Correction: Evidence-based scientific exercise guidelines for adults with spinal cord injury: an update and a new guideline.

Authors Victoria L. Goosey-Tolfrey and Karen M. Smith were listed under the incorrect affiliations at the time of publication.

Facilitators and Barriers to International Collaboration in Spinal Cord Injury: Results from a Survey of Clinicians and Researchers.

International collaboration in spinal cord injury (SCI) research is necessary to overcome the challenges often encountered by clinicians and researchers, including participant recruitment, high cost, and the need for specialized expertise. However, international collaboration poses its own obstacles. The objective of this study was to conduct an international online survey to assess barriers and facilitators to international SCI clinical research, potential initiatives to facilitate future collaborations, and the use of SCI-specific data sets and standards. Results were analyzed using descriptive statistics. Of 364 total respondents, 213 completed the survey, with the majority of these participants based in North America (38%), Asia (22%), Europe (18%), and Oceania (16%). Over half had more than 10 years of experience in SCI research or clinical practice (57%) and 60% had previous experience with international collaborations. Funding was identified as a top barrier (82%), a facilitator (93%), and a proposed future initiative (97%). Communication and technology were also identified as strong facilitators and proposed future initiatives. The International Standards for Neurological Classification of SCI were used by 69% of participants, the International Standards to document remaining Autonomic Function after SCI by 13% of participants, and the International SCI Data Sets by 45% of participants. As the need for international collaborations in SCI research increases, it is important to identify how clinicians and researchers can be supported by SCI consumer and professional organizations, funders, and networks. Furthermore, unique solutions to overcome modifiable barriers and creation of new facilitators are also needed.

Evidence-based scientific exercise guidelines for adults with spinal cord injury: an update and a new guideline.

OBJECTIVES: To describe the process and outcomes of using a new evidence base to develop scientific guidelines that specify the type and minimum dose of exercise necessary to improve fitness and cardiometabolic health in adults with spinal cord injury (SCI). SETTING: International. METHODS: Using Appraisal of Guidelines, Research and Evaluation (AGREE) II reporting criteria, steps included (a) determining the guidelines' scope; (b) conducting a systematic review of relevant literature; (c) holding three consensus panel meetings (European, Canadian and International) to formulate the guidelines; (d) obtaining stakeholder feedback; and (e) process evaluation by an AGREE II consultant. Stakeholders were actively involved in steps (c) and (d). RESULTS: For cardiorespiratory fitness and muscle strength benefits, adults with a SCI should engage in at least 20 min of moderate to vigorous intensity aerobic exercise 2 times per week AND 3 sets of strength exercises for each major functioning muscle group, at a moderate to vigorous intensity, 2 times per week (strong recommendation). For cardiometabolic health benefits, adults with a SCI are suggested to engage in at least 30 min of moderate to vigorous intensity aerobic exercise 3 times per week (conditional recommendation). CONCLUSIONS: Through a systematic, rigorous, and participatory process involving international scientists and stakeholders, a new exercise guideline was formulated for cardiometabolic health benefits. A previously published SCI guideline was endorsed for achieving fitness benefits. These guidelines represent an important step toward international harmonization of exercise guidelines for adults with SCI, and a foundation for developing exercise policies and programs for people with SCI around the world.

Advancing research and clinical care in the management of neuropathic pain after spinal cord injury: Key findings from a Canadian summit.

Background: Optimal management of neuropathic pain (NP) is essential to enhancing health-related quality of life for individuals living with spinal cord injury (SCI). A key strategic priority for the Ontario Neurotrauma Foundation (ONF) and Rick Hansen Institute (RHI) is optimizing NP management after SCI. Aims: A National Canadian Summit, sponsored by ONF and RHI, was held to develop a strategic plan to improve NP management after SCI. Methods: In a one-day meeting held in Toronto, Ontario, a multidisciplinary panel of 18 Canadian stakeholders utilized a consensus workshop methodology to (1) describe the current state of the field, (2) create a long-term vision, and (3) identify steps for moving into action. Results: A review of the current state of the field identified strengths including rigourously developed evidence syntheses and practice landscape documentation. Identified gaps included limited evidence on NP hindering recommendation development in evidence syntheses, absence of a national strategy, care silos with limited cross-continuum connections, limited consumer involvement, and limited practice standard implementation. The panel identified key themes for a long-term vision to improve the management of SCI NP in Canada, including establishing an integrated collaborative network; standardized care and outcome evaluation; education; advocacy; and directing resources to innovative solutions. The panel identified the next step as prioritization of areas that will have the greatest impact in a 5-year time frame. Conclusion: A strategic plan outlining a long-term vision to improve management of NP after SCI in Canada was developed and will inform future activities of the sponsors.

