3,4-diaminopyridine as a treatment for amyotrophic lateral sclerosis.

The slow potassium channel blocker 3,4-diaminopyridine (DAP) enhances acetylcholine release from the nerve terminal and improves conduction in unmyelinated nerve. In this open label pilot study, we examined the effect of DAP combined with inpatient rehabilitation in seven patients with motor weakness due to amyotrophic lateral sclerosis (ALS). A single daily 20 mg oral dose of DAP was gradually increased to the maximum tolerated dose, and serum DAP concentrations were measured. Videotaped motor examination (for subsequent "blinded" review and assignment of a quantitative motor score), Functional Independence Measure (FIM) assessment, nerve conduction studies and neuropsychological evaluations were performed on admission, 1 h after maximum DAP dose, and post-treatment. DAP was tolerated in all patients, though dose was limited by gastrointestinal side effects in five patients. The mean peak serum level was 128 (+/- 50) ng/ml, occurring 1.0 (+/- 0.50) h after dose. A modest but statistically significant (p = 0.045) peak in motor score occurred on DAP. A significant (p = 0.045) improvement from baseline in FIM performance was apparent with DAP. Nerve conduction studies showed small increases in evoked response amplitudes and conduction velocities on DAP, but they did not reach statistical significance. No cognitive or affective changes were apparent. This unblinded pilot study shows that DAP is tolerated in ALS patients, and may be associated with functional and electrophysiologic improvement.