4-Aminopyridine for symptomatic treatment of multiple sclerosis: a systematic review

Abstract

This systematic review summarizes the existing evidence on the effect of 4-aminopyridine (4-AP) as a symptomatic treatment of decreased walking capacity in patients with multiple sclerosis (MS) when administered as an immediate release compound and a slow release compound. It summarizes existing evidence on the basic mechanisms of 4-AP from experimental studies and evidence on the clinical use of the compound. A systematic literature search was conducted of the following databases: PubMed and EMBASE. Thirty-five studies were included in the review divided into 16 experimental studies, two clinical studies with paraclinical endpoints and 17 clinical studies with clinical endpoints. Animal studies show that 4-AP can improve impulse conduction through demyelinated lesions. In patients with MS this translates into improved walking speed and muscle strength of the lower extremities in a subset of patients at a level that is often of clinical relevance. Phase III trials demonstrate approximately 25% increase in walking speed in roughly 40% and improved muscle strength in the lower extremities. Furthermore, 4-AP might have an effect on other domains such as cognition, upper extremity function and bowel and bladder, but this warrants further investigation. Side effects are mainly mild to moderate, consisting primarily of paraesthesia, dizziness, nausea/vomiting, falls/balance disorders, insomnia, urinary tract infections and asthenia. Side effects are worse when administered intravenously and when administered as an immediate release compound. Serious adverse events are rarely seen in the marketed clinical dosages. In conclusion, 4-AP is easy and safe to use. Slow release 4-AP shows more robust clinical effects and a more beneficial side-effect profile than immediate release 4-AP.

Keywords: 4-aminopyridine; experimental studies; fampridine slow release; multiple sclerosis; translational medical research; treatment outcome.

Conflict of interest statement

Conflict of interest statement: HBJ has received travel grants and teaching honoraries from Biogen Idec, Novartis, Almirall and Merck Serono and serves as an advisory board member for Novartis and Almirall. UD has received research support, travel grants and teaching honoraries from Biogen Idec, Merck Serono and Sanofi Aventis. UD further serves as PI for the ongoing Biogen-sponsored ACTIMS study. MR has received travel grants and consultancy honoraries from Biogen Idec, Genzyme, TEVA and Novartis and serves as an advisory board member for Biogen Idec. ES has received unrestricted research grants and travel support from Biogen Idec, Merck Serono and Bayer Schering and travel grants from Novartis.

Figures

Figure 1.

Consort diagram of papers identified and included.