***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: OBJECT The aim of this paper was to characterize individual and population pharmacokinetics of enterally administered riluzole in a Phase 1 clinical trial of riluzole as a neuroprotective agent in adults 18 - 70 years old with acute spinal cord injury ( SCI ) . METHODS Thirty-five individuals with acute SCI , American Spinal Injury Association Impairment Scale Grade s A-C , neurological levels from C-4 to T-12 , who were enrolled in the Phase 1 clinical trial sponsored by the North American Clinical Trials Network for Treatment of Spinal Cord Injury , received 50 mg riluzole twice daily for 28 doses . The first dose was administered at a mean of 8.7 ± 2.2 hours postinjury . Trough plasma sample s were collected within 1 hour predose , and peak plasma sample s were collected 2 hours postdose on Days 3 and 14 of treatment . Riluzole concentrations were quantified by high-performance liquid chromatography assay . The data were analyzed for individual and population pharmacokinetics using basic structural and covariate models . The pharmacokinetic measures studied were the peak concentration ( C(max ) ) , trough concentration ( C(min ) ) , systemic exposure ( AUC(0 - 12 ) ) , clearance ( CL/F ) , and volume of distribution ( V_F ) normalized by the bioavailability ( F ) . RESULTS The C(max ) and AUC(0 - 12 ) achieved in SCI patients were lower than those in ALS patients on the same dose basis , due to a higher CL and larger V. The pharmacokinetics of riluzole ( C(max ) , C(min ) , AUC(0 - 12 ) , CL , and V ) changed during the acute and subacute phases of SCI during the 14 days of therapy . It was consistently observed in patients at all clinical sites that C(max ) , C(min ) , and AUC(0 - 12 ) ( 128.9 ng/ml , 45.6 ng/ml , and 982.0 ng × hr/ml , respectively ) were significantly higher on Day 3 than on Day 14 ( 76.5 ng/ml , 19.1 ng/ml , and 521.0 ng × hr/ml , respectively ) . These changes result ed from lower CL ( 49.5 vs 106.2 L/hour ) and smaller V ( 557.1 vs 1297.9/L ) on Day 3 . No fluid imbalance or cytochrome P 1A2 induction due to concomitant medications was identified during the treatment course to account for such increases in V and CL , respectively . Possible mechanisms underlying these changes are discussed . CONCLUSIONS This is the first report of clinical pharmacokinetics of riluzole in patients with SCI . The C(max ) and AUC(0 - 12 ) achieved in SCI patients were lower than those in ALS patients on the same dose basis , due to a higher clearance and larger volume of distribution in SCI patients . The finding in SCI patients of an increase in the clearance and distribution of riluzole between the 3rd and 14th days after SCI , with a lower plasma concentration of riluzole on the 14th day , stresses the importance of monitoring changes in drug metabolism after SCI in interpreting the safety and efficacy of therapeutic drugs that are used in clinical trials in SCI . Clinical trial registration no. : NCT00876889 Background : Riluzole is a sodium channel-blocking agent used in treating amyotrophic lateral sclerosis . It has been approved by the U.S. Food and Drug Administration , Canadian and Australian authorities , and in many other countries . A phase I trial of riluzole for acute spinal cord injury ( SCI ) provided safety and pharmacokinetic data and suggested neuroprotective benefits . A phase IIB/III double-blinded r and omized controlled trial ( RCT ) started in January 2014 ( https:// clinical trials.gov , NCT01597518 ) . This article describes the pathophysiological rationale , pre clinical experience and design of the phase IIB/III RCT of Riluzole in Acute Spinal Cord Injury Study ( RISCIS ) . Objectives : The primary objective of the trial is to evaluate the superiority of riluzole , at a dose of 100 mg BID in the first 24 h followed by 50 mg BID for the following 13 days post injury , compared with placebo in improving neurological motor outcomes in patients with C4–C8 level , International St and ards for Neurological Classification of Spinal Cord Injury Examination ( ISNCSCI ) grade A , B or C acute ( within 12 h post injury ) SCI . Setting : Acute trauma centers worldwide Methods : A double-blind , multi-center , placebo-controlled RCT will enroll 351 participants r and omized 1:1 to riluzole and placebo .  