Table 2.

4-aminopyridine

Authors Year Country Score Research Design Sample Size	Methods	Outcomes	Side Effects
DeForge et al. 2004 Canada PEDro = 8 RCT N=15 Not combined with training	Population: 15 subjects with AIS D; age 22–70 yrs; C3-T12 lesion level; 1–20 years post-injury. Treatment: Double-blind, placebo-controlled, crossover design; 4-AP: up-titration to 10 mg 4x/day stable dosing of 4-AP versus Placebo, 2 weeks each condition. Outcome measures: Isometric muscle force, gait analysis (including temporal-spatial data, EMG, joint kinematics and kinetics).	14 subjects completed study, 1 drop out due to side effects of 4-AP. No significant difference in strength or gait outcomes between placebo and 4-AP. Average increase in self-selected over ground walking speed was 0.06 m/s when on placebo and 0.08 m/s when on 4-AP. Average increase in maximum over ground walking speed was 0.09 m/s when on placebo and 0.14 m/s when on 4-AP. No effect of order of 4-AP administration.	Nausea, dizziness and sleeping difficulties in 50% of subjects. One subject did not tolerate 40 mg dosage due to nausea and dizziness and was kept at 10 mg. One subject dropped out of study due to severe side effects (dizziness, weakness, regression in walking ability).
van der Bruggen et al. 2001 Netherlands PEDro = 7 RCT N=20 Not combined with training	Population: 20 subjects, 1 AIS B, 5 AIS C, 14 AIS D; age: 25–70 yrs; C2-L3 lesion level; 3–56 yrs post-injury. Treatment: Double-blind, placebo-controlled, crossover design: up-titration to maximum of 15–45 mg, immediate-release 4-AP capsules or Placebo, 4 weeks each condition. Two-week washout between conditions. Outcome measure: functional status (Darmouth COOP Functional Health Assessment), comfortable and maximum over ground walking speed, vibration perception threshold.	1 subject dropped out due to reasons not related to study. No significant difference in outcomes between placebo and 4-AP. 3/12 ambulatory subjects showed positive change (>10%), 4/12 showed no change, and 5/12 showed >10% reduction in comfortable walking speed with 4-AP vs. placebo. 1/12 ambulatory subjects showed positive change (>10%), 6/12 showed no change, and 4/12 showed >10% decrease in maximum walking speed with 4-AP vs. placebo.	Mild and transient side-effects in 8/12 patients included giddiness (4/12), headache (4/12) and flu-like symptoms (4/12).
Segal & Brunnemann 1998 USA Downs & Black = 16 Pre-post N=9 Not combined with training	Population: 9 subjects with AIS C or D; age 28–60 yrs; C2-L4 lesion level; 4–28 yrs post-injury. Treatment: 4-AP (single 10 mg immediate-release capsule). Comparison of means at baseline and at 9 pre-determined intervals over a 24-hour follow-up. Outcome measures: Over ground gait parameters (e.g. velocity, cadence).	Significant improvements in walking speed within 24 hours of 4-AP ingestion (36% ↑ from 24.1 ± 16.5 m/min to 32.7 ± 22.9 m/min). Significant improvements in stride length (11% ↑ from 0.9 ± 0.3 meters to 1.0 ± 0.3 meters. Non-significant ↑ in cadence and gait cycle duration. Gait changes began 6 hours after drug administered and persisted during the 24 hour follow-up.	None reported.