Contexte: La gestion optimale de la douleur neuropathique est essentielle à l'amélioration de la qualité de vie liée à la santé des personnes vivant avec une lésion de la moelle épinière. L'une des priorités stratégiques de la Fondation ontarienne de neurotraumatologie et de l'Institut Rick Hansen est l'optimisation de la prise en charge de la douleur neuropathique après une lésion de la moelle épinière.Buts: Un sommet national canadien parrainé par la Fondation ontarienne de neurotraumatologie et l'Institut Rick Hansen a été tenu afin d'élaborer un plan stratégique pour l'amélioration de la gestion de la douleur neuropathique après une lésion de la moelle épinière.Méthodes: Dans le cadre d'une rencontre d'une journée tenue à Toronto, Ontario, un panel multidisciplinaire composé de 18 parties prenantes canadiennes a eu recours à la méthodologie de l'atelier consensuel pour (1) décrire la situation actuelle dans le domaine, (2) définir une vision à long terme et (3) déterminer les étapes à suivre pour passer à l'action.Résultats: Une revue de la situation actuelle dans le domaine a permis d'en répertorier les forces, parmi lesquelles on compte des synthèses de données probantes élaborées avec rigueur et la documentation des pratiques. Les lacunes suivantes ont été répertoriées: des données probantes limitées en ce qui concerne la formulation de recommandations pour empêcher la douleur neuropathique dans les synthèses de données probantes; l'absence de stratégie nationale; un mode de prestation des soins en silos, où les liens entre les continuums sont limités; une participation du consommateur limitée et une mise en œuvre limitée des normes de pratique. Le panel a répertorié les grands thèmes pour élaborer une vision à long terme afin d'améliorer la prise en charge de la douleur neuropathique occasionnée par une lésion de la moelle épinière au Canada, parmi lesquels on compte: l'établissement d'un réseau de collaboration intégré; la normalisation des soins et l'évaluation des résultats; l'éducation; le plaidoyer; et l'attribution de ressources aux solutions novatrices. Le panel a déterminé que la prochaine étape consisterait à prioriser les domaines qui auront le plus de répercussions au cours des cinq prochaines années.Conclusion: Un plan stratégique définissant une vision à long terme pour améliorer la prise en charge de la douleur neuropathique après une lésion de la moelle épinière a été élaboré. Ce plan servira de base aux prochaines activités des promoteurs.

Changes in traditional chronic disease risk factors over time and their relationship with leisure-time physical activity in people living with spinal cord injury.

This study examined whether levels of chronic disease risk factors change over time, and whether leisure-time physical activity (LTPA) can explain any of the variation in those risk factors that change, in a sample of community-dwelling people living with spinal cord injury (SCI) in or near Hamilton, Ontario, Canada. LTPA was measured using the Physical Activity Recall Assessment for People with SCI at baseline (n = 76 adults with chronic (≥1 year) paraplegia or tetraplegia), at 6 months (n = 71) and at 18 months (n = 63). Body mass index, waist circumference at the lowest rib (WC(lowest rib)) and iliac crest (WC(iliac crest)), fat mass, blood pressure, and biochemical data were collected at all 3 time points. Women's BMI was higher at baseline (least square means (LSM) = 26.2 ± SE = 1.56 kg·m(-2), p = 0.0004) and 6 months (25.9 ± 1.6, p = 0.0024) than at 18 months (22.1 ± 1.72). Men's WC(lowest rib) increased from baseline (92.1 ± 1.87 cm) to 18 months (93.6 ± 1.87, p = 0.0253). Women who were active vs. inactive at baseline had a lower BMI at 6 months (23.1 ± 2.91 vs. 29.7 ± 2.52, p = 0.0957) and WC(iliac crest) at 6 months (82.8 ± 6.59 vs. 97.7 ± 5.10, p = 0.0818). Women who were active vs. inactive at 6 months had a lower WC(iliac crest) at 18 months (73.4 ± 14.3 vs. 102.5 ± 6.41, p = 0.0723). There was little change in traditional risk factors over 18 months. Future studies should extend beyond 18 months in a larger sample, and explore traditional vs. novel risk factors and onset of cardiovascular disease and diabetes in the SCI population.