The primary end point is the change between 180 days and baseline in ISNCSCI Motor Score . This study has 90 % power to detect a change of nine points in ISNCSCI Motor Score at one-sided α=0.025 . Results : Currently enrolling in 11 centers . Conclusion : This study will provide class I evidence regarding the safety and neuroprotective efficacy of riluzole in patients with acute cervical SCI OBJECTIVE Recent studies confirmed the deleterious role of glutamate in the pathophysiology of spinal cord ischemia induced by aortic cross-clamping . We investigated the effect of riluzole , an anti-glutamate drug , in a rat model of spinal cord ischemia . MATERIAL S AND METHODS Spinal cord ischemia was induced in normothermia for 14 min in Sprague-Dawley rats using direct aortic arch plus left subclavian artery cross-clamping through a limited thoracotomy . Experimental groups were as follows :  sham-operation ( n=15 ) , control ( n=15 )  receiving only vehicle , riluzole  ( n=15 )  receiving riluzole ( 4 mg/kg ) before clamping and at the onset of reperfusion . Separate animals were used for monitoring physiologic parameters in the sham-operation ( n=3 ) , control ( n=5 ) , and riluzole ( n=5 ) groups . Neurologic status was assessed at 6 , 24 h , and then daily up to 96 h. Rats were r and omly killed at 24 , 48 , or 96 h ( n=5 for each time ) . Spinal cords were harvested for histopathology , immunohistochemistry for microtubule-associated protein 2 ( MAP-2 ) , TUNEL staining , and analysis of DNA fragmentation by agarose gel electrophoresis . RESULTS All sham-operated rats had a normal neurologic outcome , whereas all control rats suffered severe and definitive paraplegia . Riluzole-treated rats had significantly better neurologic function compared to the control . Histopathology disclosed severe neuronal necrosis in the lumbar gray matter of control rats , whereas riluzole-treated rats suffered usually mild to moderate injury . Riluzole particularly prevented motor neurons injury . MAP-2 immunoreactivity was completely lost in control rats , whereas it was preserved either completely or partly in riluzole-treated rats . TUNEL staining revealed numerous apoptotic neurons scattered within the whole gray matter of control rats . Riluzole prevented or dramatically attenuated apoptotic neuronal death in treated rats . DNA extracted from lumbar spinal cords of sham-operated and riluzole-treated rats exhibited no laddering , whereas spinal cords from control rats showed DNA laddering with fragmentation into approximately 180 multiples of base pairs . CONCLUSIONS Riluzole may protect the spinal cord in a setting of severe ischemia by preventing neuronal necrosis and apoptosis . This drug may therefore be considered for clinical use during ' high risk ' surgical procedures on the thoracoabdominal aorta In the immediate period after traumatic spinal cord injury ( SCI ) a variety of secondary injury mechanisms combine to gradually exp and the initial lesion size , potentially leading to diminished neurological outcomes at long-term follow-up . Riluzole , a benzothiazole drug , which has neuroprotective properties based on sodium channel blockade and mitigation of glutamatergic toxicity , is currently an approved drug that attenuates the extent of neuronal degeneration in patients with amyotrophic lateral sclerosis . Moreover , several pre clinical SCI studies have associated riluzole administration with improved functional outcomes and increased neural tissue preservation . Based on these findings , riluzole has attracted considerable interest as a potential neuroprotective drug for the treatment of SCI . Currently , a Phase I trial evaluating the safety and pharmacokinetic profile of riluzole in human SCI patients is being conducted by the North American Clinical Trials Network ( NACTN ) for Treatment of Spinal Cord Injury . The current review summarizes the existing pre clinical and clinical literature on riluzole , provides a detailed description of the Phase I trial , and suggests potential opportunities for future investigation . Clinical trial registration no. : NCT00876889 Spinal cord injury ( SCI ) results in loss of function below the lesion . Secondary injury following the primary impact includes a number of biochemical and cellular alterations leading to tissue necrosis and cell death . Influx of Na(+ ) ions into cells has been