In large phase III trial, 4-AP proven to improve walking ability in MS

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[S32.003] A Phase 3, Multi-Center Trial of Oral, Sustained-Release Fampridine (4-Aminopyridine) in Multiple Sclerosis

Andrew Goodman, Steven Schwid, Rochester, NY, Theodore Brown, Seattle, WA, Lauren Krupp, Stony Brook, NY, Randall Schapiro, Golden Valley, MN, Lawrence Marinucci, Ron Cohen, Andrew Blight, Hawthorne, NY.

OBJECTIVE: To assess efficacy and safety of oral sustained release fampridine (Fampridine-SR) in patients with multiple sclerosis (MS).

BACKGROUND: Prior studies of fampridine in MS have reported beneficial effects on motor function, including ambulation. This study was designed to confirm such effects and to validate their clinical meaningfulness.

DESIGN/METHODS: Randomized, double-blind, placebo-controlled, parallel-group study comparing 10 mg fampridine bid and placebo (3:1 ratio). A 2-week placebo run-in was followed by a 14 week treatment period, and a 4 week follow-up period. Eligibility criteria included: definite MS diagnosis, with any type of MS clinical course; age 18-70; completion of the Timed 25-Foot Walk (T25FW) within 8-45 seconds at screening; concomitant medications permitted on a stable regimen throughout trial.

The primary outcome measure was the proportion of responders with consistent improvement in walking speed on the T25FW during the treatment period. The Multiple Sclerosis Walking Scale 12 (MSWS-12) was used to assess clinical meaningfulness.

RESULTS: 301 patients were randomized; 229 received fampridine and 72 placebo. 283 patients completed the trial (n = 212, 71). The fampridine-treated group had a higher proportion of responders, compared to the placebo group (34.8 % v. 8.3 %; p < 0.001). Response rates were higher across all clinical course types. Improvement in walking speed was consistent through the 14 week treatment period among patients who responded to fampridine and remained significantly different from placebo after 14 weeks (p < 0.001).

Responders v. non-responders showed significant improvement in the MSWS-12 (p < 0.001). Adverse events were similar to those observed in previous studies of fampridine in MS. Two serious adverse events attributed to fampridine that led to discontinuation were anxiety in one participant and a seizure during a period of urosepsis in another.

CONCLUSIONS/RELEVANCE: A significant proportion of MS patients treated with fampridine experienced consistently improved walking speed during 14 weeks of treatment. Improvement in the MSWS-12 score among responders appears to validate the clinical meaningfulness of this improvement.

Supported by: Acorda Therapeutics Inc., Hawthorne, NY.

[BBS1951]

I"ve had my eye on this drug for a while, in case my walking gets worse. Resesarch is still looking good for 4AP

After hearing about 4 AP here on BT a few years ago, I passed it on to my pharmacist whose friend had a spinal cord injury and couldnt walk at all. He started 4 AP and can now walk with a cane. Its amazing cuz his docs at Univ of Miami never thought of trying it.

[bluesky63]

A great med to try, but one caution: apparently it lowers the seizure threshold and is therefore not OK for people who have seizures.

[mark53]

thanks Mark, i see my MS Doctor in April, i'm going to ask him about 4 AP

[Braindead]

It seems that Vinpocetine could lower seizure risk. I wonder if it could also lower effectiveness of the 4AP. I am already taking 10 Mg of Vinpocetine twice a day for bladder and general neuron health.

Braindead



1: Neurochem Int. 2005 Jun;46(7):533-40.

Vinpocetine blockade of sodium channels inhibits the rise in sodium and calcium
induced by 4-aminopyridine in synaptosomes.

Sitges M, Galvan E, Nekrassov V.

Departmento de Biologia Celular y Fisiologia, Instituto de Investigaciones
Biomedicas, UNAM, Apartado Postal 70228, Ciudad Universitaria 04510, Mexico,
D.F., Mexico.

The objective of this study was to get a more understandable picture of the
mechanism underlying the anticonvulsant action of vinpocetine. The question of
how the cerebral excitability is affected was investigated by determining the
effect of vinpocetine on the changes on the internal concentrations of Na(+)
(Na(i)) and Ca(2+) (Ca(i)) induced by different concentrations of the convulsing
agent 4-aminopyridine (4-AP) in striatal isolated nerve endings. The cytosolic
concentrations of Na(i) and Ca(i) were detected fluorimetrically with
sodium-binding benzofuran isophthalate (SBFI) and fura-2, respectively.
Vinpocetine, like the Na(+) channel blocker, tetrodotoxin, abolished the
increase in Na(i) induced by 0.1 mM 4-AP and only inhibited in 30% the rise in
Na(i) induced by 1mM 4-AP. In contrast with the different sensitivity of the
rise in Na(i) induced by 0.1 and 1mM 4-AP to vinpocetine and tetrodotoxin, the
rise in Ca(i) induced by the two concentrations of 4-AP was markedly inhibited
by vinpocetine (and tetrodotoxin), indicating that only the voltage-sensitive
sodium channels (VSSC)-mediated fraction of the rise in Na(i) induced by 4-AP is
linked with the activation of pre-synaptic Ca(2+) channels. The elevation of
Ca(2+) induced by high K(+) (30 mM) does not require a Na(+) gradient and is
vinpocetine and tetrodotoxin insensitive. In contrast, the elevation of Ca(i)
induced by 4-AP, requires a physiological (out/in) Na(+) gradient and is
vinpocetine and tetrodotoxin-sensitive. It is concluded that by blocking the
tetrodotoxin-sensitive fraction of the rise in Na(i) induced by 4-AP,
vinpocetine inhibits the concomitant rise in Ca(i) induced by 4-AP. The
inhibitory effect of vinpocetine on pre-synaptic voltage-sensitive sodium
channels may underlie the in vivo anticonvulsant action of vinpocetine.

PMID: 15843047 [PubMed - indexed for MEDLINE]