PubMed Health⌕ Search

Biomedical subjects

A R Blight

Publications and source records attributed to A R Blight.

At least 19 recordsLinked to original sources
PubMed2006

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials.

The International Campaign for Cures of Spinal Cord Injury Paralysis (ICCP) supported an international panel tasked with reviewing the methodology for clinical trials in spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the first of four papers. Here, we examine the spontaneous rate of recovery after SCI and resulting consequences for achieving statistically significant results in clinical trials. We have reanalysed data from the Sygen trial to provide some of this information. Almost all people living with SCI show some recovery of motor function below the initial spinal injury level. While the spontaneous recovery of motor function in patients with motor-complete SCI is fairly limited and predictable, recovery in incomplete SCI patients (American spinal injury Association impairment scale (AIS) C and AIS D) is both more substantial and highly variable. With motor complete lesions (AIS A/AIS B) the majority of functional return is within the zone of partial preservation, and may be sufficient to reclassify the injury level to a lower spinal level. The vast majority of recovery occurs in the first 3 months, but a small amount can persist for up to 18 months or longer. Some sensory recovery occurs after SCI, on roughly the same time course as motor recovery. Based on previous data of the magnitude of spontaneous recovery after SCI, as measured by changes in ASIA motor scores, power calculations suggest that the number of subjects required to achieve a significant result from a trial declines considerably as the start of the study is delayed after SCI. Trials of treatments that are most efficacious when given soon after injury will therefore, require larger patient numbers than trials of treatments that are effective at later time points. As AIS B patients show greater spontaneous recovery than AIS A patients, the number of AIS A patients requiring to be enrolled into a trial is lower. This factor will have to be balanced against the possibility that some treatments will be more effective in incomplete patients. Trials involving motor incomplete SCI patients, or trials where an accurate assessment of AIS grade cannot be made before the start of the trial, will require large subject numbers and/or better objective assessment methods.

Clinical Trials as Topic↗
PubMed2006

Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: clinical trial outcome measures.

An international panel reviewed the methodology for clinical trials of spinal cord injury (SCI), and provided recommendations for the valid conduct of future trials. This is the second of four papers. It examines clinical trial end points that have been used previously, reviews alternative outcome tools and identifies unmet needs for demonstrating the efficacy of an experimental intervention after SCI. The panel focused on outcome measures that are relevant to clinical trials of experimental cell-based and pharmaceutical drug treatments. Outcome measures are of three main classes: (1) those that provide an anatomical or neurological assessment for the connectivity of the spinal cord, (2) those that categorize a subject's functional ability to engage in activities of daily living, and (3) those that measure an individual's quality of life (QoL). The American Spinal Injury Association impairment scale forms the standard basis for measuring neurologic outcomes. Various electrophysiological measures and imaging tools are in development, which may provide more precise information on functional changes following treatment and/or the therapeutic action of experimental agents. When compared to appropriate controls, an improved functional outcome, in response to an experimental treatment, is the necessary goal of a clinical trial program. Several new functional outcome tools are being developed for measuring an individual's ability to engage in activities of daily living. Such clinical end points will need to be incorporated into Phase 2 and Phase 3 trials. QoL measures often do not correlate tightly with the above outcome tools, but may need to form part of Phase 3 trial measures.

Activities of Daily Living↗
PubMed2006

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP Panel: clinical trial inclusion/exclusion criteria and ethics.

The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the third of four papers. It examines inclusion and exclusion criteria that can influence the design and analysis of clinical trials in SCI, together with confounding variables and ethical considerations. Inclusion and exclusion criteria for clinical trials should consider several factors. Among these are (1) the enrollment of subjects at appropriate stages after SCI, where there is supporting data from animal models or previous human studies; (2) the severity, level, type, or size of the cord injury, which can influence spontaneous recovery rate and likelihood that an experimental treatment will clinically benefit the subject; and (3) the confounding effects of various independent variables such as pre-existing or concomitant medical conditions, other medications, surgical interventions, and rehabilitation regimens. An issue of substantial importance in the design of clinical trials for SCI is the inclusion of blinded assessments and sham surgery controls: every effort should be made to address these major issues prospectively and carefully, if clear and objective information is to be gained from a clinical trial. The highest ethical standards must be respected in the performance of clinical trials, including the adequacy and clarity of informed consent.

