What is the information concerning the treatment of MS with 4-aminopyridine? What is mechanism of a

Fråga: What is the information concerning the treatment of MS with 4-aminopyridine? What is mechanism of action, therapeutic effectiveness and side effects of 4-AP? Can it be prescribed on license or ex tempore in Sweden?

Sammanfattning: 4-AP blocks potassium channel and restores action potential propagation in demyelinated fibers.

Several studies suggest that 4-AP has therapeutic potential for symptomatic treatment of MS in temperature-sensitive patients and patients with a longer duration of disease and in a progressive phase of disease. However, the therapeutic effects of this compound have not been unequivocally demonstrated and the pharmacokinetics are not well documented.

The most common side effects are dizziness, paresthesia, abdominal pain, gait instability. The side effects in intravenously treated patients occurred more frequently and were more troublesome than in orally treated patients. The most serious side effects were seizures, confusion and hepatitis, but they occurred quite rarely. With a maximal daily oral dosage of 0.5 mg/kg body weight no serious side effects were registered.

4-AP is neither registered nor licensed in Sweden, but it can be prescribed ex tempore.

Svar: 4-aminopyridine (4-AP) is a potassium channel blocker. It blocks potassium channel activation, increases action potential duration and amplitude in demyelinated fibers and restores action potential propagation in vitro (1). 4-AP affects normal, mature, myelinated axons less than at sites of demyelination or nerve injury. Also 4-AP has different effects on motor and sensory fibers. Motor fibers show broadening of the action potential, while sensory become hyperexcitable and give rise to spike burst activity (2). The burst activity and increased spontaneous activity may account for the hyperexcitability phenomena such as paresthesis and dysesthesias in patients given 4-AP (2).

Early clinical trials suggested that AP might improve conduction in demyelinated axons in MS patients. Treatment related improvements were reported in initial small, open label trials of 4-AP on visual function in chronic MS patients (1). Blinded, controlled trials of intravenous (3) and oral (4, 5) 4-AP in temperature-sensitive MS patients also suggested benefit, but these studies were limited because they did not use a randomised treatment design, were not double blinded, and relied on outcome measures that were not widely accepted (eg static quantitative perimetry, critical flicker-fusion, visual acuity, visual evoked potentials, and videotaped neurological examinations).

Larger randomised, double-blind, placebo-controlled cross-over trials of 4-AP show improvements of residual deficits in MS patients. Seventy patients with definite MS were enrolled in one such study, they were treated with 4-AP and placebo for 12 weeks each. The efficacy of treatment was measured with the Kurtzke expanded disability status scale (EDSS). The mean EDSS on treatment improved by 0.28 compared with placebo and 10 patients improved by one or more points on the EDSS on 4-AP while none had comparable improvement on placebo. A significant subjective improvement (defined as an improvement that significantly affected the activities of normal daily life) was indicated by 18 patients during 4-AP treatment and by one patient during placebo treatment (6).

This study also showed that especially temperature-sensitive patients and patients with a longer duration of disease and in a progressive phase of the disease had beneficial effects of 4-AP.

The relationship between dosage, serum level, efficacy, and safety of intravenous and orally administered 4-AP in the same group of 70 MS patients was described (7). After both intravenous and oral administration there was a significant relationship between serum levels and 4-AP doses used.

Later the long-term efficacy and safety of 4-AP in patients with MS was studied. Thirty-one patients with definite MS were enrolled in this study (23 of them have been exposed to long-term administration in the study mentioned above, since they showed a favourable initial response to the drug) (8). In this study ambulation and fatigue (each in 13 patients) and visual function (in 5 patients) were most frequently reported to be improved. It should be mentioned that only a small minority of the favourable effects reported by the patients resulted in significant changes in the EDSS. In a number of patients the response to 4-AP gradually decreased. It could be explained by either a decrease in the efficacy of 4-AP or a further progression of disease.

4-AP causes a number of dose and serum concentration related side effects, the most serious of which is seizures. 4-AP causes dizziness in 50 per cent of patients, paresthesia in 25 per cent, abdominal pain in less than 10 per cent, gait instability in more than 10 per cent of patients (6). These side effects occurred at highly variable doses. The side effects in the intravenously treated patients occurred frequently and were very troublesome. Therefore, it could not be recommended administration of 4-AP intravenously (7). In the orally treated patients side effects were mild and always reached a maximum 30 to 45 minutes after intake of 4-AP and generally resolved within 2 to 5 hours (7). With a maximal daily oral dosage of 0.5 mg/kg body weight no serious side effects were registered. This drug rarely caused seizures at the doses used in MS trials (8, 9). Seizures have occurred on 4-AP doses of 50 mg/day, which resulted in peak serum 4-AP level of 104 ng/ml. One possible instance of AP-induced hepatitis has been reported (8).

This drug is neither registered nor licensed in Sweden. It could be prescribed ex tempore.