Predictors of leisure time physical activity among people with spinal cord injury.

BACKGROUND: Most studies of physical activity predictors in people with disability have lacked a guiding theoretical framework. Identifying theory-based predictors is important for developing activity-enhancing strategies. PURPOSE: To use the World Health Organization's International Classification of Functioning, Disability and Health (ICF) framework to identify predictors of leisure time physical activity among people with spinal cord injury (SCI). METHODS: Six hundred ninety-five persons with SCI (M age=47; 76% male) completed measures of Body Functions and Structures, Activities and Participation, Personal Factors, and Environmental Factors at baseline and 6-months. Activity was measured at 6 and 18 months. Logistic and linear regression models were computed to prospectively examine predictors of activity status and activity minutes per day. RESULTS: Models explained 19%-25% of variance in leisure time physical activity. Activities and Participation and Personal Factors were the strongest, most consistent predictors. CONCLUSIONS: The ICF framework shows promise for identifying and conceptualizing predictors of leisure time physical activity in persons with disability.

Impact of extended-release dalfampridine on walking ability in patients with multiple sclerosis.

Dalfampridine extended release (ER) 10 mg is an oral tablet form of the potassium (K(+)) channel-blocking compounded dalfampridine, also known as fampridine, and chemically 4-aminopyridine or 4-AP, which received regulatory approval in the United States for the treatment of walking in patients with multiple sclerosis (MS) in January 2010. Two pivotal Phase 3 clinical trials demonstrated significant improvements in walking in patients with the four primary forms of MS following administration of dalfampridine ER tablets 10 mg twice daily. The drug is thought to act by restoring conduction in focally demyelinated axons and by enhancing neurotransmission, thereby leading to improved neurological function. This review describes how dalfampridine represents a new pharmacotherapeutic approach to the clinical management of mobility impairment. It describes the mechanism of action and chemistry of dalfampridine ER, its pharmacokinetics, tolerability, and side effects, and the outcomes of multicenter trials showing its efficacy in improving walking speed. Clinician and patient global assessments, as well as patient self-assessment of the impact of MS on their gait disability, confirm clinically relevant benefit from the therapy. Patients tolerate the drug well and their improvement in terms of household and community ambulation, inferred from analysis of pooled data from several studies, is likely to translate into benefits in the performance of instrumental activities of daily living and a reduction in the neuropsychiatric burden of disease.

Electrical stimulation therapy increases rate of healing of pressure ulcers in community-dwelling people with spinal cord injury.

OBJECTIVE: To investigate whether electric stimulation therapy (EST) administered as part of a community-based, interdisciplinary wound care program accelerates healing of pressure ulcers in people with spinal cord injury (SCI). DESIGN: Single-blind, parallel-group, randomized, controlled, clinical trial. SETTING: Community-based home care setting, Ontario, Canada. PARTICIPANTS: Adults (N=34; mean age +/- SD, 51+/-14y) with SCI and stage II to IV pressure ulcers. INTERVENTIONS: Subjects were stratified based on wound severity and duration and randomly assigned to receive either a customized, community-based standard wound care (SWC) program that included pressure management or the wound care program plus high-voltage pulsed current applied to the wound bed (EST+SWC). MAIN OUTCOME MEASURES: Wound healing measured by reduction in wound size and improvement in wound appearance at 3 months of treatment with EST+SWC or SWC. RESULTS: The percentage decrease in wound surface area (WSA) at the end of the intervention period was significantly greater in the EST+SWC group (mean +/- SD, 70+/-25%) than in the SWC group (36+/-61%; P=.048). The proportion of stage III, IV, or X pressure ulcers improving by at least 50% WSA was significantly greater in the EST+SWC group than in the SWC group (P=.02). Wound appearance assessed using the photographic wound assessment tool was improved in wounds treated with EST+SWC but not SWC alone. CONCLUSIONS: These results demonstrate that EST can stimulate healing of pressure ulcers of people with SCI. EST can be incorporated successfully into an interdisciplinary wound care program in the community.