Clinical Trials as Topic↗
PubMed2006

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: clinical trial design.

The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the fourth of four papers. Here, we examine the phases of a clinical trial program, the elements, types, and protocols for valid clinical trial design. The most rigorous and valid SCI clinical trial would be a prospective double-blind randomized control trial utilizing appropriate placebo control subjects. However, in specific situations, it is recognized that other trial procedures may have to be considered. We review the strengths and limitations of the various types of clinical trials with specific reference to SCI. It is imperative that the design and conduct of SCI clinical trials should meet appropriate standards of scientific inquiry to insure that meaningful conclusions about efficacy and safety can be achieved and that the interests of trial subjects are protected. We propose these clinical trials guidelines for use by the SCI clinical research community.

Clinical Trials as Topic↗
PubMed2006

Phase 2 trial of sustained-release fampridine in chronic spinal cord injury.

STUDY DESIGN: Double-blind, randomized, placebo-controlled, parallel-group clinical trial. OBJECTIVE: Assess safety and efficacy of sustained-release fampridine in subjects with chronic spinal cord injury. SETTING: A total of 11 academic rehabilitation research centers in the United States. METHODS: A total of 91 subjects with motor-incomplete spinal cord injury (SCI), randomized to three arms: fampridine, sustained release, 25 mg b.i.d. (Group I), 40 mg b.i.d. (Group II), and placebo (Group III) for 8 weeks. OUTCOME MEASURES: Patient diary questionnaire, Ashworth score, American Spinal Cord Injury Association International Standards, International Index of Erectile Function, bladder and bowel management questionnaires, and Clinician and Subject Global Impressions (Clinician Global Impression of change, Subject Global Impression (SGI)). Safety was evaluated from adverse events, physical examinations, vital signs, electrocardiograms, and laboratory tests. RESULTS: In total, 78% of the subjects completed the study. More (13/30) discontinued from Group II than Group I (4/30) and Group III (3/31). The most frequent adverse events across groups were hypertonia, generalized spasm, insomnia, dizziness, asthenia, pain, constipation, and headache. One subject in Group II experienced a seizure. SGI changed significantly in favor of Group I (P=0.02). Subgroup analysis of subjects with baseline Ashworth scores >1 showed significant improvement in spasticity in Group I versus III (P=0.02). CONCLUSIONS: Group I showed significant improvement in SGI, and potential benefit on spasticity. The drug was well tolerated. Group II showed more adverse events and discontinuations.

4-Aminopyridine↗
PubMed2003

Pharmacokinetics of an immediate-release oral formulation of Fampridine (4-aminopyridine) in normal subjects and patients with spinal cord injury.

Plasma concentration profiles of the K+ channel-blocking compound Fampridine were obtained from (1) control subjects (n = 6) following oral administration of doses of 10, 15, 20, and 25 mg and (2) patients with spinal cord injury (SCI) (n = 11) following a single oral dose of 10 mg of an immediate-release formulation. Plasma concentrations were determined using a reversed-phase ion-pair high-performance liquid chromatography (HPLC) assay with ultraviolet light detection employing liquid extraction. The drug was rapidly absorbed with a tmax approximately 1 hour for both groups; tmax was independent of dose. Cmax and AUC0-infinity were linearly related to dose, and t 1/2 was 3 to 4 hours for both groups. There were no obvious differences in the (10-mg) plasma concentration profiles between control subjects and SCI patients. The drug was well tolerated, with only mild and transient side effects of light-headedness, dysesthesias, and dizziness.

4-Aminopyridine↗
PubMed2001

Acute spinal cord injury: pharmacotherapy and drug development perspectives.

