Quantitative assessment of sustained-release 4-aminopyridine for symptomatic treatment of multiple sclerosis. The effects of 4-aminopyridine in multiple sclerosis patients: results of a randomized, placebo-controlled, double-blind, concentration-controlled, crossover trial. The effect of 4-aminopyridine on clinical signs in multiple sclerosis: a randomized, placebo-controlled, double-blind, cross-over study. Fatigue in progressive multiple sclerosis: results of a randomized, double-blind, placebo-controlled, crossover trial of oral 4-aminopyridine. The effects of 4-aminopyridine on cognitive function in patients with multiple sclerosis: a pilot study. Treatment with oral 3,4 diaminopyridine improves leg strength in multiple sclerosis patients: results of a randomized, double-blind, placebo-controlled, crossover trial.
To evaluate the efficacy of 4-aminopyridine sustained release (4AP SR) (fampridine, EL-970) using quantitative measures of motor function in multiple sclerosis (MS) patients.
                In vitro, 4AP improves conduction through demyelinated axons. A previous multicenter trial of 4AP SR using the Expanded Disability Status Scale (EDSS) as the primary outcome was unable to establish clinical efficacy.
                Ten MS patients with stable motor deficits (EDSS 6.0-7.5) were given 4AP SR 17.5 mg bid and placebo for 1 week each in a double-blind, placebo-controlled, crossover trial. Time to walk 8 meters, time to climb four stairs, maximum voluntary isometric contraction measured quantitatively (MVICT), manual muscle testing (MMT), grip strength, EDSS, and the patient's global impression were measured.
                Timed gait was improved on 4AP SR compared with placebo in 9 of 10 subjects (p = 0.02). Timed stair climbing, MVICT, MMT, grip strength, and EDSS showed nonsignificant improvements on 4AP SR. Based on their global impressions, seven subjects preferred 4AP SR over placebo; only one preferred placebo. There were no serious side effects.
                4AP SR improved motor function in MS patients. The quantitative outcomes used in this study permit more sensitive evaluation of the therapeutic effect and promise to be useful in future trials of symptomatic treatments for MS. Because 4-aminopyridine (AP) improves residual deficits in some multiple sclerosis (MS) patients but has a narrow toxic-to-therapeutic margin, we compared the safety and efficacy of two target peak serum concentration ranges (low: 30 to 59 ng/ml and high: 60 to 100 ng/ml). We enrolled eight MS patients with temperature-sensitive visual and motor deficits in a randomized, placebo-controlled, double-blind, crossover trial of short-term oral AP treatment. We randomized patients to a sequence of three treatments on three separate days: placebo, low serum concentration, and high serum concentration. We determined dosing to achieve the desired steady-state peak serum concentration ranges from a test dose and population pharmacokinetic parameters using bayesian estimation. Contrast sensitivity, standard neurologic examination, ratings of videotaped neurologic examinations, and quantitative strength assessment all improved with treatment, but flicker fusion frequency, visual evoked response latencies, and Expanded Disability Status Scale scores did not. All patients experienced side effects during the high-serum-concentration arm. A grand mal seizure occurred at a serum AP level of 104 ng/ml, and an acute confusional episode occurred at 114 ng/ml. AP treatment produced improvements in residual deficits in MS patients, but the occurrence of significant toxicity suggests that AP serum levels should be monitored and peak levels above 100 ng/ml should be avoided. Concentration-control methodology may be useful in testing putative treatments for other neurologic diseases. To find out whether treatment with 4-aminopyridine is beneficial in multiple sclerosis (MS), 70 patients with definite MS entered into a randomized, double-blind, placebo-controlled, cross-over trial in which they were treated with 4-aminopyridine and placebo for 12 weeks each (maximum dose, 0.5 mg/kg of body weight). The estimated effect of the treatment as measured with the Kurtzke expanded disability status scale, which was the main evaluation parameter, was 0.28 point (p = 0.001). A significant decrease in the scale score (1.0 point or more) was encountered in 10 patients (16.4%) during oral treatment with 4-aminopyridine whereas it was not seen during placebo treatment (p less than 0.05). A significant subjective improvement (defined as an improvement that significantly affected the activities of normal daily life) was indicated by 18 patients (29.5%) during 4-aminopyridine treatment