Leisure time physical activity in a population-based sample of people with spinal cord injury part I: demographic and injury-related correlates.

OBJECTIVES: To estimate the number of minutes a day of leisure time physical activity (LTPA) performed by people with chronic spinal cord injury (SCI) and to identify the demographic and injury-related characteristics associated with LTPA in a population-based sample of people with chronic SCI. DESIGN: Cross-sectional telephone survey. SETTING: General community. PARTICIPANTS: Men and women with SCI (N=695). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The number of minutes/day of LTPA performed at a mild intensity or greater. RESULTS: Respondents reported mean minutes +/- SD of 27.14+/-49.36 of LTPA/d; however, 50% reported no LTPA whatsoever. In a multiple regression analysis, sex, age, years postinjury, injury severity, and primary mode of mobility each emerged as a unique predictor of LTPA. Multiple correspondence analysis indicated that being a man over the age of 34 years and greater than 11 years postinjury was associated with inactivity, while being a manual wheelchair user and having motor complete paraplegia were associated with the highest level of daily LTPA. CONCLUSIONS: Daily LTPA levels are generally low in people with SCI. Women, older adults, people with less recent injuries, people with more severe injuries, and users of power wheelchairs and gait aids are general subgroups that may require special attention and resources to overcome unique barriers to LTPA. Specific subgroups may also require targeted interventions.

Leisure time physical activity in a population-based sample of people with spinal cord injury part II: activity types, intensities, and durations.

OBJECTIVE: To describe the types, intensities, and average duration of leisure time physical activities (LTPAs) performed by people with chronic spinal cord injury (SCI). DESIGN: Cross-sectional telephone survey. SETTING: General community. PARTICIPANTS: Men and women with SCI (N=347) who reported engaging in LTPA over the previous 3 days. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Mean minutes a day of LTPA performed at mild, moderate, and heavy intensities; proportion of respondents performing specific types of LTPA. RESULTS: Participants reported a mean +/- SD of 55.15+/-59.05min/d of LTPA at a mild intensity or greater. Median LTPA was 33.33min/d. More activity was done at a moderate intensity (mean +/- SD, 25.49+/-42.11min/d) than mild (mean +/- SD, 19.14+/-37.77min/d) or heavy intensities (mean +/- SD, 10.52+/-22.17min/d). Most participants reported mild (54%) or moderate intensity LTPA (68%), while a minority reported heavy intensity LTPA (43%). The 3 most frequently reported types of LTPA were resistance training (33%), aerobic exercise (25%), and wheeling (24%). Craftsmanship (mean +/- SD, 83.79+/-96.00min/d) and sports activities (mean +/- SD, 60.86+/-59.76 min/d) were performed for the longest durations. CONCLUSIONS: There is considerable variability in daily LTPA among active people with SCI and variability across different types of LTPA in terms of typical durations and intensities. This information can be used to help people with chronic SCI become more active by highlighting activities that meet individual abilities, needs, and desires.

On the interaction of disability and aging: Accelerated degradation models and their influence on projections of future care needs and costs for personal injury litigation.

PURPOSE: Accelerated degradation models are emerging as ways to characterize the interaction between disability and the functional decline of aging and to provide insights about the processes of aging with disability. Typically the models employ sophisticated mathematical treatments that are beyond the scope of many clinicians, lawyers, and others who might benefit from the information they contain. The purpose of this report is to characterize some rudimentary features of the models, in more readily understandable language, and illustrate how understanding of the underlying constructs can influence decisions regarding resource allocation and other projections of future care needs. METHODS: A literature review of longitudinal aging and disability studies was completed and simplified mathematical modeling undertaken, with hypothetical data, to illustrate various outcomes of the interaction of disability with the functional decline of aging. A specific example, drawn from personal injury litigation, i.e. projection of future care costs, was used to illustrate the practical applicability of this conceptual model. CONCLUSION: Awareness of the accelerated functional decline brought about by the superimposition of age-related functional losses on pre-existing disability reveals a need to provide for aids and personnel supports at an earlier age than might be expected because of the multiplicative interaction and the inadequacy of functional reserves to compensate for the disability.