There are no drugs specifically approved for spinal cord injury that directly address the underlying damage to neural tissue. Immediate treatment with methylprednisolone sodium succinate has been shown to improve outcome from injury in a series of preclinical and clinical studies, and it is now widely used, though the benefits appear to be modest. A variety of other approaches to protecting the injured spinal cord from secondary pathological processes have been examined experimentally, including antioxidants, membrane stabilizers, glutamate antagonists, anti-inflammatories, caspase inhibitors, calpain inhibitors and other compounds of uncertain mechanism. All of these approaches have been supported by positive animal studies but their efficacy relative to the widely used methylprednisolone has not been established.

Animals↗
PubMed2000

Intravenous infusion of 4-AP in chronic spinal cord injured subjects.

STUDY DESIGN: A prospective double blind cross over trial of intravenous 4-Aminopyridine (4-AP). OBJECTIVE: To determine the efficacy of this drug in the treatment of spinal cord injured (SCI) patients for neurologic impairment, pain and spasticity. SETTING: The post anesthesia care unit (PACU) of a tertiary care acute hospital. METHODS: Twelve paraplegic patients were enrolled in a double blind cross over intravenous trial of 4-Aminopyridine (4-AP). Thirty milligrams of 4-AP or placebo were administered over a 2 h period. Patients were serially examined during and after the infusion clinically for pain, sensorimotor function, hypertonicity and motor control using electromyography (EMG). Samples of blood and cerebrospinal fluid (CSF) were also analyzed at similar intervals. RESULTS: Despite penetration of 4-AP into the CSF, no significant differences were noted in the clinical and EMG parameters at the times measured. Individual changes in sensory function were reported by some patients in both the placebo and 4-AP trials, however mean values were not robust. Frequently, patients complained of unpleasant symptoms during the 4-AP infusion. CONCLUSION: The intravenous route may not be the best way to administer this drug as no short term benefits were observed.

4-Aminopyridine↗
PubMed2000

Intrathecal administration of 4-aminopyridine in chronic spinal injured patients.

STUDY DESIGN: Intrathecal administration of 4-aminopyridine (4-AP) in chronic spinal cord injured (SCI) patients. OBJECTIVE: To determine the safety and effects of intrathecal administration of 4-AP in a small population of chronic SCI patients. SETTING: The post anesthesia care unit of a tertiary care hospital. METHODS: Following animal mode studies to establish dosing safety, six subjects with chronic SCI were examined. In each subject, an intrathecal catheter was placed with the tip as close to the lesion level as possible. 4-AP was infused at 5 microg/h for a period of 4-5 h. Vital signs were recorded and sensory-motor physical examinations and pain questionnaires were administered for 24 h. In two patients, samples of cerebrospinal fluid for analysis were drawn from a second intrathecal catheter. RESULTS: No adverse systemic side effects were noted. One patient showed transient improvement in sensory function; two showed transient increases in spasticity; three showed transient increases in cutaneomuscular reflexes and two showed an apparent small increase in volitional motor control. The concentration of 4-aminopyridine in the cerebrospinal fluid reached a peak of 163 ng/ml at 4 h in one subject and 122 ng/ml at 5 h in the other subject examined. CONCLUSION: Intrathecal administration of 4-aminopyridine at a rate of 5 microg/h does not appear to cause adverse effects and may modify spinal cord function. This route of administration allows local cerebrospinal fluid concentrations equivalent to those produced by maximum tolerable systemic doses, which require 1000 times more drug substance to be delivered to the subject as a whole. Intrathecal administration offers the potential to focus therapeutic effects to the lesion site while minimizing systemic side effects.

4-Aminopyridine↗
PubMed2000

Control of membrane sealing in injured mammalian spinal cord axons.

