Safety and Efficacy of 4‐Aminopyridine in Humans with Spinal Cord Injury: A Long‐Term, Controlled Trial

Segal, Jack L.; Pathak, Mayank; Hernández, Jesús Pérez; Himber, Peter L.; Brunnemann, Sherry R.; Charter, Richard S.

doi:10.1592/phco.19.9.713.31540

Cited by 82 publications

(91 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Clinicians equate improvement with quantitative measures while subjects may perceive general positive changes due to an increase in energy level and mood. Segal et al 32 reported enhanced pulmonary function in SCI subjects after 4-AP. Walking efficiency, which was not measured in the present trial, may be worth future study.…”

Section: Discussionmentioning

confidence: 98%

Effect of 4-aminopyridine on gait in ambulatory spinal cord injuries: a double-blind, placebo-controlled, crossover trial

et al. 2004

View full text Add to dashboard Cite

Animal and human research have shown that the drug 4-aminopyridine (4-AP) may improve gait in spinal cord lesions by enhancing nerve transmission to affected muscles. Study design: Prospective, randomized, double-blind, placebo-controlled, crossover trial. Objectives: To determine the efficacy of 4-AP in improving lower limb muscle strength and biomechanical gait patterns of chronic spinal cord injuries (SCI). Setting: The Rehabilitation Centre (Ottawa, Canada). Methods: In all, 15 chronic, ambulatory SCI persons were randomized to an initial 2 weeks of 40 mg/day, oral medication of either placebo or immediate-release, 4-AP and subsequently crossed over to the alternate medication for the following 2 weeks. Evaluations were conducted at baseline (before starting 4-AP or placebo medication), 2 weeks, and 4 weeks. Measures included dynamometer lower limb isometric muscle force and biomechanical gait measures including temporal-spatial parameters, electromyographic activation patterns, joint kinematics and kinetics. Subjective impressions of the drug by the participants were obtained from an exit survey. Results: Despite some positive comments from subjects, statistical and clinical analyses showed no within-subject differences between placebo and 4-AP measures of lower limb muscle force and objective gait analyses (ANOVA statistic P40.05). Conclusion: Results demonstrated the importance of placebo-controlled trials and quantitative outcome measures for the evaluation of 4-AP aimed to enhance gait for chronic, ambulatory SCI persons. Energy expenditure measures and mood may relate more to subjective comments and is suggested for future investigations.

show abstract

Section: Discussionmentioning

confidence: 98%

Effect of 4-aminopyridine on gait in ambulatory spinal cord injuries: a double-blind, placebo-controlled, crossover trial

et al. 2004

View full text Add to dashboard Cite

show abstract

“…4-AP and its analogs have numerous clinical applications, including treatment of neuromuscular and neurodegenerative disorders and traumatic injuries of the CNS (Li and Zhang, 1994;Pinter et al, 1997;Fujihara and Miyoshi, 1998;Gruner and Yee, 1999;Segal et al, 1999;Andreani et al, 2000). All of the therapeutic activities of 4-AP are currently explained by blockade of voltageactivated K ϩ channels (Vislobokoe et al, 1983;Davies et al, 1991;Choquet and Korn, 1992;Kirsch and Drewe, 1993;Castle et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…A number of reports address the beneficial role of 4-AP and related compounds in multiple sclerosis (Schwid et al, 1997;Fujihara and Miyoshi, 1998), myasthenia gravis (Li and Zhang, 1994), and in the canine model of motoneuron disease (Pinter et al, 1997). Clinical applications of 4-AP have been extended to traumatic spinal cord injury (Segal et al, 1999) and to neurodegenerative disorders such as Alzheimer's disease (Andreani et al, 2000). In all these instances, 4-AP has been thought to improve symptomatology through the blockade of voltage-activated K ϩ channels, in turn, causing neuronal depolarization and potentiation of neurotransmission (Smith et al, 2000).…”

mentioning

confidence: 99%

Mobilization of Calcium from Intracellular Stores, Potentiation of Neurotransmitter-Induced Calcium Transients, and Capacitative Calcium Entry by 4-Aminopyridine

et al. 2001

View full text Add to dashboard Cite

In this study we analyzed the effect of 4-aminopyridine (4-AP) on free cytosolic calcium concentration ([Ca 2ϩ ] i ) in basal conditions, after stimulation with neurotransmitters, and during capacitative calcium entry.Using fura-2 ratiometric calcium imaging, we found that 4-AP increased [Ca 2ϩ ] i in type I astrocytes, neurons, and in skeletal muscle cells. The [Ca 2ϩ ] i elevation induced by 4-AP was concentration-dependent and consisted of two phases: the first was dependent on intracellular calcium mobilization, and the second was dependent on extracellular calcium influx. 4-AP also increased the second messenger inositol trisphosphate in both neurons and astrocytes.In astrocytes, 4-AP treatment potentiated the sustained phase of the [Ca 2ϩ ] i elevation induced by ATP and bradykinin. In addition, capacitative calcium entry was potentiated severalfold by 4-AP, in astrocytes and muscle cells but not in neurons. These effects of 4-AP were completely and promptly reversible. 4-AP blocked voltage-sensitive K ϩ currents in astrocytes. However, voltage-sensitive K ϩ channel blockers inhibiting these currents did not affect agonist-induced calcium transients or capacitative calcium entry, indicating that 4-AP effects on [Ca 2ϩ ] i were not caused by the blockade of voltagegated K ϩ channels. We conclude that 4-AP is able to affect calcium homeostasis at multiple levels, from increasing basal [Ca 2ϩ ] i to potentiating capacitative calcium entry. The potentiation of capacitative calcium entry in astrocytes or muscle cells may explain some of the therapeutic activities of 4-AP as a neurotransmission enhancer.

show abstract

“…Unfortunately, research regarding its efficacy in SCI has been inconclusive. Although animal models and some early studies reported improvement in function and sensation, subsequent randomized, placebo-controlled studies have not demonstrated clinically significant benefits [16][17][18][19][20][21][22]. Summative interpretation of these results is difficult due to small numbers, mixed patient populations and variations in duration, dosage, and mechanism of administration.…”

Section: Introductionmentioning

confidence: 99%

4-Aminopyridine Toxicity: a Case Report and Review of the Literature

et al. 2012

View full text Add to dashboard Cite

Safety and Efficacy of 4‐Aminopyridine in Humans with Spinal Cord Injury: A Long‐Term, Controlled Trial

Cited by 82 publications

References 26 publications

Effect of 4-aminopyridine on gait in ambulatory spinal cord injuries: a double-blind, placebo-controlled, crossover trial

Effect of 4-aminopyridine on gait in ambulatory spinal cord injuries: a double-blind, placebo-controlled, crossover trial

Mobilization of Calcium from Intracellular Stores, Potentiation of Neurotransmitter-Induced Calcium Transients, and Capacitative Calcium Entry by 4-Aminopyridine

4-Aminopyridine Toxicity: a Case Report and Review of the Literature

Contact Info

Product

Resources

About