Greater daily leisure time physical activity is associated with lower chronic disease risk in adults with spinal cord injury.

The objective of this study was to examine the relationship between leisure time physical activity (LTPA) and common risk factors for cardiovascular disease (CVD) and type 2 diabetes in community-dwelling adults with chronic spinal cord injury (SCI). LTPA was measured using the Physical Activity Recall Assessment for People with SCI in 76 men and women with chronic (> or =1 year) paraplegia or tetraplegia, living in or near Hamilton, Ontario. Body mass index (BMI), waist circumference, body composition (fat mass (FM) and fat-free mass (FFM)), blood pressure, and biochemical data were collected. Thirty-seven percent (n = 28 participants) were inactive, reporting no LTPA whatsoever, and were compared with an equal-sized group consisting of the most active study participants (> or =25 min of LTPA per day). After adjusting for significant covariates, BMI (18.7%), %FM (19.4%), and C-reactive protein (143%) were all lower, and %FFM was higher (7.2%), in active participants (all p < or = 0.05). Ten percent of active participants vs. 33% of inactive participants were insulin resistant (p = 0.03). Waist circumference (17.6%) and systolic blood pressure (15.3%) were lower in active vs. inactive participants with paraplegia (both p < or = 0.05), but not tetraplegia. In conclusion, greater daily LTPA is associated with lower levels of selected CVD and type 2 diabetes risk factors in individuals living with SCI. Whether this relationship translates into a lower incidence of these chronic diseases has yet to be determined.

Intermittent catheterization practices following spinal cord injury: a national survey.

OBJECTIVE: To identify intermittent catheterization (IC) practices and factors associated with urinary tract infection (UTI) in community-dwelling people living with spinal cord injury (SCI) in Canada. STUDY DESIGN: A national survey employing a 36-item self-report questionnaire that was mailed to members of the Canadian Paraplegic Association (CPA). RESULTS: There were 912 respondents with SCI of either traumatic or nontraumatic etiology. Fifty-five percent of the respondents used IC. The mean age of users (47+/-14 years) was significantly younger than non-users (53+/-13 years) and a greater percentage of males (57%) than females (50%) used IC. Of those who used IC, 26% use hydrophilic catheters either exclusively or sometimes. The mean frequency of UTIs in the past 12 months for IC users was 2.6+/-2.6. Among IC users, females had a significantly greater number of UTIs than males (p=0.003). Linear regression analysis revealed that the variables of sex, number of catheterizations per day, age, and tetraplegia versus paraplegia were individually correlated with infection rate but collectively only explained a small proportion of the variance. Time lost from social activities due to UTIs was associated with compromised quality of life more so than the actual number of UTIs or days lost from work. CONCLUSION: The survey identifies existing IC practices and confirms previous reports of UTI rate being dependent on frequency of catheterization and reduced infection rates in individuals using hydrophilic catheters. UTI rates were significantly associated with several clinical and demographic variables but only poorly modeled by the IC practices and lifestyle variables investigated in this study.

Clinical correlates of elevated serum concentrations of cytokines and autoantibodies in patients with spinal cord injury.