The process of sealing of damaged axons was examined in isolated strips of white matter from guinea pig spinal cord by recording the "compound membrane potential," using a sucrose-gap technique, and by examining uptake of horseradish peroxidase (HRP). Following axonal transection, exponential recovery of membrane potential occurred with a time constant of 20 +/- 5 min, at 37 degrees C, and extracellular calcium activity ([Ca(2+)](o)) of 2 mM. Most axons excluded HRP by 30 min following transection. The rate of sealing was reduced by lowering calcium and was effectively blocked at [Ca(2+)](o) </= 0.5 mM, under which condition most axons continued to take up HRP for more than 1 h. Sealing at higher [Ca(2+)](o) was blocked by calpain inhibitors (calpeptin and calpain inhibitor-1) indicating a requirement for type II (mM) calpain in the sealing process. Following compression injury, the amplitude of the maximal compound action potential conducted through the injury site was reduced. The extent of amplitude reduction was increased when the tract was superfused with calcium-free Krebs' solution (Ca(2+) replaced by Mg(2+)). These results suggest that the fall in [Ca(2+)](o) seen following injury in vivo is sufficient to prevent membrane sealing and may paradoxically contribute to axonal dieback, retrograde cell death, and "secondary" axonal disruption.

Action Potentials↗
PubMed1999

Functional reconnection of severed mammalian spinal cord axons with polyethylene glycol.

We describe a technique using the water-soluble polymer polyethylene glycol (PEG) to reconnect the two segments of completely transected mammalian spinal axons within minutes. This was accomplished by fusing completely severed strips of isolated guinea pig thoracic white matter maintained in vitro in a double sucrose gap recording chamber. The faces of the severed segments were pressed together, and PEG (MW 1,400-3,500 d; approximately 50% by weight in distilled water) was applied directly to this region through a micropipette and removed by aspiration within 2 min. Successful fusion was documented by the immediate restored conduction of compound action potentials through the original transection and by the variable numbers of fused axons in which anatomical continuity was shown to be restored by high-resolution light microscopy and by the diffusion of intracellular fluorescent dyes through fused axons. These data support the conclusion that some severed and subsequently PEG-fused spinal axons both demonstrate restored anatomical continuity and also are physiologically competent to conduct action potentials. This work adds to our previous demonstration that PEG application can immediately repair severely crushed, rather than cut, spinal cord white matter, and may lead to novel treatments for acute trauma to the central and peripheral nervous systems.

Action Potentials↗
PubMed1999

Quinolinic acid in the cerebrospinal fluid of children after traumatic brain injury.

OBJECTIVE: To measure quinolinic acid, a macrophage-derived neurotoxin, in the cerebrospinal fluid (CSF) of children after traumatic brain injury (TBI) and to correlate CSF quinolinic acid concentrations to clinically important variables. DESIGN: A prospective, observational study. SETTING: The pediatric intensive care unit in Children's Hospital of Pittsburgh, a tertiary care, university-based children's hospital. PATIENTS: Seventeen critically ill children following severe TBI (Glasgow Coma Scale score <8) whose care required the placement of an intraventricular catheter for continuous drainage of CSF. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients ranged in age from 2 mos to 16 yrs (mean 6.0 yrs). CSF was collected immediately on placement of the ventricular catheter and daily thereafter. Quinolinic acid concentration was measured by gas chromatography/mass spectroscopy in 69 samples (4.0 +/- 0.4 [SEM] samples per patient). CSF quinolinic acid concentration progressively increased after injury (p = .034, multivariate analysis) and was increased in nonsurvivors vs. survivors (p = .002, multivariate analysis). CSF quinolinic acid concentration was not associated with age. Although overall CSF quinolinic acid concentration was not associated with shaken injury (p = .16, multivariate analysis), infants suffering with shaken infant syndrome had increased admission CSF quinolinic acid concentrations compared with children with accidental mechanisms of injury (p = .027, Mann-Whitney Rank Sum test). CONCLUSIONS: A large and progressive increase in the macrophage-derived neurotoxin quinolinic acid is seen following severe TBI in children. The increase is strongly associated with increased mortality. Increased CSF quinolinic acid concentration on admission in children with shaken infant syndrome could reflect a delay in presentation to medical attention or age-related differences in quinolinic acid production. These findings raise the possibility that quinolinic acid may play a role in secondary injury after TBI in children and suggest an interaction between inflammatory and excitotoxic mechanisms of injury following TBI.

Accidents, Traffic↗
PubMed1998

Quinolinic acid is increased in CSF and associated with mortality after traumatic brain injury in humans.