postulated to be a key early event in the pathogenesis of secondary traumatic and ischemic central nervous system injury . Previous studies have shown that some voltage-sensitive sodium channel blockers provide powerful neuroprotection . The purpose of the present study was to compare the neuroprotective effect of three sodium channel blockers-mexiletine , phenytoin and riluzole -- after SCI . Ninety rats were r and omly and blindly divided into five groups of 18 rats each :  sham-operated group , trauma group ( bolus injection of 1 mL physiological saline intraperiteonally [ i.p . ] ) , mexiletine treatment group ( 80 mg/kg , i.p . ) , phenytoin treatment group ( 200 mg/kg , i.p . ) and riluzole treatment group ( 8 mg/kg , i.p . ) . Twenty-four hours after injury , the rats were killed for determination of spinal cord water content and malondialdehyde ( MDA ) levels . Motor function scores of six rats from each group were evaluated weekly for six weeks . Then the rats were killed for histopathological assessment . Although all the treatment groups revealed significantly lower MDA levels and spinal cord edema than the trauma group ( p<0.05 ) , the riluzole and mexiletine treatment groups were better than the phenytoin treatment group . In the chronic stage , riluzole and mexiletine treatment achieved better results for neurobehavioral and histopathological recovery than phenytoin treatment . In conclusion , all the tested Na(+ ) blockers had a neuroprotective effect after SCI ; riluzole and mexiletine were superior to phenytoin Background Massive release of central excitatory neurotransmitters is an important initial step in ischemic neuronal injury , and modification of this process may provide neuroprotection . We studied the protective effects of the voltage-dependent sodium channel antagonist riluzole and the N-methyl-d-aspartate receptor antagonist ketamine on hind limb motor function and histopathologic outcome in an experimental model of spinal cord ischemia . Methods Temporary spinal cord ischemia was induced by 29 min of infrarenal balloon occlusion of the aorta in 60 anesthetized New Zeal and white rabbits . Animals were r and omly assigned to one of four treatment groups ( n = 15 each ) : group C , saline ( control ) ; group R , riluzole , 8 mg/kg intravenously ; group K , ketamine , 55 mg/kg intravenously ; group RK , riluzole and ketamine . After reperfusion , riluzole treatment was continued with intraperitoneal infusions . Normothermia ( 38 ° C ) was maintained during ischemia , and rectal temperature was assessed before and after intraperitoneal infusions . Neurologic function , according to Tarlov ’s criteria , was evaluated every 24 h , and infa rct ion volume and the number of eosinophilic neurons and viable motoneurons in the lumbosacral spinal cord was evaluated after 72 h. Results Neurologic outcome was better in groups R and RK than in groups C and K. All animals in group C ( 100 % ) and all animals but one in group K ( 93 % ) were paraplegic 72 h after the ischemic insult versus 53 % in group R and 67 % in group RK ( P < 0.01 each ) . More viable motoneurons were present in groups R and RK than in controls ( P < 0.05 ) . Conclusions The data indicate that treatment with riluzole can increase the tolerance of spinal cord motoneurons to a period of normothermic ischemia . Intraischemic ketamine did not provide neuroprotection in this model A prospect i ve , 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 grade 
    Output:
    
For the clinical trials included within this study , the American Spinal Injury Association Impairment Scale distributions for SCI were 42.6 % grade A , 25 % grade B , 26.6 % grade C , and 6.2 % grade D. Key findings from studies in humans included decreased nociception , improved motor function , and attenuated spastic reflexes .
Key findings from animal studies included behavioral improvement , histopathological tissue sparing , and modified electrophysiology after SCI .
Key findings from pharmacological studies included riluzole dose-dependent effects on glutamate uptake and its modified bioavailability after SCI in both animal and clinical models .
While still relatively new in its applications for SCI , both animal and human studies demonstrate riluzole to be a promising pharmacological intervention to attenuate the devastating effects of this condition