OBJECTIVE: To determine the serum cytokine profiles of patients with spinal cord injury (SCI) and varying clinical presentations relative to healthy, able-bodied, age-matched control subjects. DESIGN: Cross-sectional study. SETTING: Clinical research unit. PARTICIPANTS: People with SCI (N=56) and different clinical presentations, and healthy, able-bodied, age-matched control subjects (N=35). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Serum levels of the proinflammatory cytokines interleukin (IL) 1beta, IL-6, tumor necrosis factor alpha (TNF-alpha), the anti-inflammatory cytokines IL-4 and IL-10, the regulatory cytokine IL-2, the IL-1 receptor antagonist (IL-1RA), and autoantibodies against myelin-associated glycoprotein and GM(1) ganglioside (anti-GM(1)) immunoglobulin (IgG and IgM), as determined by enzyme-linked immunosorbent assay. The relationship between elevated serum cytokine levels and clinical variables was also studied. RESULTS: SCI subjects exhibited serum concentrations of IL-6, TNF-alpha, IL-1RA, and anti-GM(1) (IgG) that were greater (P<.05) than control group values. Elevated cytokine concentrations were not associated with high white blood cell counts, level of injury, or American Spinal Injury Association classification; they were evident in SCI subjects who were asymptomatic for medical complications, but were further elevated in subjects with pain, urinary tract infection (UTI), and pressure ulcers. CONCLUSIONS: Elevated levels of circulating proinflammatory cytokines and autoantibodies are present in the serum of SCI subjects without medical complications, and are further elevated in SCI subjects with neuropathic pain, UTI, or pressure ulcers, relative to healthy, able-bodied control subjects. These findings may be indicative of a protective autoimmunity, simply a consequence of occult or evident infection, or evidence of cytokine dysregulation that may contribute to an immune-mediated impairment of axonal conduction.

Fampridine-SR for multiple sclerosis and spinal cord injury.

Fampridine-SR is a sustained-release tablet form of the K(+) channel-blocking compound 4-aminopyridine that has been shown to restore conduction in focally demyelinated axons, to enhance synaptic transmission in many types of neurons and to potentiate muscle contraction. The present review describes the mechanism of action and chemistry of Fampridine-SR, its pharmacokinetics and safety, and the outcomes of clinical trials of its safety and efficacy for enhancing neuromuscular function in patients with multiple sclerosis or spinal cord injury. Randomized clinical trials completed to date indicate that this form of K(+) channel blockade may be useful for the improvement of walking ability in patients with multiple sclerosis.

Nitric oxide reversibly impairs axonal conduction in Guinea pig spinal cord.

Increased expression of the inducible and neuronal isoforms of nitric oxide synthase (NOS), and elevated concentrations of nitric oxide (NO) metabolites, are present within the central nervous system (CNS) following neurotrauma and are implicated in the pathogenesis of the accompanying neurologic deficits. We tested the hypothesis that elevated extracellular concentrations of NO introduced by the donor Spermine NONOate, induce reversible axonal conduction deficits in neurons of the guinea pig spinal cord. The compound action potential (CAP) and compound membrane potential (CMP) of excised ventral cord white matter were recorded before, during, and after bathing the tissue (30 min) in varying concentrations (0.25-3.0 mM) of Spermine NONOate. The principal results were a rapid onset, dose-dependent, reduction in amplitude of the CAP (p < 0.05) accompanied by depolarization of the CMP during NO exposure. These effects were largely reversible on washout, at low concentration of the donor (0.5 mM), but were only partially reversed at higher concentrations. Changes in the electrophysiological properties were not evident when the donor had been a priori depleted of NO. The results extend previous reports that NO induces reversible axonal conduction deficits. They provide new evidence of dissociation of the effects of NO on CAP and CMP during washout, and after prolonged exposure to the donor. They add support to the emerging concept that immune-mediated axonal conduction failure contributes to reversible neurologic deficits following neurotrauma and aid in understanding clinical phenomena such as spinal shock and neurologic recovery.

Recombinant human TNFalpha induces concentration-dependent and reversible alterations in the electrophysiological properties of axons in mammalian spinal cord.