We tested the hypothesis that quinolinic acid, a tryptophan-derived N-methyl-D-aspartate agonist produced by macrophages and microglia, would be increased in CSF after severe traumatic brain injury (TBI) in humans, and that this increase would be associated with outcome. We also sought to determine whether therapeutic hypothermia reduced CSF quinolinic acid after injury. Samples of CSF (n = 230) were collected from ventricular catheters in 39 patients (16 to 73 years old) during the first week after TBI, (Glasgow Coma Scale [GCS] < 8). As part of an ongoing study, patients were randomized within 6 hours after injury to either hypothermia (32 degrees C) or normothermia (37 degrees C) treatments for 24 hours. Otherwise, patients received standard neurointensive care. Quinolinic acid was measured by mass spectrometry. Univariate and multivariate analyses were used to compare CSF quinolinic acid concentrations with age, gender, GCS, time after injury, mortality, and treatment (hypothermia versus normothermia). Quinolinic acid concentration in CSF increased maximally to 463 +/- 128 nmol/L (mean +/- SEM) at 72 to 83 hours after TBI. Normal values for quinolinic acid concentration in CSF are less than 50 nmol/L. Quinolinic acid concentration was increased 5- to 50-fold in many patients. There was a powerful association between time after TBI and increased quinolinic acid (P < 0.00001), and quinolinic acid was higher in patients who died than in survivors (P = 0.003). Age, gender, GCS, and treatment (32 degrees C versus 37 degrees C) did not correlate with CSF quinolinic acid. These data reveal a large increase in quinolinic acid concentration in CSF after TBI in humans and raise the possibility that this macrophage-derived excitotoxin may contribute to secondary damage.

Adolescent↗
PubMed1997

A quantitative immunohistochemical study of the cellular response to crush injury in optic nerve.

Computer-enhanced immunohistochemical techniques were applied to quantify the cellular response of rat optic nerve to crush injury to attain the spatial and temporal detail necessary for resolving trends in the process that may be affected by experimental therapy. Changes in the major cell populations of the optic nerve during 6 weeks following crush injury were analyzed using antibodies against beta-tubulin (TuJ1), neurofilament (8-152), glial fibrillary acidic protein (GFAP), galactocerebrosides (GalC), ED-1, and von Willebrand factor to detect the presence of axons, astrocytes, oligodendrocytes, macrophages, and endothelial cells. The markers for axons, astrocytes, oligodendrocytes, and endothelial cells decreased their activity and remained depressed in the area of direct mechanical injury throughout 6 weeks following crush injury. A spatial peak in the axonal makers TuJ1 and 8-152 at the proximal boundary of the injury at both 2 and 3 weeks is consistent with the idea that the injury zone is a barrier obstructing distal elongation of sprouted neurites. Reactive astrocytes were GFAP-positive in the nerve segments proximal and distal to the injury with marker density above 1.5 times normal at 2 and 3 weeks. GFAP appeared to be absent in the site of injury even at 6 weeks postinjury, as shown by both immunohistochemistry and Western blot analysis. ED-1-positive macrophages were the most numerous population in the injury site from 1 through 6 weeks with a peak value measured at 2 weeks. The optical density of ED-1 activity in the distal and proximal nerve segments was less than 20% the density in the injury at all measured time points.

Animals↗
PubMed1997

Spinal cord compression injury in guinea pigs: structural changes of endothelium and its perivascular cell associations after blood-brain barrier breakdown and repair.