and by 1 patient (1.6%) during placebo treatment (p less than 0.05). Significant improvements related to 4-aminopyridine occurred in a number of neurophysiological parameters. No serious side effects were encountered. However, subjective side effects such as paresthesias, dizziness, and light-headedness were frequently reported during 4-aminopyridine treatment. Analysis of subgroups revealed that there was no difference in efficacy between those patients randomized to receive 4-aminopyridine and then placebo and those randomized to receive placebo and then 4-aminopyridine or between patients with and those without subjective side effects. Especially patients with temperature-sensitive symptoms and patients characterized by having a longer duration of the disease and being in a progressive phase of the disease were likely to show clear clinical benefit. Previous studies suggest that aminopyridine may play a role in the symptomatic treatment of fatigue in multiple sclerosis. Although the mechanism underlying the beneficial effect on fatigue remains unclear, it has been proposed that aminopyridines may help to improve conduction in demyelinated central pathways, implicating both axonal and synaptic mechanisms. The objective of the present study is to determine whether 4-AP decreases daily-living fatigue in progressive multiple sclerosis. The effect of 4-AP on other neurophysiological and neuropsychological parameters was also considered. A 'double-blind', randomized, 'placebo-controlled', crossover trial was conducted on 54 patients with progressive multiple sclerosis. All patients received treatment with placebo and 32 mg per day of 4-AP, each for 6 months. The main outcome measure was the Fatigue Severity Scale. Secondary measures were EDSS, cognitive functions and neurophysiological parameters. Forty-nine patients (91%) completed the study. Changes in fatigue scores, EDSS and cognitive functions were not significantly different between 4-AP and placebo. However, when patients treated with 4-AP were divided into two groups according to the serum level of 4-AP, a significant effect on fatigue compared with placebo was observed in the 'high level' (>30 ng/ml) group (P=0.05). Synchronization of motor evoked potentials improved during 4-AP with respect to placebo (P=0.019) and this correlated positively with fatigue reduction (P=0.010). No relevant side effects were observed. 4-Aminopyridine (4-AP) has a favorable effect on the disability of certain patients with MS. We investigated the effect of 4-AP on neuropsychological performance in 20 MS patients using a randomized, double-blind, placebo-controlled, crossover design. Although there was a trend for improved performance with 4-AP for two of the tests, we could not demonstrate significant effects of 4-AP on cognitive function. To examine the efficacy and toxicity of oral 3,4 diaminopyridine (DAP) in dosages up to 100 mg/day, 36 patients with multiple sclerosis (MS) enrolled in a randomized, double-blind, placebo-controlled, crossover trial. The primary outcome measure was improvement of a prospectively defined neurologic deficit, which was leg weakness in 34 patients. Secondary outcome measures included the patient's subjective response, scored manual motor testing (MMT) of leg strength, scored leg strength from videotaped motor testing (VMT), quadriceps and hamstrings strength (QMT) measured by isometric dynamometry, neuropsychological testing (NPT), ambulation index (AI), and Expanded Disability Status Scale (EDSS) score. Paresthesias and abdominal pain were common and were dose limiting in eight patients. Three patients had episodes of confusion, and one patient had a seizure while on DAP. Eight patients withdrew from the study, leaving 28 evaluable patients for the efficacy analysis. The prospectively defined neurologic deficit improved in 24 patients-22 on DAP and 2 on placebo (p = 0.0005). All improvements were in leg weakness. Subjective response and measures of leg strength and function (MMT, VMT, QMT, and AI) improved on DAP compared with placebo. Neither NPT nor EDSS scores improved. DAP treatment can induce improvements in leg strength in MS patients, but toxicity is limiting in many patients.
Currently available information allows no unbiased statement about safety or efficacy of aminopyridines for treating MS symptoms. Furthermore, we could not obtain any data on three unpublished RCTs (more than 300 participants). We conclude that publication bias remains a pervasive problem in this area, and that until the results of these unpublished studies are available to the scientific community, no confident estimate of effectiveness of aminopyridines in the management of MS symptoms is possible.