Increased expression of the proinflammatory cytokine tumor necrosis factor-alpha (TNFalpha) and its soluble receptors is evident within the central nervous system (CNS) following traumatic brain injury and spinal cord injury. TNFalpha is integral to the acute inflammatory cascade that follows neurotrauma and has been shown to have both beneficial and detrimental properties. We examined the effects of varying concentrations (1-5000 ng/mL) of recombinant human TNFalpha (rhTNFalpha) on select electrophysiological properties of excised guinea pig spinal cord tissue. Pulsed electrical stimuli (0.33 Hz) were delivered to strips of isolated ventral white matter in a double sucrose gap chamber. Recordings were made of the compound action potential (CAP) and membrane potential before, during, and after bathing the tissue with rhTNFalpha for 30 min. Increasing concentrations of rhTNFalpha yielded progressively greater reductions in amplitude of the CAP that were temporally associated with depolarization of the resting compound membrane potential. These effects were largely reversed on washout of rhTNFalpha and were not present when heat-denatured rhTNFalpha was introduced. The results provide evidence that elevated concentrations of TNFalpha induce reversible depolarization of the compound membrane potential and reduction in CAP amplitude, sometimes to the point of extinction of the CAP, suggestive of impaired axonal conduction. These observations point to a new mechanism of immune-mediated central conduction deficit. Cytokine-induced alterations in membrane properties and axonal conduction may contribute to neurological deficits following CNS injury by compounding trauma-induced myelinopathy and axonopathy.

The use of 4-aminopyridine (fampridine) in demyelinating disorders.

4-Aminopyridine (4-AP or fampridine) is a potassium channel-blocking agent that has been shown to restore conduction in focally demyelinated axons. A sustained-release matrix tablet form of 4-AP (fampridine-SR) is currently undergoing multicenter clinical trials in patients with multiple sclerosis or chronic spinal cord injury. This review describes the pharmacology and mechanisms of action of 4-AP, its pharmacokinetics in human subjects, and the outcomes of clinical trials employing either immediate-release or sustained-release formulations of the drug. The randomized clinical trials that have been completed to date indicate that K+ channel blockade may prove to be a useful strategy for ameliorating central conduction deficits due to demyelination. Diverse neurological gains have been reported for both motor and sensory domains. At the present time, however, the clinical trials have not provided sufficiently robust or definitive evidence of efficacy to gain regulatory approval for the symptomatic management of patients with either multiple sclerosis or spinal cord injury.

Pharmacokinetics and safety of multiple oral doses of sustained-release 4-aminopyridine (Fampridine-SR) in subjects with chronic, incomplete spinal cord injury.

OBJECTIVE: To examine the pharmacokinetics and safety of sustained-release 4-aminopyridine (Fampridine-SR), a potassium channel blocker, in subjects with chronic, incomplete spinal cord injury (SCI). DESIGN: Open-label. SETTING: Clinical research unit in Ontario. PARTICIPANTS: Sixteen neurologically stable subjects with chronic, incomplete SCI (American Spinal Injury Association Impairment Scale grade B, C, or D). INTERVENTION: Oral administration of Fampridine-SR (25, 30, 35, 40, 50, 60 mg twice daily, each for 1 wk). MAIN OUTCOME MEASURES: Steady-state pharmacokinetic parameters: maximum observed plasma concentration (Cmax), minimum observed plasma concentration (Cmin), average observed plasma concentration (Cav), area under the plasma concentration-time curve from 0 to 12 hours (AUC(0-12)), time to Cmax (tmax), plasma half-life (t(1/2)), apparent volume of distribution (Vd/F), and apparent total clearance (Cl/F). Safety assessments: physical examinations, vital sign measurements, clinical laboratory tests, electrocardiogram recordings, and adverse events. RESULTS: Mean steady-state Cmax, Cmin, Cav, and AUC(0-12) increased over the entire Fampridine-SR dosage range and were dosage dependent up to 50 mg twice daily. Fampridine-SR had a mean tmax of 2.2 to 3.0 hours and a mean t(1/2) of 5.7 to 6.9 hours. Mean Vd/F (415.4-528.0 L) and Cl/F (51.4-57.7 L/h) were independent of dosage, as were mean tmax and t(1/2) across dosages. Adverse events were mild or moderate and were not dosage related. During the entire study period (17 wk), dizziness was the most frequently reported adverse event, followed by urinary tract infection, paresthesia, ataxia, and insomnia. CONCLUSION: In subjects with chronic, incomplete SCI, Fampridine-SR was slowly absorbed and eliminated, which will allow Fampridine-SR to be administered in a convenient twice-daily manner. Fampridine-SR was well tolerated at dosages from 25 to 60 mg twice daily.