This study examines morphological changes of the blood-brain barrier (BBB) after spinal cord compression. The lowest thoracic segment (T13) of female guinea pigs was injured and the BBB was tested from 7 days to 5.5 months postinjury using intravenously injected horseradish peroxidase (HRP) as a tracer. Tracer leakage in the injured segment was verified with the light microscope and the fine structure of capillaries was examined. Diffuse tissue staining was observed at T13 up to 2 weeks following injury. A leaky BBB correlated with expected changes in the fine structure of endothelial cell junctions. These were predominantly nonoverlapping cell junctions which, in many instances, were separated by clefts between adjacent cells. At early survival times, numerous capillary profiles with juxtaposed astrocyte foot processes were noted in addition to altered cell associations. Complete sealing of the BBB against interstitial HRP leakage was not observed until 17 days postinjury. After the first week, some of the endothelial cells were contacted by macrophages, processes of perivascular microglia, and processes of swollen and degenerating astrocytes. Perivascular spaces varied in extent and contained amorphous deposits of extracellular materials in addition to supernumerary layers of basal lamina. The early changes were followed by profound tissue restructuring due to loss of both neurons and glia. At longer survival times the BBB to HRP repaired. Endothelial cells formed complex overlapping junctions with zonulae occludentes. Most of the capillaries in the injured segment were no longer in direct contact with astrocyte foot processes, although reactive astrocytes constituted the predominant cell type in the remaining gray matter. Substantial expansion of perivascular spaces was evident. The cytoplasm of endothelial cells had numerous pinocytotic vesicles. Perivascular spaces contained layers of assembled collagen arranged perpendicularly to each other in addition to amorphous matrix materials. The findings suggest that decoupling of astrocyte foot processes from endothelial cell surfaces does not prevent reformation of tight junctions. It remains to be examined what effects the larger perivascular spaces, extracellular matrix deposits, and changes of cell associations may have on transport systems and ionic buffering. The data are relevant for estimating an opportune time for application of barrier-impermeable drugs to the lesion area.

Animals↗
PubMed1997

Conduction block in acute and chronic spinal cord injury: different dose-response characteristics for reversal by 4-aminopyridine.

The effect of the potassium channel blocker, 4-aminopyridine (4-AP), on conduction of action potentials in injured guinea pig spinal cord axons was measured using isolated tracts in oxygenated Krebs' solution at 37 degrees C. The dose-response characteristics of acutely and chronically injured axons were compared. The maximal improvement of conduction occurred in acutely injured axons at a concentration of 100 microM 4-AP, but in chronically injured spinal cord at 10 microM. The threshold for significant response to 4-AP was between 0.5 and 1 microM in chronically injured cords, and between 1 and 10 microM following acute compression injury. The difference in susceptibility to potassium channel blockade may be related to underlying differences in the mechanism of conduction block at the two stages of injury. Initially, junctions between axons and myelin are acutely disrupted, altering primarily the leakage resistance of the myelin sheath and periaxonal space. In chronically injured cords, there is widespread but incomplete process of repair in the lesion site, which leaves many axons partially myelinated. The difference in sensitivity to 4-AP suggests there is also some modification of the accessibility of axonal potassium channel or a change in their affinity for the drug.

4-Aminopyridine↗
PubMed1997

Differential effects of low and high concentrations of 4-aminopyridine on axonal conduction in normal and injured spinal cord.

Blockade of potassium channels with the drug 4-aminopyridine has been shown to effect recovery of action potential conduction in myelinated axons under a variety of pathological conditions, but the mechanism and significance of this phenomenon are not completely understood. This study examined the effects of a range of 4-aminopyridine concentrations on conduction in an experimental model of chronic spinal cord injury in guinea-pigs, using sucrose-gap recording from isolated spinal cord strips. The amplitude of the compound action potential increased in response to bath application of 4-aminopyridine, with a threshold between 0.5 and 1 microM and the peak response between 10 and 100 microns. Conduction was suppressed at concentrations of 1 and 10 mM. Uninjured white matter showed no effect on the compound potential of 4-aminopyridine below 1 mM, but there was a similar suppression at concentrations above 1 mM, accompanied by marked membrane depolarization. Peripheral nerve showed only slight action potential suppression and depolarization in the presence of 10 mM 4-aminopyridine. The sensitivity of injured axons to 1 microM 4-aminopyridine is consistent with the hypothesis that some beneficial effects of the drug seen in patients with spinal cord injury are related to improved conduction in myelinated axons, since cerebrospinal fluid levels of 4-aminopyridine should approach this concentration following clinical systemic doses, although it remains likely that synaptic effects also play a role. The blockade of action potential conduction produced by much higher levels of 4-aminopyridine in vitro is possibly a consequence of interference with the resting potential mechanism of the axon membrane, which appears to differ between central and peripheral nerve fibers.

4-Aminopyridine↗