and peaked at higher levels than we previously demonstrated for the KD in models of spinal cord injury. However, ketone levels in KD + KS treated rats with SCI did not exceed the previously observed levels in rats treated with KD alone. We still demonstrated neuroprotective effects of KD + KS treatment that extend our previous neuroprotective observations with KD only. The results showed increased neuronal and axonal sparing in the dorsal corticospinal tract. Also, better performance of forelimb motor abilities were observed on the Montoya staircase (for testing food pellets reaching) at 4 and 6 weeks post-injury and rearing in a cylinder (for testing forelimb usage) at 6 and 8 weeks post-injury. Taken together, the findings of this study add to the growing body of work demonstrating the potential benefits of inducing ketosis following neurotrauma. Ketone salt combined with a ketogenic diet gavage in rats with acute spinal cord injury can rapidly increase ketone body levels in the blood and promote motor function recovery. This study was approved by the Animal Care Committee of the University of British Columbia (protocol No. A14-350) on August 31, 2015.
| S-EPMC7513973 | biostudies-literature
Project description:Excess glutamate release and associated neurotoxicity contributes to cell death after spinal cord injury (SCI). Indeed, delayed administration of glutamate receptor antagonists after SCI in rodents improves tissue sparing and functional recovery. Despite their therapeutic potential, most glutamate receptor antagonists have detrimental side effects and have largely failed clinical trials. Topiramate is an AMPA-specific, glutamate receptor antagonists that is FDA-approved to treat CNS disorders. In the current study we tested whether topiramate treatment is neuroprotective after cervical contusion injury in rats. We report that topiramate, delivered 15-minutes after SCI, increases tissue sparing and preserves oligodendrocytes and neurons when compared to vehicle treatment. In addition, topiramate is more effective than the AMPA-receptor antagonist, NBQX. To the best of our knowledge, this is the first report documenting a neuroprotective effect of topiramate treatment after spinal cord injury.
| S-EPMC3302770 | biostudies-literature
