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Biomedical subjects

Andrew R Blight

Publications and source records attributed to Andrew R Blight.

7 recordsLinked to original sources
PubMed2006

4-chloro-3-hydroxyanthranilate reduces local quinolinic acid synthesis, improves functional recovery, and preserves white matter after spinal cord injury.

Inflammatory processes within the central nervous system (CNS) contribute significantly to the pathogenesis of a broad range of neurologic diseases, including spinal cord injury (SCI). One mechanism by which immune activation causes neurologic symptoms and tissue injury is via the production of neurotoxins by activated macrophages and microglia. In the present study, the role of the endogenous tryptophan metabolite and neurotoxin quinolinic acid (QUIN) in secondary pathology following traumatic SCI was investigated. Adult Hartley guinea pigs were injured by lateral compression of the spinal cord at the 12th thoracic segment (T12). QUIN had accumulated at the site of injury on day 12 post-injury in proportion to the severity of functional neurologic deficits (as assessed by the cutaneus trunci muscle reflex and motor function score at 5 h post-injury). Systemic administration of the 3-hydroxyanthranilate-3,4-dioxygenase (3-HAD) inhibitor, 4-chloro-3-hydroxyanthranilate (4Cl-3HAA; approximately 100 mg/kg every 12 h, beginning 5 h after injury) attenuated local QUIN production and reduced QUIN accumulation at the site of injury by approximately 50% at day 12, without enhanced accumulations of the neuroprotective metabolite kynurenic acid (KYNA). The severity of secondary functional deficits was also reduced by 4Cl-3HAA. In toluidine blue-stained spinal cord sections, the area of surviving intact white matter at the injury site was increased by approximately 100% in the 4Cl-3HAA-treated group. Sparing of both axons and myelin contributed to this increase. These results support the conclusion that QUIN accumulations at the site of injury contribute to secondary functional deficits and tissue damage following SCI.

3-Hydroxyanthranilic Acid↗
PubMed2005

Chondroitinase ABCI improves locomotion and bladder function following contusion injury of the rat spinal cord.

Chondroitin sulfate proteoglycans are synthesized and deposited in the spinal cord following injury. These proteoglycans may restrict regeneration and plasticity and contribute to the limited recovery seen after an injury. Chondroitinase, a bacterial enzyme that catalyzes the hydrolysis of the chondroitin chains on proteoglycans, has been shown to improve motor and sensory function following partial transection lesions of the spinal cord. To assess the effects of chondroitinase in a clinically relevant model of spinal cord injury, 128 female Long-Evans rats received either a severe, moderate, or mild contusion injury at the vertebral level T9/T10 with a forceps model and were treated for 2 weeks with chondroitinase ABCI at 0.06 Units per dose, penicillinase, or vehicle control via an intrathecal catheter placed near the injury. Motor behavior was measured by open-field testing of locomotion and bladder function monitored by measuring daily residual urine volumes. Animals treated with chondroitinase showed significant improvements in open-field locomotor activity as measured by the Basso, Beattie and Bresnahan scoring system after both severe and moderate SCI (p<0.05 and 0.01, respectively). No significant locomotor differences were observed in the mild injury group. In the moderate injury group, residual urine volumes were reduced with chondroitinase treatment by 2 weeks after injury (p<0.05) and in the severe injury group, by 6 weeks after injury (NS). These results demonstrate that chondroitinase is effective at promoting both somatic and autonomic motor recovery following a clinically relevant contusion spinal cord injury and is a candidate as a therapeutic for human spinal cord injury.

Animals↗
PubMed2004

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.

4-Aminopyridine↗
PubMed2002

Miracles and molecules--progress in spinal cord repair.

Severe spinal cord injury (SCI) leads to devastating loss of neurological function below the level of injury and adversely affects multiple body systems. Most basic research on SCI is designed to find ways to improve the unsatisfactory cellular and molecular responses of spinal cord to injury, which include an array of early processes of autodestruction and a subsequent lack of functional tissue repair. This research has brought us to the threshold of practical application along three lines of approach, derived from animal model studies: acute neuroprotection, enhanced axonal regeneration or plasticity, and treatment of demyelination. There is a growing commercial interest in this previously neglected therapeutic area.

Animals↗
PubMedDate not supplied

Clinical trials in spinal cord injury.

Progress in promoting axonal plasticity and regeneration in animal models of spinal cord injury (SCI) has led to novel prospects for the initiation of human clinical trials in the near future. This review discusses a number of considerations in the path to translating a preclinical candidate from the laboratory to clinical testing. We will also briefly discuss issues associated with the design, performance, analysis, and reporting of human clinical trials in SCI. It is important, for both the medical community and the spinal cord injured community, that objective scientific and medical standards are adopted in the clinical translation of potentially promising, but as yet unproven, therapies for SCI.

Clinical Trials as Topic↗
PubMedDate not supplied

Pharmacokinetic studies of single and multiple oral doses of fampridine-SR (sustained-release 4-aminopyridine) in patients with chronic spinal cord injury.

Fampridine (4-aminopyridine) is a potassium channel blocking agent that restores conduction in demyelinated axons and improves neurologic function in patients with chronic spinal cord injury (SCI). Based on the pharmacokinetic profile of orally administered fampridine, multiple daily doses (4 or more) would need to be taken to sustain its therapeutic effects. Two studies were conducted to determine the pharmacokinetics and safety profile of an oral, sustained-release (SR) formulation of fampridine (fampridine-SR, 10-25 mg) administered as a single dose (n = 14) and twice daily for 1 week (n = 16) in patients with chronic, incomplete SCI. Mean plasma concentrations and area under the plasma concentration-time curve were proportional to the dose administered, whereas other pharmacokinetic parameters were independent of dose. Fampridine-SR was absorbed slowly (peak plasma concentration shortly after dosing, 2.6-3.7 hours) and eliminated (plasma half-life, 5.6-7.6 hours), and reached steady state after 4 days of twice-daily administration. Fampridine-SR was well tolerated, with only mild to moderate adverse events reported, and no serious adverse events. The extended plasma half-life of fampridine-SR allows convenient twice-daily dosing. Clinical trials designed to assess neurologic and functional improvement using fampridine-SR in patients with chronic SCI are currently underway.

4-Aminopyridine↗